TORONTO: A trial-oriented multidimensional psychometric testing algorithm.

Bayesian adaptive methods for sensory threshold determination were conceived originally to track a single threshold. When applied to the testing of vision, they do not exploit the spatial patterns that underlie thresholds at different locations in the visual field. Exploiting these patterns has been recognized as key to further improving visual field test efficiency. We present a new approach (TORONTO) that outperforms other existing methods in terms of speed and accuracy. TORONTO generalizes the QUEST/ZEST algorithm to estimate simultaneously multiple thresholds. After each trial, without waiting for a fully determined threshold, the trial-oriented approach updates not only the location currently tested but also all other locations based on patterns in a reference data set. Since the availability of reference data can be limited, techniques are developed to overcome this limitation. TORONTO was evaluated using computer-simulated visual field tests: In the reliable condition (false positive [FP] = false negative [FN] = 3%), the median termination and root mean square error (RMSE) of TORONTO was 153 trials and 2.0 dB, twice as fast with equal accuracy as ZEST. In the FP = FN = 15% condition, TORONTO terminated in 151 trials and was 2.2 times faster than ZEST with better RMSE (2.6 vs. 3.7 dB). In the FP = FN = 30% condition, TORONTO achieved 4.2 dB RMSE in 148 trials, while all other techniques had > 6.5 dB RMSE and terminated much slower. In conclusion, TORONTO is a fast and accurate algorithm for determining multiple thresholds under a wide range of reliability and subject conditions.

Engineering Bioactive M2 Macrophage-Polarized, Anti-inflammatory, miRNA-Based Liposomes for Functional Muscle Repair: From Exosomal Mechanisms to Biomaterials.

Severe inflammation and myogenic differentiation disorder are the major obstacles to skeletal muscle healing after injury. MicroRNAs (miRNAs) play an important role as regulatory molecules during the process of muscle healing, but the detailed mechanism of miRNA-mediated intercellular communication between myoblasts and macrophages remains unclear. Here, it is reported that myoblasts secrete miRNAs-enriched exosomes in the inflammatory environment, through which miR-224 is transferred into macrophages to inhibit M2 polarization. Further data demonstrate that WNT-9a may be a direct target of miR-224 for macrophage polarization. In turn, the secretome of M1 macrophages impairs myogenic differentiation and promotes proliferation. Single-cell integration analysis suggests that the elevation of exosome-derived miR-224 is caused by the activation of the key factor E2F1 in myoblasts and demonstrates the RB/E2F1/miR-224/WNT-9a axis. In vivo results show that treatment with antagomir-224 or liposomes containing miR-224 inhibitors suppresses fibrosis and improves muscle recovery. These findings indicate the importance of the crosstalk between myoblasts and macrophages via miRNA-containing exosomes in the regulation of macrophage polarization and myogenic differentiation/proliferation during muscle healing. This study provides a strategy for treating muscle injury through designing an M2 polarization-enabling anti-inflammatory and miRNA-based bioactive material.

Topical cannabis-based medicines - A novel adjuvant treatment for venous leg ulcers: An open-label trial.

Venous leg ulcers are highly prevalent lower limb integumentary wounds that remain challenging to heal despite the use of evidence-based compression therapies. A multitude of adjuvant treatments has been studied but none have demonstrated enough efficacy to gain adoption into treatment guidelines. Global attention on Cannabis-Based Therapies is increasing and has been driven by quantum scientific advancements in the understanding of the endocannabinoid signalling system. Topical Cannabis-Based Medicines represent a novel treatment paradigm for venous leg ulcers in terms of promoting wound closure. Fourteen complex patients with sixteen recalcitrant leg ulcers were treated with Topical Cannabis-Based Medicines in conjunction with compression bandaging, every second day, to both wound bed and peri-wound tissues. The cohort had a mean age of 75.8 years and was medically complex as reflected by a mean M3 multimorbidity index score of 2.94 and a mean Palliative Performance Scale score of 67.1%. Complete wound closure, defined as being fully epithelialized, was achieved among 11 patients (79%) and 13 wounds (81%) within a median of 34 days. All three remaining patients demonstrated progressive healing trends but were lost to follow-up. The treatments were well tolerated, and no significant adverse reactions were experienced. The rapid wound closure of previously non-healing venous leg ulcers among elderly and highly complex patients suggests that Topical Cannabis-Based Medicines may become effective adjuvants in conjunction with compression therapy. This may also indicate that they may have an even broader role within integumentary and wound management. Therefore, this treatment paradigm warrants being subjected to controlled trials.

Topical cannabis-based medicines - A novel paradigm and treatment for non-uremic calciphylaxis leg ulcers: An open label trial.

Non-Uremic Calciphylaxis (NUC) is a rare condition that often manifests as intractable and painful integumentary wounds, afflicting patients with a high burden of co-morbidity. The Endocannabinoid System (ECS) is a ubiquitous signalling system that is theorised to be dysregulated within wound beds and associated peri-wound tissues. Preclinical research has shown that the dominant chemical classes derived from the cannabis plant, cannabinoids, terpenes, and flavonoids, interact with the integumentary ECS to promote wound closure and analgesia. This is a prospective open label cohort study involving two elderly Caucasian females with recalcitrant NUC leg ulcers of greater than 6 months duration. Topical Cannabis-Based Medicines (TCBM) composed of cannabinoids, terpenes, and flavonoids were applied daily to both the wound bed and peri-wound tissues until complete wound closure was achieved. Wounds were photographed regularly, and the digital images were subjected to planimetric analysis to objectively quantify the degree of granulation and epithelization. Analgesic utilisation, as a surrogate/proxy for pain scores, was also tracked. The cohort had a mean M3 multimorbidity index score of 3.31. Complete wound closure was achieved in a mean of 76.3 days. Additionally, no analgesics were required after a mean of 63 days. The treatments were well tolerated with no adverse reactions. The positive results demonstrated in very challenging wounds such as NUC, among highly complex patients, suggest that TCBM may have an even broader role within integumentary and wound management. This treatment paradigm warrants being trialled in other wound types and classes, and ultimately should be subjected to randomised controlled trials.

Towards algorithm-enabled home wound monitoring with smartphone photography: A hue-saturation-value colour space thresholding technique for wound content tracking.

Automated tracking of wound-healing progress using images from smartphones can be useful and convenient for the patient to perform at home. To evaluate the feasibility, 119 images were taken with an iPhone smartphone during the treatment of a chronic wound at one patient's home. An image analysis algorithm was developed to quantitatively classify wound content as an index of wound healing. The core of the algorithm involves transforming the colour image into hue-saturation-value colour space, after which a threshold can be reliably applied to produce segmentation using the Black-Yellow-Red wound model. Morphological transforms are used to refine the classification. This method was found to be accurate and robust with respect to lighting conditions for smartphone-captured photos. The wound composition percentage showed a different trend from the wound area measurements, suggesting its role as a complementary metric. Overall, smartphone photography and automated image analysis is a promising cost-effective way of monitoring patients. While the current setup limits our capability of measuring wound area, future smartphones equipped with depth-sensing technology will enable accurate volumetric evaluation in addition to composition analysis.

Influence of gender and age on the Dysphonia Severity Index: A normative study in a Shanghainese population.

Dysphonia Severity Index (DSI) is an objective multi-parametric measurement of voice quality, which has been widely used in different countries. Studies indicate that DSI may be influenced by vocal pathology, age and geographical factors, whereas gender does not significantly affect DSI. The purpose of this study was to investigate the effects of gender and age on the DSI and related parameters in a Shanghainese population. The present study measured the DSI and the parameters maximum phonation time (MPT), highest fundamental frequency (HF0), lowest intensity (LI) and Jitter in 187 Shanghainese subjects, including 106 young adults aged 18-23 years (52 males and 54 females) and 81 children aged 7-9 years (44 boys and 37 girls). Two-way analysis of variance indicated that HF0 was significantly higher in female subjects than in male subjects, in both young adults and children. Gender was not significantly associated with MPT, LI, jitter or DSI. With regard to age, MPT and DSI were significantly higher in young adults than in children, and HF0 and LI were significantly lower. No significant associations between age and jitter were detected. In terms of clinic significance, the results of this study may contribute to the establishment of a normal reference range for Shanghainese DSI values, and the influence of gender and age on DSI and its separate components.

Is There a Role for Craniofacial Surgery in the Treatment of Extensive or Recurrent Head and Neck Tumors Involving the Cranial Base?

PURPOSE: Extensive or recurrent head and neck tumors involving the cranial base are extremely difficult to treat from a surgical perspective. The purposes of this study were to estimate and identify factors associated with overall survival after traditional craniofacial resection in these cases and to discuss the specific indications and treatment outcomes. MATERIALS AND METHODS: From January 2005 to December 2014, a retrospective cohort study was performed with the analysis of patients diagnosed with extensive or recurrent head and neck tumors extending to the skull base. The clinical records were reviewed for predictor variables regarding demographic characteristics, prior treatment status, pathologic characteristics, tumor sites and sizes, skull base bone or brain parenchyma invasion, reconstructive approaches, surgical margins, and adjuvant therapies. The outcome variable was overall survival. Overall survival was estimated by Kaplan-Meier methods, and risk factors were identified by use of Cox modeling. RESULTS: The cohort was composed of 119 patients with a mean age of 44.53 years; there were 67 male patients (56.30%). Through-and-through resection of the skull base bones (dural exposure) was performed in 100 patients (84.03%). The overall complication rate for the entire group was 42.86%, and the perioperative mortality rate was 2.52% (n = 3). The mean follow-up period reached 43.88 months. Of the patients without perioperative death (n = 116), 39 had local recurrences. After multivariate analysis, surgical margins (P = .001), pathologic classification (P = .016), and extent of skull base involvement (P = .001) were found to be independent factors affecting overall survival. CONCLUSIONS: Craniofacial surgery for extensive or recurrent skull base lesions is feasible in well-selected patients.

A Feed-Forward Regulatory Loop between HuR and the Long Noncoding RNA HOTAIR Promotes Head and Neck Squamous Cell Carcinoma Progression and Metastasis.

BACKGROUND/AIMS: The lncRNA Homeobox (HOX) transcript antisense RNA (HOTAIR) is overexpressed in numerous cancers. HuR is also overexpressed during tumourigenesis and is abnormally present within the cytoplasm, where it binds to AU-rich elements in the 3'UTRs of target mRNA and post-transcriptionally regulates the expression of its target genes. However, whether HOTAIR is regulated and the mechanisms by which it affects head and neck squamous cell carcinoma (HNSCC) are not well understood. METHODS: MTT, cell cycle arrest and apoptotic assays were used to examine the effects of HOTAIR and HuR on cell viability in SCC25 and FaDu cells. Wound healing and transwell invasion analysis were performed to detect the effects of HOTAIR and HuR on cell migration and invasion. The interaction between HuR and HOTAIR was confirmed via qRT-PCR, western blots, luciferase reporter and RIP assays. Finally, qRT-PCR analysis was used to detect the levels of HuR and HOTAIR in HNSCC tumours and adjacent normal tissues. RESULTS: Knockdown of HOTAIR and HuR decreased cell viability, cellular migration and invasion. Moreover, HuR interacted and stabilized HOTAIR stability and thus promoted HOTAIR expression. Notably, HOTAIR acted as a miRNA sponge for HuR. HuR also reinforced HOTAIR sponge activity through miRNA recruitment, thus enhancing HuR expression in turn. Finally, HuR and HOTAIR levels were positively correlated and significantly up-regulated in tumours samples. CONCLUSION: We demonstrated the existence of a regulatory loop in which the expression of HOTAIR and HuR is reciprocally and temporally regulated during the metastasis and progression of HNSCC.

Improving the robustness of the Sequentially Optimized Reconstruction Strategy (SORS) for visual field testing.

Perimetry, or visual field test, estimates differential light sensitivity thresholds across many locations in the visual field (e.g., 54 locations in the 24-2 grid). Recent developments have shown that an entire visual field may be relatively accurately reconstructed from measurements of a subset of these locations using a linear regression model. Here, we show that incorporating a dimensionality reduction layer can improve the robustness of this reconstruction. Specifically, we propose to use principal component analysis to transform the training dataset to a lower dimensional representation and then use this representation to reconstruct the visual field. We named our new reconstruction method the transformed-target principal component regression (TTPCR). When trained on a large dataset, our new method yielded results comparable with the original linear regression method, demonstrating that there is no underfitting associated with parameter reduction. However, when trained on a small dataset, our new method used on average 22% fewer trials to reach the same error. Our results suggest that dimensionality reduction techniques can improve the robustness of visual field testing reconstruction algorithms.

ERCC4: a potential regulatory factor in inflammatory bowel disease and inflammation-associated colorectal cancer.

The pathogenesis of inflammatory bowel disease (IBD) remains unclear and is associated with an increased risk of developing colitis-associated cancer (CAC). Under sustained inflammatory stimulation in the intestines, loss of early DNA damage response genes can lead to tumor formation. Many proteins are involved in the pathways of DNA damage response and play critical roles in protecting genes from various potential damages that DNA may undergo. ERCC4 is a structure-specific endonuclease that participates in the nucleotide excision repair (NER) pathway. The catalytic site of ERCC4 determines the activity of NER and is an indispensable gene in the NER pathway. ERCC4 may be involved in the imbalanced process of DNA damage and repair in IBD-related inflammation and CAC. This article primarily reviews the function of ERCC4 in the DNA repair pathway and discusses its potential role in the processes of IBD-related inflammation and carcinogenesis. Finally, we explore how this knowledge may open novel avenues for the treatment of IBD and IBD-related cancer.

Metabolomics reveals the potential metabolic mechanism of infliximab against DSS-induced acute and chronic ulcerative colitis.

Inflammatory bowel disease (IBD) is often accompanied by metabolic imbalance, and infliximab (IFX) can alleviate IBD symptoms, but its metabolic mechanisms remain unclear. To investigate the relationship between IBD, metabolism, and IFX, an acute and chronic ulcerative colitis (UC) model induced by dextran sulfate sodium (DSS) was established. Plasma samples were analyzed using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, followed by multivariate statistical analysis. The results showed that IFX could alleviate colonic shortening and reduce colonic pathological damage in acute and chronic mouse colitis, improve acute and chronic UC, and ameliorate metabolic disturbances. Among the 104 elevated metabolites and 170 decreased metabolites, these metabolites mainly belonged to amino acids, glucose, and purines. The changes in these metabolites were mainly associated with drug metabolism-other enzymes, riboflavin metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, phosphonate and phosphinate metabolism, and phenylalanine metabolism. In summary, this study provides a valuable approach to explore the metabolic mechanisms of IFX in treating acute and chronic UC from a metabolomics perspective.

Investigating the effects of a temperature dependent photodynamic dose: A numerical study.

SIGNIFICANCE: Photodynamic therapy (PDT) and photothermal therapy (PTT) show promise as cancer treatments, but challenges in generating large ablative volumes for deep-seated tumours persist. Using simulations, this study investigates combined PDT and PTT to increase treatment volumes, including the impact of a temperature-dependent PDT dose on the treatment volume radius. APPROACH: A finite-element model, using the open-source SfePy package, was developed to simulate combined interstitial photothermal and photodynamic treatments. Results compared an additive dose model to a temperature-dependent dose model with enhanced PDT dosimetry and examined typical clinical scenarios for possible synergistic effects. RESULTS: Findings revealed that the temperature-dependent dose model could significantly expand the damage radius compared to the additive model, depending on the tissue and drug properties. CONCLUSIONS: Characterizing synergistic effects of PDT and PTT could enhance treatment planning. Future work is ongoing to implement additional variables, such as photosensitizer photobleaching, and spatial and temporally varying oxygenation.

Using Fused Data from Perimetry and Optical Coherence Tomography to Improve the Detection of Visual Field Progression in Glaucoma.

Perimetry and optical coherence tomography (OCT) are both used to monitor glaucoma progression. However, combining these modalities can be a challenge due to differences in data types. To overcome this, we have developed an autoencoder data fusion (AEDF) model to learn compact encoding (AE-fused data) from both perimetry and OCT. The AEDF model, optimized specifically for visual field (VF) progression detection, incorporates an encoding loss to ensure the interpretation of the AE-fused data is similar to VF data while capturing key features from OCT measurements. For model training and evaluation, our study included 2504 longitudinal VF and OCT tests from 140 glaucoma patients. VF progression was determined from linear regression slopes of longitudinal mean deviations. Progression detection with AE-fused data was compared to VF-only data (standard clinical method) as well as data from a Bayesian linear regression (BLR) model. In the initial 2-year follow-up period, AE-fused data achieved a detection F1 score of 0.60 (95% CI: 0.57 to 0.62), significantly outperforming (p < 0.001) the clinical method (0.45, 95% CI: 0.43 to 0.47) and the BLR model (0.48, 95% CI: 0.45 to 0.51). The capacity of the AEDF model to generate clinically interpretable fused data that improves VF progression detection makes it a promising data integration tool in glaucoma management.

Expression of CXCR4 is associated with progression and invasion in patients with nasal-surface basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is the most common type of skin cancer with an increasing incidence worldwide that imposes a considerable burden on public health. C-X-C chemokine receptor (CXCR4) plays a vital role in initiation, progression and metastasis of several types of cancers. The aim of the present study was to investigate the expression and clinical significance of CXCR4 in BCC. METHODS: In this study, 80 samples of primary BCC were assessed for CXCR4 expression using immunohistochemistry. The mRNA and protein expression levels of CXCR4 were evaluated by real-time reverse transcription polymerase chain reaction and Western blot analysis, respectively. RESULTS: CXCR4-positive staining was detected in 70% of BCC samples. Overexpression of CXCR4 was significantly associated with tumor size (>2 vs. 2 cm, p = 0.002) and pathological type (invasive vs. noninvasive, p = 0.007). CXCR4 was also upregulated at transcriptional and translational levels. CONCLUSION: Our study revealed that the expression of CXCR4 was associated with progression and invasion in patients with BCC. It may be a considerable biomarker to assess invasiveness of nasal-surface BCC and to guide clinical management of such tumors.

Relative efficacy of intracameral moxifloxacin injection methods.

PURPOSE: To determine the amount of moxifloxacin remaining in the anterior chamber (AC), immediately after its injection using 3 current injection methods, assuming mixing and fluid exchange with the AC contents during injection of the drug, and to determine the most desirable injection method. SETTING: Department of Ophthalmology and Vision Sciences and Institute of Biomedical Engineering, University of Toronto, Toronto, Canada. DESIGN: Mathematical modeling. METHODS: Mathematical modeling using first-order mixing methods were used to assess mixing. RESULTS: The Kaiser method of injecting 0.5 mL × 100 µg/0.1 mL does not achieve the desired 500 µg level of moxifloxacin in the AC. The "straight from the bottle" method of injecting 0.1 mL × 500 µg/0.1 mL is fraught with potential error, yielding a relatively unreliable final amount in the AC. Injecting 0.5 to 0.6 mL × 150 µg/0.1 mL yields a result closest to the desired goal. CONCLUSIONS: Based on the calculation, the most accurate of current methods to deliver 500 µg moxifloxacin intracamerally is the method of 150 µg/0.1 mL × 0.5 to 0.6 mL.

A Data-Driven Model for Simulating Longitudinal Visual Field Tests in Glaucoma.

Purpose: To develop a simulation model for glaucomatous longitudinal visual field (VF) tests with controlled progression rates. Methods: Longitudinal VF tests of 1008 eyes from 755 patients with glaucoma were used to learn the statistical characteristics of VF progression. The learned statistics and known anatomic correlations between VF test points were used to automatically generate progression patterns for baseline fields of patients with glaucoma. VF sequences were constructed by adding spatially correlated noise templates to the generated progression patterns. The two one-sided test (TOST) procedure was used to analyze the equivalence between simulated data and data from patients with glaucoma. VF progression detection rates in the simulated VF data were compared to those in patients with glaucoma using mean deviation (MD), cluster, and pointwise trend analysis. Results: VF indices (MD, pattern standard deviation), MD linear regression slopes, and progression detection rates for the simulated and patients' data were practically equivalent (TOST P < 0.01). In patients with glaucoma, the detection rates in 7 years using MD, cluster, and pointwise trend analysis were 24.4%, 26.2%, and 38.4%, respectively. In the simulated data, the mean detection rates (95% confidence interval) for MD, cluster, and pointwise trend analysis were 24.7% (24.1%-25.2%), 24.9% (24.2%-25.5%), and 35.7% (34.9%-36.5%), respectively. Conclusions: A novel simulation model generates glaucomatous VF sequences that are practically equivalent to longitudinal VFs from patients with glaucoma. Translational Relevance: Simulated VF sequences with controlled progression rates can support the evaluation and optimization of methods to detect VF progression and can provide guidance for the interpretation of longitudinal VFs.

Effects of Endoscopic Sinus Surgery Combined with Budesonide Treatment on Nasal Cavity Function and Serum Inflammatory Factors in Patients with Chronic Sinusitis.

In this article, we have explored the effects of endoscopic sinus surgery together with budesonide treatment on nasal function and serum inflammatory factors on patients with chronic sinusitis. We retrospectively analyzed 120 patients with chronic sinusitis who were admitted to our hospital from March 2018 to March 2021 and were eligible for this study. They were separated into 2 groups according to different treatments, that is, the control group (treated with endoscopic surgery alone) of 58 cases and observation group (treated with endoscopic sinus surgery combined with budesonide) with 62 cases. Treatment efficacy, surgical status, overall symptom score before and after treatment, nasal mucociliary clearance function, serum eosinophils (EOS), serum immunoglobulin E (IgE), serum inflammatory factors, and occurrence of adverse reactions of both groups were recorded and compared. Total effective rate in the observation group presented strikingly more positive compared with that among patients in control group (P<0.05), as well as the data recorded in terms of operation time, blood loss during surgery and postoperative improvement time of patients (P<0.05). Overall symptom score, nasal mucociliary clearance, EOS, IgE and serum inflammatory factors in both groups were improved notably after treatment, while the observation group held a more obvious improvement. And it also had a markedly lower incidence of adverse reaction (P<0.05). Endoscopic sinus surgery combined with budesonide in the treatment of chronic sinusitis could effectively improve the clinical symptoms of patients, reestablish the function of the nasal cavity and improve their inflammation level. Meanwhile, it was of high safety and is worthy of clinical promotion.

Three-Dimensional Cartilage Regeneration Using Engineered Cartilage Gel With a 3D-Printed Polycaprolactone Framework.

The feasibility of the three-dimensional (3D) cartilage regeneration technology based on the "steel (framework)-reinforced concrete (engineered cartilage gel, ECG)" concept has been verified in large animals using a decalcified bone matrix (DBM) as the framework. However, the instability of the source, large sample variation, and lack of control over the 3D shape of DBM have greatly hindered clinical translation of this technology. To optimize cartilage regeneration using the ECG-framework model, the current study explores the feasibility of replacing the DBM framework with a 3D-printed polycaprolactone (PCL) framework. The PCL framework showed good biocompatibility with ECG and achieved a high ECG loading efficiency, similar to that of the DBM framework. Furthermore, PCL-ECG constructs caused a milder inflammatory response in vivo than that induced by DBM-ECG constructs, which was further supported by an in vitro macrophage activation experiment. Notably, the PCL-ECG constructs successfully regenerated mature cartilage and essentially maintained their original shape throughout 8 weeks of subcutaneous implantation. Quantitative analysis revealed that the GAG and total collagen contents of the regenerated cartilage in the PCL-ECG group were significantly higher than those in the DBM-ECG group. The results indicated that the 3D-printed PCL framework-a clinically approved biomaterial with multiple advantages including customizable shape design, mechanical strength control, and standardized production-can serve as an excellent framework for supporting the 3D cartilage regeneration of ECG. This provides a feasible novel strategy for the clinical translation of ECG-based 3D cartilage regeneration.