Risk factors associated with prevalent vertebral fractures in Duchenne muscular dystrophy.

Patients with Duchenne muscular dystrophy (DMD) have a high fracture burden due to progressive myopathy and steroid-induced osteoporosis. This study in males with DMD showed that markers of systemic glucocorticoid exposure including shorter stature, greater bone age delay, and lower lumbar spine bone mineral density were associated with spine fragility. INTRODUCTION: Fragility  fractures are frequent in DMD. The purpose of this study was to identify clinical factors associated with prevalent vertebral fractures (VF) in boys, teens/young adults with Duchenne muscular dystrophy (DMD). METHODS: This was a cross-sectional study of males aged 4-25 years with DMD. VF were evaluated using the modified Genant semi-quantitative method on T4-L4 lateral spine radiographs. Areal bone mineral density (aBMD) was measured at the lumbar spine (LS) and used to estimate volumetric BMD (vBMD). Clinical factors were analyzed for their association with the Spinal Deformity Index (SDI, the sum of the Genant grades). RESULTS: Sixty participants were enrolled (mean age 11.5 years, range 5.4-19.5). Nineteen participants (32%) had a total of 67 VF; 23/67 VF (34%) were moderate or severe. Participants with VF were shorter (mean height Z-score ± standard deviation: - 3.1 ± 1.4 vs. - 1.8 ± 1.4, p = 0.001), had longer glucocorticoid exposure (mean duration 6.0 ± 3.3 vs. 3.9 ± 3.3 years, p = 0.027), greater bone age (BA) delay (mean BA to chronological age difference - 3.2 ± 3.4 vs. - 1.3 ± 1.2 years, p = 0.035), and lower LSaBMD Z-scores (mean - 3.0 ± 1.0 vs. - 2.2 ± 1.2, p = 0.023). There was no difference in LSvBMD Z-scores. Multivariable Poisson regression showed that every 0.1 mg/kg/day increment in average glucocorticoid daily dose was associated with a 1.4-fold SDI increase (95% confidence interval: 1.1-1.7, p = 0.013). Greater BA delay (p < 0.001), higher weight Z-score (p = 0.004), decreased height Z-score (p = 0.025), and lower LSvBMD Z-score (p = 0.025) were also associated with SDI increase. CONCLUSION: Readily measurable clinical variables were associated with prevalent VF in males with glucocorticoid-treated DMD. These variables may be useful to identify candidates for primary osteoporosis prevention after glucocorticoid initiation.

The effect of carboxymethyl cellulose and ß-cyclodextrin as debittering agents on bitterness and physicochemical properties of bitter gourd extract.

Bitter gourd extract (BGE) is rich in antioxidants and anti-diabetic components that promote good human health; however, its bitter taste makes it challenging to use in food. In this study, the effect of carboxymethyl cellulose and ß-cyclodextrin (ß-CD) on the bitterness and properties of BGE were investigated. The bitterness intensity was evaluated by the trained sensory panel, and the physicochemical properties were also determined, including viscosity, total saponin, polyphenol content, antioxidant capacity, and α-amylase inhibition activity. It was found that the bitterness of BGE with 0.75%, w/v ß-cyclodextrin decreased significantly by more than 90%. Additionally, FTIR, 1 H-NMR, and thermogravimetric analysis of BGE supplemented with ß-CD confirmed the formation of a complex between ß-CD and components of BGE. The findings of the current study also reveal that debittering agents did not inhibit the bioactivities of BGE.

Bisphosphonates in Glucocorticoid-Treated Patients With Duchenne Muscular Dystrophy: A Systematic Review and Grading of the Evidence

BACKGROUND AND OBJECTIVES: Bisphosphonates are routinely used to treat osteoporosis in patients with Duchenne muscular dystrophy (DMD), a rare, severely debilitating neuromuscular disease. We sought to synthesize and grade benefits and harms evidence of bisphosphonates in glucocorticoid-treated patients with DMD. METHODS: In this systematic review (PROSPERO identifier: CRD42020157606), we searched MEDLINE, CINAHL, Embase, PsycINFO, Web of Science, and CENTRAL for articles published from inception up to and including March 31, 2023, reporting results in any language from any study type. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. RESULTS: We identified 19 publications involving 1,010 children and adults from 12 countries across all inhabited continents except South America. We found high-quality evidence that bisphosphonates significantly increase the areal lumbar spine bone mineral density (BMD) Z score in glucocorticoid-treated patients with DMD. The greatest improvements were recorded in controlled settings among patients treated with intravenous zoledronate. Evidence of benefits to fracture risks was inconclusive and/or of low quality, primarily due to lack of controlled data and small samples. Bisphosphonates were generally well-tolerated, although adverse events related to the first infusion (i.e., "acute phase reaction") were frequently reported. DISCUSSION: There is high-quality evidence supporting the use of bisphosphonates to increase the areal lumbar spine BMD Z score in patients with DMD and glucocorticoid-induced osteoporosis. Our synthesis and grading affirm current recommendations put forward in the 2018 DMD Clinical Care Considerations and should be helpful in raising awareness about anticipated benefits of bisphosphonates, prevailing unmet needs, and potential safety issues in their use.

Burosumab for the treatment of cutaneous-skeletal hypophosphatemia syndrome.

Cutaneous-skeletal hypophosphatemia syndrome (CSHS) is a rare bone disorder featuring fibroblast growth factor-23 (FGF23)-mediated hypophosphatemic rickets. We report a 2-year, 10-month-old girl with CSHS treated with burosumab, a novel human monoclonal antibody targeting FGF23. This approach was associated with rickets healing, improvement in growth and lower limb deformity, and clinically significant benefit to her functional mobility and motor development. This case report provides evidence for the effective use of FGF23-neutralizing antibody therapy beyond the classic FGF23-mediated disorders of X-linked hypophosphatemia and tumor-induced osteomalacia.

Risk Factors Associated with Incident Vertebral Fractures in Steroid-treated Males with Duchenne Muscular Dystrophy.

PURPOSE: Prevention of fractures is an unmet need in glucocorticoid (GC)-treated Duchenne muscular dystrophy. This study explored factors associated with incident vertebral fractures (VFs) to inform future fracture prevention efforts. METHODS: VFs were evaluated prospectively at study baseline and 12 months on lateral spine radiographs in participants aged 4 to 25 years with Duchenne muscular dystrophy. Clinical factors were analyzed for their association with the change in Spinal Deformity Index (sum of the Genant-defined VF grades from T4 to L4) between baseline and 12 months. RESULTS: Thirty-eight males were evaluated (mean ± SD age at baseline 11.0 ± 3.6 years; mean ± SD GC duration at baseline 4.1 ± 3.1 years; 74% ambulatory). Nine of 38 participants (24%) had 17 incident VFs, of which 3/17 VFs (18%) were moderate/severe. Participants with 12-month incident VF had lower mean ± SD baseline lumbar spine areal bone mineral density Z-scores (-2.9 ± 1.0 vs -1.9 ± 1.1; P = .049) and lower total body less head areal bone mineral density Z-scores (-3.1 ± 1.2 vs -1.6 ± 1.7; P = .036). Multivariable linear regression showed that at least 1 VF at baseline (P < .001), a higher number of antecedent non-VF (P < .001), and greater bone age delay at baseline (P = .027) were significant predictors of an increase in the Spinal Deformity Index from baseline to 12 months. CONCLUSION: The observation that ≥ 1 prevalent VF and/or non-VF were the strongest predictors of incident VFs at 12 months supports the need for prevention of first fractures in this high-risk setting. Bone age delay, a marker of GC exposure, may assist in the prioritization of patients in efforts to prevent first fractures.

Revisiting natural user interaction in virtual world.

Natural user interaction in virtual environment is a prominent factor in any mixed reality applications. In this paper, we revisit the assessment of natural user interaction via a case study of a virtual aquarium. Viewers with the wearable headsets are able to interact with virtual objects via head orientation, gaze, gesture, and visual markers. The virtual environment is operated on both Google Cardboard and HoloLens, the two popular wireless head-mounted displays. Evaluation results reveal the preferences of users over different natural user interaction methods.

Enhancement of the Solubility of BS Class II Drugs with MOF and MOF/GO Composite Materials: Case Studies of Felodipine, Ketoprofen and Ibuprofen.

In this research, a novel composite material composed of Metal-Organic Framework material (MOF) and graphite oxide was synthesized and evaluated as a possible drug-loading vehicle. HKUST-1, a MOF material originally designed by the Hong Kong University of Science and Technology, was used as a model porous material. The aim was to synthesize a drug delivery vehicle for modifying the release kinetics and solubility of poorly soluble drugs (BSC Class II drugs); these are drugs that are known to have poor bioavailability due to their low solubility. We used ketoprofen, ibuprofen, and felodipine as models for BSC Class II drugs. The drugs were loaded onto composite materials through adsorption. The adsorption of these three drugs into the matrix of HKUST-1/GO (graphite oxide), HKUST-1, and graphite oxide was compared. The loading efficiency of the drugs onto the carrier was dependent on the drug molecule and the composition of the drug carrier. The inclusion of graphite oxide in the drug carrier matrix improved the drug loading capacity and modified the drug release rate. The loading of the three drugs felodipine, ketoprofen, and ibuprofen onto HKUST-1 were 33.7, 58, and 79 mg/g respectively. The incorporation of GO into the HKUST-1 matrix resulted in an increase in the loading by 16 and 4 mg/g for the ketoprofen and ibuprofen drugs. When compared to the pure drugs, the solubility of all three drugs in the HKUST-1/GO matrix increased by at least 6 folds.

Bis(4-glycosyloxybenzyl) 2-isobutyltartrate and dihydrophenanthrene derivatives from the pseudobulbs of Pholidota chinensis and their anti-inflammatory activity.

Six previously undescribed components, bis(4-glycosyloxybenzyl) 2-isobutyltartrate derivatives (pholidotoside A-E) and phenolic glycoside (pholidotosin A), together with twenty known compounds were isolated from the pseudobulbs of Pholidota chinensis. Their structures and absolute configuration were elucidated and established through various spectroscopic and chemical methods. The anti-inflammatory potential of selected compounds was examined using a human neutrophil cell model activated by N-formyl-methionyl-leucyl-phenylalanine/cytochalasin B (fMLP/CB). Among these, dihydrophenanthrenes exhibited potent inhibitory effect on both superoxide anion generation and elastase release assays with IC50 values ranging from 0.41 ± 0.05 to 7.14 ± 0.30 µM.

Disease Recognition in X-ray Images with Doctor Consultation-Inspired Model.

The application of chest X-ray imaging for early disease screening is attracting interest from the computer vision and deep learning community. To date, various deep learning models have been applied in X-ray image analysis. However, models perform inconsistently depending on the dataset. In this paper, we consider each individual model as a medical doctor. We then propose a doctor consultation-inspired method that fuses multiple models. In particular, we consider both early and late fusion mechanisms for consultation. The early fusion mechanism combines the deep learned features from multiple models, whereas the late fusion method combines the confidence scores of all individual models. Experiments on two X-ray imaging datasets demonstrate the superiority of the proposed method relative to baseline. The experimental results also show that early consultation consistently outperforms the late consultation mechanism in both benchmark datasets. In particular, the early doctor consultation-inspired model outperforms all individual models by a large margin, i.e., 3.03 and 1.86 in terms of accuracy in the UIT COVID-19 and chest X-ray datasets, respectively.

Engineering Stable Pseudomonas putida S12 by CRISPR for 2,5-Furandicarboxylic Acid (FDCA) Production.

FDCA (2,5-furandicarboxylic acid) can be enzymatically converted from HMF (5-hydroxymethylfurfural). Pseudomonas putida S12 is promising for FDCA production, but generating stable P. putida S12 is difficult due to its polyploidy and lack of genome engineering tools. Here we showed that coupling CRISPR and λ-Red recombineering enabled one-step gene integration with high efficiency and frequency, and simultaneously replaced endogenous genes in all chromosomes. Using this approach, we generated two stable P. putida S12 strains expressing HMF/furfural oxidoreductase (HMFH) and HMF oxidase (HMFO), both being able to convert 50 mM HMF to ≈42-43 mM FDCA in 24 h. Cosupplementation of MnO2 and CaCO3 to the medium drastically improved the cell tolerance to HMF and enhanced FDCA production. Cointegrating HMFH and HMFT1 (HMF transporter) genes further improved FDCA production, enabling the cells to convert 250 mM HMF to 196 mM (30.6 g/L) FDCA in 24 h. This study implicates the potentials of CRISPR for generating stable P. putida S12 strains for FDCA production.

Breath biomarkers of active pulmonary tuberculosis.

BACKGROUND: Volatile organic compounds (VOCs) in breath may contain biomarkers of active pulmonary tuberculosis derived from the infectious organism (metabolites of Mycobacterium tuberculosis) and from the infected host (products of oxidative stress). METHODS: We analyzed breath VOCs in 226 symptomatic high-risk patients in USA, Philippines, and UK, using gas chromatography/mass spectroscopy. Diagnosis of disease was based on sputum culture, smear microscopy, chest radiography and clinical suspicion of tuberculosis (CSTB). Chromatograms were converted to a series of 8s overlapping time slices. Biomarkers of active pulmonary tuberculosis were identified with a Monte Carlo analysis of time-slice alveolar gradients (abundance in breath minus abundance in room air). RESULTS: Breath VOCs contained apparent biomarkers of active pulmonary tuberculosis comprising oxidative stress products (alkanes and alkane derivatives) and volatile metabolites of M. tuberculosis (cyclohexane and benzene derivatives). Breath biomarkers identified active pulmonary tuberculosis with C-statistic (area under curve of receiver operating characteristic)=0.85 (i.e. 85% overall accuracy, sensitivity=84.0%, specificity=64.7%) when sputum culture, microscopy, and chest radiography were either all positive or all negative. Employing a single criterion of disease, C-statistic=0.76 (smear microscopy), 0.68 (sputum culture), 0.66 (chest radiography) and 0.65 (CSTB). CONCLUSION: A breath test identified apparent biomarkers of active pulmonary tuberculosis with 85% accuracy in symptomatic high-risk subjects.

Intratumoral administration of paclitaxel in an in situ gelling poloxamer 407 formulation.

In order to examine the efficacy of paclitaxel (Taxol, Bristol-Myers Squibb) after administration locally at the tumor site, we have developed a thermo-reversible gelling formulation in poloxamer 407 (Pluronic F-127) solution. Paclitaxel was incorporated in poloxamer 407 [20% (w/w)] at 0.5- and 1.0-mg/mL concentrations. The in vitro release studies were carried out in phosphate-buffered saline (pH 7.4) at 37 degrees C. Control and paclitaxel-poloxamer 407 formulations were administered intratumorally at a dose of 20 mg/kg in B16F1 melanoma-bearing mice. The change in tumor volume as a function of time and the survival of treated animals were used as measures of efficacy. Poloxamer 407 solution undergoes a reversible sol-gel transition when the temperature is raised to above 21 degrees C. In vitro paclitaxel release from poloxamer 407 gels was very slow (only 6.1% after 6 hr) probably due to the poor aqueous solubility of the drug. Significant enhancement in the anti-tumor efficacy was noted following intratumoral administration of paclitaxel-poloxamer 407 formulation. The initial tumor growth rate was delayed by 67% and the tumor volume doubling time was increased by 72% relative to saline control. In addition, more than 91% of the tumor-bearing animals that received paclitaxel in poloxamer 407 gel survived on day 15 post-administration as compared to 58% in the control group. The results of this study show significant benefit of paclitaxel for solid tumor when administered locally in an in situ gelling poloxamer 407 formulation.