Inertial measurement unit sensor-based gait analysis in adults and older adults: A cross-sectional study.

BACKGROUND: Gait assessment has been used in a wide range of clinical applications, and gait velocity is also a leading predictor of disease and physical functional aspects in older adults. RESEARCH QUESTION: The study aim to examine the changes in IMU-based gait parameters according to age in healthy adults aged 50 and older, to analyze differences between aging patients. METHODS: A total of 296 healthy adults (65.32 ± 6.74 yrs; 83.10 % female) were recruited. Gait assessment was performed using an IMU sensor-based gait analysis system, and 3D motion information of hip and knee joints was obtained using magnetic sensors. The basic characteristics of the study sample were stratified by age category, and the baseline characteristics between the groups were compared using analysis of variance (ANOVA). Pearson's correlation analysis was used to analyze the relationship between age as the dependent variable and several measures of gait parameters and joint angles as independent variables. RESULTS: The results of this study found that there were significant differences in gait velocity and both terminal double support in the three groups according to age, and statistically significant differences in the three groups in hip joint angle and knee joints angle. In addition, it was found that the gait velocity and knee/hip joint angle changed with age, and the gait velocity and knee/hip joint angle were also different in the elderly and adult groups. CONCLUSIONS: We found changes in gait parameters and joint angles according to age in healthy adults and older adults and confirmed the difference in gait velocity and joint angles between adults and older adults.

Targeted and high-throughput gene knockdown in diverse bacteria using synthetic sRNAs.

Synthetic sRNAs allow knockdown of target genes at translational level, but have been restricted to a limited number of bacteria. Here, we report the development of a broad-host-range synthetic sRNA (BHR-sRNA) platform employing the RoxS scaffold and the Hfq chaperone from Bacillus subtilis. BHR-sRNA is tested in 16 bacterial species including commensal, probiotic, pathogenic, and industrial bacteria, with >50% of target gene knockdown achieved in 12 bacterial species. For medical applications, virulence factors in Staphylococcus epidermidis and Klebsiella pneumoniae are knocked down to mitigate their virulence-associated phenotypes. For metabolic engineering applications, high performance Corynebacterium glutamicum strains capable of producing valerolactam (bulk chemical) and methyl anthranilate (fine chemical) are developed by combinatorial knockdown of target genes. A genome-scale sRNA library covering 2959 C. glutamicum genes is constructed for high-throughput colorimetric screening of indigoidine (natural colorant) overproducers. The BHR-sRNA platform will expedite engineering of diverse bacteria of both industrial and medical interest.

Factors affecting the competitiveness of bacterial fermentation.

Sustainable production of chemicals and materials from renewable non-food biomass using biorefineries has become increasingly important in an effort toward the vision of 'net zero carbon' that has recently been pledged by countries around the world. Systems metabolic engineering has allowed the efficient development of microbial strains overproducing an increasing number of chemicals and materials, some of which have been translated to industrial-scale production. Fermentation is one of the key processes determining the overall economics of bioprocesses, but has recently been attracting less research attention. In this Review, we revisit and discuss factors affecting the competitiveness of bacterial fermentation in connection to strain development by systems metabolic engineering. Future perspectives for developing efficient fermentation processes are also discussed.

Pseudomembranous Aspergillus Tracheobronchitis: Case Report of a Rare Manifestation of Airway Invasive Aspergillosis.

Aspergillus tracheobronchitis, an uncommon form of invasive pulmonary aspergillosis, is characterized by the development of a pseudomembrane, ulcers, or an obstruction that is predominantly confined to the tracheobronchial tree. Pseudomembranous Aspergillus tracheobronchitis is the most severe form of Aspergillus tracheobronchitis, and only a few cases have been reported in Korea. We report the characteristic chest CT findings in a patient diagnosed with pseudomembranous Aspergillus tracheobronchitis after bronchoscopy and successfully treated by proper antifungal treatment.

Designing Microbial Cell Factories for the Production of Chemicals.

The sustainable production of chemicals from renewable, nonedible biomass has emerged as an essential alternative to address pressing environmental issues arising from our heavy dependence on fossil resources. Microbial cell factories are engineered microorganisms harboring biosynthetic pathways streamlined to produce chemicals of interests from renewable carbon sources. The biosynthetic pathways for the production of chemicals can be defined into three categories with reference to the microbial host selected for engineering: native-existing pathways, nonnative-existing pathways, and nonnative-created pathways. Recent trends in leveraging native-existing pathways, discovering nonnative-existing pathways, and designing de novo pathways (as nonnative-created pathways) are discussed in this Perspective. We highlight key approaches and successful case studies that exemplify these concepts. Once these pathways are designed and constructed in the microbial cell factory, systems metabolic engineering strategies can be used to improve the performance of the strain to meet industrial production standards. In the second part of the Perspective, current trends in design tools and strategies for systems metabolic engineering are discussed with an eye toward the future. Finally, we survey current and future challenges that need to be addressed to advance microbial cell factories for the sustainable production of chemicals.

Analysis of Gait Characteristics Using Hip-Knee Cyclograms in Patients with Hemiplegic Stroke.

Gait disturbance is a common sequela of stroke. Conventional gait analysis has limitations in simultaneously assessing multiple joints. Therefore, we investigated the gait characteristics in stroke patients using hip-knee cyclograms, which have the advantage of simultaneously visualizing the gait kinematics of multiple joints. Stroke patients (n = 47) were categorized into two groups according to stroke severity, and healthy controls (n = 32) were recruited. An inertial measurement unit sensor-based gait analysis system, which requires placing seven sensors on the dorsum of both feet, the shafts of both tibias, the middle of both femurs, and the lower abdomen, was used for the gait analysis. Then, the hip-knee cyclogram parameters (range of motion, perimeter, and area) were obtained from the collected data. The coefficient of variance of the cyclogram parameters was obtained to evaluate gait variability. The cyclogram parameters differed between the stroke patients and healthy controls, and differences according to stroke severity were also observed. The gait variability parameters mainly differed in patients with more severe stroke, and specific visualized gait patterns of stroke patients were obtained through cyclograms. In conclusion, the hip-knee cyclograms, which show inter-joint coordination and visualized gait cycle in stroke patients, are clinically significant.

Effects of knee osteoarthritis severity on inter-joint coordination and gait variability as measured by hip-knee cyclograms.

Inter-joint coordination and gait variability in knee osteoarthritis (KOA) has not been well investigated. Hip-knee cyclograms can visualize the relationship between the hip and knee joint simultaneously. The aim of this study was to elucidate differences in inter-joint coordination and gait variability with respect to KOA severity using hip-knee cyclograms. Fifty participants with KOA (early KOA, n = 20; advanced KOA, n = 30) and 26 participants (≥ 50 years) without KOA were recruited. We analyzed inter-joint coordination by hip-knee cyclogram parameters including range of motion (RoM), center of mass (CoM), perimeter, and area. Gait variability was assessed by the coefficient of variance (CV) of hip-knee cyclogram parameters. Knee RoM was significantly reduced and total perimeter tended to be decreased with KOA progression. KOA patients (both early and advanced) had reduced stance phase perimeter, swing phase area, and total area than controls. Reduced knee CoM and swing phase perimeter were observed only in advanced KOA. Both KOA groups had a greater CV for CoM, knee RoM, perimeter (stance phase, swing phase and total) and swing phase area than the controls. Increased CV of hip RoM was only observed in advanced KOA. These results demonstrate that hip-knee cyclograms can provide insights into KOA patient gait.

Microbial production of 4-amino-1-butanol, a four-carbon amino alcohol.

4-Amino-1-butanol (4AB) serves as an important intermediate compound for drugs and a precursor of biodegradable polymers used for gene delivery. Here, we report for the first time the fermentative production of 4AB from glucose by metabolically engineered Corynebacterium glutamicum harboring a newly designed pathway comprising a putrescine (PUT) aminotransferase (encoded by ygjG) and an aldehyde dehydrogenase (encoded by yqhD) from Escherichia coli, which convert PUT to 4AB. Application of several metabolic engineering strategies such as fine-tuning the expression levels of ygjG and yqhD, eliminating competing pathways, and optimizing culture condition further improved 4AB production. Fed-batch culture of the final metabolically engineered C. glutamicum strain produced 24.7 g/L of 4AB. The strategies reported here should be useful for the microbial production of primary amino alcohols from renewable resources.

Midterm outcomes in patients with upper extremity deep vein thrombosis.

BACKGROUND: Outcomes and the necessity for anticoagulation in patients with upper extremity deep vein thrombosis (UE DVT) are unclear. The purpose of this study was to determine the incidence of UE DVT, the outcomes of patients stratified by anticoagulation treatment, and which factors were significantly associated with mortality. METHODS: This study was a single-center, retrospective review of all patients undergoing UE venous duplex imaging in 2016. Information on patients' demographics, relevant comorbidities, use of anticoagulation at the time of diagnosis, characteristics of the UE DVT, treatment regimen(s), and outcomes was collected. Data were analyzed using descriptive and univariate statistics; multivariate logistic regression and Cox proportional hazard models were used to identify which of the aforementioned covariates are significantly associated with mortality rates at 30 days and 6 months, respectively, at a 95% confidence level. RESULTS: Of the 911 patients undergoing UE venous duplex imaging, 182 (20.0%) were positive for UE DVT. Within the first 30 days, 30 patients (16.5%) died, 13 (7.1%) had pulmonary emboli, 42 (23.1%) had either pulmonary emboli or died, and 3 (1.6%) had ischemic strokes. Within the first 6 months, 50 patients (27.5%) died. The mortality rate at 30 days was found to be significantly increased in patients who were older (odds ratio [OR], 1.06; P < .01), had high-risk contraindications to anticoagulation (OR, 5.14; P < .01), were on dialysis (OR, 3.03; P = .04), had centrally located UE DVTs (OR, 2.72; P < .05), and had a stroke (OR, 20.34; P = .03). Mortality was significantly decreased in patients who were treated with anticoagulation (OR, 0.16; P < .05). At 6 months, however, age (hazard ratio [HR], 1.05; P < .001), male sex (HR, 2.16; P = .02), dialysis (HR, 2.90; P = .01), high-risk contraindications to anticoagulation (HR, 2.67; P = .02), UE DVTs in both central and peripheral veins (HR, 4.55; P = .03), and ischemic stroke in the first 30 days (HR, 71.63; P < .001) were associated with significant increases in mortality. CONCLUSIONS: These data suggest that mortality rates among patients with UE DVT are relatively high and that treatment with anticoagulation is associated with a decrease in mortality at 30 days. Mortality was also associated with multiple comorbid conditions and demographics and not necessarily venous thromboembolism.

Merits of and Technical Tips for Supra-Mesenteric Aortic Cross Clamping.

Supra-celiac aortic cross clamping is often utilized during aortic reconstruction for aneurysmal/occlusive disease involving the pararenal aorta. However, this may be accompanied a myriad of complications related to hemodynamic disturbances, cardiopulmonary compromise and hepatic ischemia. Supra-mesenteric aortic cross clamping may be an excellent option in selected patients with suitable anatomy to minimize or avoid these complications. Herein, the merits of and technical tips for supra-mesenteric aortic cross clamping are discussed.

Microbial production of methyl anthranilate, a grape flavor compound.

Methyl anthranilate (MANT) is a widely used compound to give grape scent and flavor, but is currently produced by petroleum-based processes. Here, we report the direct fermentative production of MANT from glucose by metabolically engineered Escherichia coli and Corynebacterium glutamicum strains harboring a synthetic plant-derived metabolic pathway. Optimizing the key enzyme anthranilic acid (ANT) methyltransferase1 (AAMT1) expression, increasing the direct precursor ANT supply, and enhancing the intracellular availability and salvage of the cofactor S-adenosyl-l-methionine required by AAMT1, results in improved MANT production in both engineered microorganisms. Furthermore, in situ two-phase extractive fermentation using tributyrin as an extractant is developed to overcome MANT toxicity. Fed-batch cultures of the final engineered E. coli and C. glutamicum strains in two-phase cultivation mode led to the production of 4.47 and 5.74 g/L MANT, respectively, in minimal media containing glucose. The metabolic engineering strategies developed here will be useful for the production of volatile aromatic esters including MANT.

Systems Metabolic Engineering Strategies: Integrating Systems and Synthetic Biology with Metabolic Engineering.

Metabolic engineering allows development of microbial strains efficiently producing chemicals and materials, but it requires much time, effort, and cost to make the strains industrially competitive. Systems metabolic engineering, which integrates tools and strategies of systems biology, synthetic biology, and evolutionary engineering with traditional metabolic engineering, has recently been used to facilitate development of high-performance strains. The past decade has witnessed this interdisciplinary strategy continuously being improved toward the development of industrially competitive overproducer strains. In this article, current trends in systems metabolic engineering including tools and strategies are reviewed, focusing on recent developments in selection of host strains, metabolic pathway reconstruction, tolerance enhancement, and metabolic flux optimization. Also, future challenges and prospects are discussed.

Markerless gene knockout and integration to express heterologous biosynthetic gene clusters in Pseudomonas putida.

Pseudomonas putida has gained much interest among metabolic engineers as a workhorse for producing valuable natural products. While a few gene knockout tools for P. putida have been reported, integration of heterologous genes into the chromosome of P. putida, an essential strategy to develop stable industrial strains producing heterologous bioproducts, requires development of a more efficient method. Current methods rely on time-consuming homologous recombination techniques and transposon-mediated random insertions. Here we report a RecET recombineering system for markerless integration of heterologous genes into the P. putida chromosome. The efficiency and capacity of the recombineering system were first demonstrated by knocking out various genetic loci on the P. putida chromosome with knockout lengths widely spanning 0.6-101.7 kb. The RecET recombineering system developed here allowed successful integration of biosynthetic gene clusters for four proof-of-concept bioproducts, including protein, polyketide, isoprenoid, and amino acid derivative, into the target genetic locus of P. putida chromosome. The markerless recombineering system was completed by combining Cre/lox system and developing efficient plasmid curing systems, generating final strains free of antibiotic markers and plasmids. This markerless recombineering system for efficient gene knockout and integration will expedite metabolic engineering of P. putida, a bacterial host strain of increasing academic and industrial interest.

Effect of Placenta-Derived Mesenchymal Stem Cells in a Dementia Rat Model via Microglial Mediation: a Comparison between Stem Cell Transplant Methods.

PURPOSE: Loss of cholinergic neurons in the hippocampus is a hallmark of many dementias. Administration of stem cells as a therapeutic intervention for patients is under active investigation, but the optimal stem cell type and transplantation modality has not yet been established. In this study, we studied the therapeutic effects of human placenta-derived mesenchymal stem cells (pMSCs) in dementia rat model using either intracerebroventricular (ICV) or intravenous (IV) injections and analyzed their mechanisms of therapeutic action. MATERIALS AND METHODS: Dementia modeling was established by intraventricular injection of 192 IgG-saporin, which causes lesion of cholinergic neurons. Sixty-five male Sprague-Dawley rats were divided into five groups: control, lesion, lesion+ICV injection of pMSCs, lesion+IV injection of pMSCs, and lesion+donepezil. Rats were subjected to the Morris water maze and subsequent immunostaining analyses. RESULTS: Both ICV and IV pMSC administrations allowed significant cognitive recovery compared to the lesioned rats. Acetylcholinesterase activity was significantly rescued in the hippocampus of rats injected with pMSCs post-lesion. Choline acetyltransferase did not co-localize with pMSCs, showing that pMSCs did not directly differentiate into cholinergic cells. Number of microglial cells increased in lesioned rats and significantly decreased back to normal levels with pMSC injection. CONCLUSION: Our results suggest that ICV and IV injections of pMSCs facilitate the recovery of cholinergic neuronal populations and cognitive behavior. This recovery likely occurs through paracrine effects that resemble microglia function rather than direct differentiation of injected pMSCs into cholinergic neurons.

Focused ultrasound-mediated noninvasive blood-brain barrier modulation: preclinical examination of efficacy and safety in various sonication parameters.

OBJECTIVE The application of pharmacological therapeutics in neurological disorders is limited by the ability of these agents to penetrate the blood-brain barrier (BBB). Focused ultrasound (FUS) has recently gained attention for its potential application as a method for locally opening the BBB and thereby facilitating drug delivery into the brain parenchyma. However, this method still requires optimization to maximize its safety and efficacy for clinical use. In the present study, the authors examined several sonication parameters of FUS influencing BBB opening in small animals. METHODS Changes in BBB permeability were observed during transcranial sonication using low-intensity FUS in 20 adult male Sprague-Dawley rats. The authors examined the effects of FUS sonication with different sonication parameters, varying acoustic pressure, center frequency, burst duration, microbubble (MB) type, MB dose, pulse repetition frequency (PRF), and total exposure time. The focal region of BBB opening was identified by Evans blue dye. Additionally, H & E staining was used to identify blood vessel damage. RESULTS Acoustic pressure amplitude and burst duration were closely associated with enhancement of BBB opening efficiency, but these parameters were also highly correlated with tissue damage in the sonicated region. In contrast, MB types, MB dose, total exposure time, and PRF had an influence on BBB opening without conspicuous tissue damage after FUS sonication. CONCLUSIONS The study aimed to identify these influential conditions and provide safety and efficacy values for further studies. Future work based on the current results is anticipated to facilitate the implementation of FUS sonication for drug delivery in various CNS disease states in the near future.

Evaluation of Validity and Reliability of Inertial Measurement Unit-Based Gait Analysis Systems.

OBJECTIVE: To replace camera-based three-dimensional motion analyzers which are widely used to analyze body movements and gait but are also costly and require a large dedicated space, this study evaluates the validity and reliability of inertial measurement unit (IMU)-based systems by analyzing their spatio-temporal and kinematic measurement parameters. METHODS: The investigation was conducted in three separate hospitals with three healthy participants. IMUs were attached to the abdomen as well as the thigh, shank, and foot of both legs of each participant. Each participant then completed a 10-m gait course 10 times. During each gait cycle, the hips, knees, and ankle joints were observed from the sagittal, frontal, and transverse planes. The experiments were conducted with both a camerabased system and an IMU-based system. The measured gait analysis data were evaluated for validity and reliability using root mean square error (RMSE) and intraclass correlation coefficient (ICC) analyses. RESULTS: The differences between the RMSE values of the two systems determined through kinematic parameters ranged from a minimum of 1.83 to a maximum of 3.98 with a tolerance close to 1%. The results of this study also confirmed the reliability of the IMU-based system, and all of the variables showed a statistically high ICC. CONCLUSION: These results confirmed that IMU-based systems can reliably replace camera-based systems for clinical body motion and gait analyses.

Systems metabolic engineering as an enabling technology in accomplishing sustainable development goals.

With pressing issues arising in recent years, the United Nations proposed 17 Sustainable Development Goals (SDGs) as an agenda urging international cooperations for sustainable development. In this perspective, we examine the roles of systems metabolic engineering (SysME) and its contribution to improving the quality of life and protecting our environment, presenting how this field of study offers resolutions to the SDGs with relevant examples. We conclude with offering our opinion on the current state of SysME and the direction it should move forward in the generations to come, explicitly focusing on addressing the SDGs.

CRISPR/Cas9-coupled recombineering for metabolic engineering of Corynebacterium glutamicum.

Genome engineering of Corynebacterium glutamicum, an important industrial microorganism for amino acids production, currently relies on random mutagenesis and inefficient double crossover events. Here we report a rapid genome engineering strategy to scarlessly knock out one or more genes in C. glutamicum in sequential and iterative manner. Recombinase RecT is used to incorporate synthetic single-stranded oligodeoxyribonucleotides into the genome and CRISPR/Cas9 to counter-select negative mutants. We completed the system by engineering the respective plasmids harboring CRISPR/Cas9 and RecT for efficient curing such that multiple gene targets can be done iteratively and final strains will be free of plasmids. To demonstrate the system, seven different mutants were constructed within two weeks to study the combinatorial deletion effects of three different genes on the production of γ-aminobutyric acid, an industrially relevant chemical of much interest. This genome engineering strategy will expedite metabolic engineering of C. glutamicum.

Systems Metabolic Engineering of Escherichia coli.

Systems metabolic engineering, which recently emerged as metabolic engineering integrated with systems biology, synthetic biology, and evolutionary engineering, allows engineering of microorganisms on a systemic level for the production of valuable chemicals far beyond its native capabilities. Here, we review the strategies for systems metabolic engineering and particularly its applications in Escherichia coli. First, we cover the various tools developed for genetic manipulation in E. coli to increase the production titers of desired chemicals. Next, we detail the strategies for systems metabolic engineering in E. coli, covering the engineering of the native metabolism, the expansion of metabolism with synthetic pathways, and the process engineering aspects undertaken to achieve higher production titers of desired chemicals. Finally, we examine a couple of notable products as case studies produced in E. coli strains developed by systems metabolic engineering. The large portfolio of chemical products successfully produced by engineered E. coli listed here demonstrates the sheer capacity of what can be envisioned and achieved with respect to microbial production of chemicals. Systems metabolic engineering is no longer in its infancy; it is now widely employed and is also positioned to further embrace next-generation interdisciplinary principles and innovation for its upgrade. Systems metabolic engineering will play increasingly important roles in developing industrial strains including E. coli that are capable of efficiently producing natural and nonnatural chemicals and materials from renewable nonfood biomass.

Computed Tomography Features of Appendiceal Metastasis in Patients With Underlying Malignancy: Comparison With Pathological Findings.

OBJECTIVE: To evaluate the computed tomography (CT) findings compared with pathologic features and to determine whether CT findings are useful for diagnosis of appendiceal metastasis in patients with underlying malignancy. MATERIALS AND METHODS: Preoperative CT examinations of 59 patients who had underlying malignancy and underwent appendectomy were evaluated. Appendiceal metastasis (n = 21) and nonmetastasis (n = 38) were pathologically confirmed. Computed tomography features (appendiceal morphology and diameter, presence of ascites, rectal shelf, omental cake, lymphadenopathy or organ metastasis) were retrospectively reviewed, and compared with histopathological findings. Fisher exact test and Wilcoxon rank sum test were performed for statistical analysis. RESULTS: Mean diameter of appendiceal metastasis was significantly larger (9.1 mm) than that of nonmetastasis (5.2 mm), (P < 0.0001). The CT morphology of appendiceal metastasis showed broad spectrum, and 3 cases of nodular thickening was only detected in appendiceal metastasis. There was a significant difference between groups (P = 0.0102). Appendiceal metastasis was more frequently associated with peritoneal seeding (ascitis, rectal shelf, omental cake) than nonmetastasis (P < 0.0001). Histopathological invasion of appendiceal metastasis was more frequently seen in serosa-mesoappendix (n = 20, 100%) or muscularis propria (n = 17, 85%), than in submucosa (n = 10, 50%) or mucosa layer (n = 7, 35%). Acute appendicitis was more commonly detected in metastasis (n = 4) than in nonmetastasis (n = 1) (P = 0.0495). CONCLUSIONS: Evaluation of CT features of appendix and peritoneum may be useful for prediction of appendiceal metastasis in patients with underlying malignancy.