Enhancing Wearable Gait Monitoring Systems: Identifying Optimal Kinematic Inputs in Typical Adolescents.

Machine learning-based gait systems facilitate the real-time control of gait assistive technologies in neurological conditions. Improving such systems needs the identification of kinematic signals from inertial measurement unit wearables (IMUs) that are robust across different walking conditions without extensive data processing. We quantify changes in two kinematic signals, acceleration and angular velocity, from IMUs worn on the frontal plane of bilateral shanks and thighs in 30 adolescents (8-18 years) on a treadmills and outdoor overground walking at three different speeds (self-selected, slow, and fast). Primary curve-based analyses included similarity analyses such as cosine, Euclidean distance, Poincare analysis, and a newly defined bilateral symmetry dissimilarity test (BSDT). Analysis indicated that superior-inferior shank acceleration (SI shank Acc) and medial-lateral shank angular velocity (ML shank AV) demonstrated no differences to the control signal in BSDT, indicating the least variability across the different walking conditions. Both SI shank Acc and ML shank AV were also robust in Poincare analysis. Secondary parameter-based similarity analyses with conventional spatiotemporal gait parameters were also performed. This normative dataset of walking reports raw signal kinematics that demonstrate the least to most variability in switching between treadmill and outdoor walking to help guide future machine learning models to assist gait in pediatric neurological conditions.

Subthreshold electrical noise alters walking balance control in individuals with cerebral palsy.

BACKGROUND: Sensory deficits in individuals with cerebral palsy (CP) play a critical role in balance control. However, there is a lack of effective interventions that address sensory facilitation to improve walking balance. Stochastic Resonance (SR) stimulation involves delivering sub threshold noise to improve balance in patients with sensory deficits by enhancing the detection of sensory input. RESEARCH QUESTION: To investigate the immediate effects of SR on walking balance in individuals with and without CP. METHODS: Thirty-four participants (17 CP, 17 age-and sex-matched typically developing controls or TD) between 8 and 24 years of age were recruited. SR stimulation was applied to the muscles and ligaments of ankle and hip joint. An optimal SR intensity during walking was determined for each subject. Participants walked on a self-paced treadmill for three trials of two minutes each using a random order of SR stimulation (SR) and no stimulation (noSR) control conditions. Our primary outcome measure was minimum lateral margin of stability (MOS). Secondary outcome measures include anterior MOS before heelstrike and spatiotemporal gait parameters. We performed two-way mixed ANOVAs with group (CP, TD) as between-subject and condition (noSR, SR) as within subject factors. RESULTS: Compared to walking without SR, there was a small but significant increase in the lateral and anterior MOS with SR stimulation, implying that a larger impulse was needed to become unstable, in turn implying higher stability. Step width and step ength decreased with SR for the CP group with SR stimulation. There were no significant effects for other spatiotemporal variables. SIGNIFICANCE: Sub threshold electrical noise can slightly improve walking balance control in individuals with CP. SR stimulation, through enhanced proprioception, may have improved the CP group's awareness of body motion during walking, thus leading them to adopt a more conservative stability strategy to prevent a potential fall.

Inhaled Adjunct Therapy with Second-Line Drug Candidates for Dose Reduction in Chemotherapeutic Regimens for Multi-drug-Resistant Tuberculosis.

Chemotherapy of multi-drug-resistant tuberculosis (TB) requires prolonged administration of multiple drugs. We investigated whether pulmonary delivery of minute doses of drugs, along with reduced oral doses of the same agents, would affect preclinical efficacy. We prepared dry powder inhalation (DPI) formulations comprising sutezolid (SUT), the second-generation pretomanid analog TBA-354 (TBA), or a fluorinated derivative of TBA-354 (32,625) in a matrix of the biodegradable polymer poly(L-lactide). We established formulation characteristics, doses inhaled by healthy mice, and preclinical efficacy in a mouse model of TB. Oral doses of 100 mg/kg/day or DPI doses of 0.25-0.5 mg/kg/day of drugs SUT, TBA-354, or 32,625 administered over 28 days were sub-optimally effective in reducing lung and spleen burden of Mycobacterium tuberculosis (Mtb) in infected mice. The addition of 0.25-0.5 mg/kg/day of SUT, TBA-354, or 32,625 as DPI to oral doses of 50 mg/kg/day was non-inferior in clearing Mtb from the lungs of infected mice. We concluded that adjunct therapy with inhaled second-line agents has the potential to reduce the efficacious oral dose.

Multifocal polymorphous cutaneous tuberculosis with Poncet's disease: A case report.

Extrapulmonary tuberculosis (ETB) involving skin with multiple lesions is an uncommon presentation of mycobacterial infection. Cutaneous tuberculosis (TB) having multiple lesions with Poncet's disease (tuberculous Rheumatism) is rarely reported. We hereby report a multifocal cutaneous tuberculosis with Poncet's disease in a 19-year-old immunocompetent female.

Automatic Segmentation and Quantitative Assessment of Stroke Lesions on MR Images.

Lesion studies are crucial in establishing brain-behavior relationships, and accurately segmenting the lesion represents the first step in achieving this. Manual lesion segmentation is the gold standard for chronic strokes. However, it is labor-intensive, subject to bias, and limits sample size. Therefore, our objective is to develop an automatic segmentation algorithm for chronic stroke lesions on T1-weighted MR images. Methods: To train our model, we utilized an open-source dataset: ATLAS v2.0 (Anatomical Tracings of Lesions After Stroke). We partitioned the dataset of 655 T1 images with manual segmentation labels into five subsets and performed a 5-fold cross-validation to avoid overfitting of the model. We used a deep neural network (DNN) architecture for model training. Results: To evaluate the model performance, we used three metrics that pertain to diverse aspects of volumetric segmentation, including shape, location, and size. The Dice similarity coefficient (DSC) compares the spatial overlap between manual and machine segmentation. The average DSC was 0.65 (0.61−0.67; 95% bootstrapped CI). Average symmetric surface distance (ASSD) measures contour distances between the two segmentations. ASSD between manual and automatic segmentation was 12 mm. Finally, we compared the total lesion volumes and the Pearson correlation coefficient (ρ) between the manual and automatically segmented lesion volumes, which was 0.97 (p-value < 0.001). Conclusions: We present the first automated segmentation model trained on a large multicentric dataset. This model will enable automated on-demand processing of MRI scans and quantitative chronic stroke lesion assessment.

Preparation and Evaluation of Low-Dose Calcitriol Dry Powder Inhalation as Host-Directed Adjunct Therapy for Tuberculosis.

BACKGROUND: It is unclear whether Vitamin D is efficacious as a host-directed therapy (HDT) for patients of tuberculosis (TB). We investigated pulmonary delivery of the active metabolite of Vitamin D3, i.e., 1, 25-dihydroxy vitamin D3 (calcitriol) in a mouse model of infection with Mycobacterium tuberculosis (Mtb). METHODS: We optimized a spray drying process to prepare a dry powder inhalation (DPI) of calcitriol using a Quality by Design (QbD) approach. We then compared outcomes when Mtb-infected mice were treated with inhaled calcitriol at 5 ng/kg as a stand-alone intervention versus DPI as adjunct to standard oral anti-tuberculosis therapy (ATT). RESULTS: The DPI with or without concomitant ATT markedly improved the morphology of the lungs and mitigated histopathology in both the lungs and the spleens. The number of nodular lesions on the lung surface decreased from 43.7 ± 3.1 to 22.5 ± 3.9 with the DPI alone and to 9.8 ± 2.5 with DPI + ATT. However, no statistically significant induction of host antimicrobial peptide cathelicidin or reduction in bacterial burden was seen with the DPI alone. DPI + ATT did not significantly reduce the bacterial burden in the lungs compared to ATT alone. CONCLUSIONS: We concluded that HDT using the low dose calcitriol DPI contributed markedly to mitigation of pathology, but higher dose may be required to evoke significant induction of bactericidal host response and bactericidal activity in the lung.

Transient, inhaled gene therapy with gamma interferon mitigates pathology induced by host response in a mouse model of tuberculosis.

Transient transfection of the respiratory mucosa of mice infected with Mycobacterium tuberculosis (Mtb) with gamma interferon (IFN-γ) promises benefits in disease therapy. We investigated preclinical efficacy of a dry powder inhalation (DPI) as a stand-alone versus adjunct to oral anti-tuberculosis (TB) chemotherapy in mice. We observed that this host-directed therapy mitigates the gross organ pathology and histopathology of lung and spleen tissue of infected mice receiving the DPI, either alone or as adjunct therapy. However, no statistically significant reduction in Mtb colony forming units (CFU) occurred if mice were given only DPI; but not drugs. We compared one and three doses a week of the DPI over four weeks; with or without concomitant oral drugs. There was no significant difference in lung CFU after four or 12 doses of the DPI alone, but, surprisingly, four doses were qualitatively better than 12 doses in mitigating lung pathology. Nodular lesions on the lung surface and the area occupied by these was significantly reduced after four doses of the DPI, even without oral drugs. Transient transfection with IFN-γ did not induce pathological inflammation of the lungs and airways. We conclude that IFN-γ, as expected of host-directed therapy, 'heals the host; ' but does not 'kill the bug.'

Aerobic Responses to FES-Assisted and Volitional Cycling in Children with Cerebral Palsy.

Recumbent stationary cycling is a potential exercise modality for individuals with cerebral palsy (CP) that lack the postural control needed for upright exercises. Functional electrical stimulation (FES) of lower extremity muscles can help such individuals reach the cycling intensities that are required for aerobic benefits. The aim of this study was to examine the effect of cycling with and without FES assistance to that of a no-intervention control group on the cardiorespiratory fitness of children with CP. Thirty-nine participants were randomized to a FES group that underwent an 8-week FES-assisted cycling program, the volitional group (VOL), who cycled without FES, or a no-intervention control group (CON) (15 FES, 11 VOL, 13 CON). Cadence, peak VO2, and net rise in heart rate were assessed at baseline, end of training, and washout (8-weeks after cessation of training). Latent growth curve modeling was used for analysis. The FES group showed significantly higher cycling cadences than the VOL and CON groups at POST and WO. There were no differences in improvements in the peak VO2 and peak net HR between groups. FES-assisted cycling may help children with CP attain higher cycling cadences and to retain these gains after training cessation. Higher training intensities may be necessary to obtain improvements in peak VO2 and heart rate.

Selective N-Alkylation of Amines with DMC over Biogenic Cu-Zr Bimetallic Nanoparticles.

Herein, we report the green synthesis of copper-zirconium bimetallic nanoparticles (Cu-Zr BNPs) from aqueous solutions using Azadirachta indica leaf extract as a reducing and stabilizing agent. The CuO, ZrO2 NP, and Cu-Zr BNP samples were characterized by X-ray diffraction and Fourier transform infrared (FTIR) spectroscopy, and the morphologies of the samples were analyzed by high-resolution transmission electron microscopy (HR-TEM) with selected area electron diffraction analysis (SAED). The synthesized Cu-Zr BNPs have been employed as efficient catalysts for the selective N-methylation of aromatic and aliphatic amines with dimethyl carbonate. The effect of process conditions on the percentage conversion of benzylamine with dimethyl carbonate as a model reaction has been investigated. The Cu-Zr bimetallic nanoparticle catalytic system in a 1:2 molar ratio was able to convert amines into the corresponding N-methylated amines with a selectivity up to 91% at 180 °C in 4 h. The analysis of catalytic reusability confirmed that the reported heterogeneous catalyst can be used for five consecutive cycles without much loss in activity. Thus, the current protocol can be considered as a simpler, reproducible, and environmentally benign approach for N-methylation of amines.

Transient Transfection of the Respiratory Epithelium with Gamma Interferon for Host-Directed Therapy in Pulmonary Tuberculosis.

Nebulized gamma interferon (IFN-γ) protein has been studied for clinical safety and efficacy against pulmonary tuberculosis (TB). The protein is expensive, requires a cold chain, and is difficult to deploy in limited-resource, high-incidence settings. We generated a preclinical proof of concept (PoC) for a dry powder inhalation (DPI) containing DNA constructs to transiently transfect the lung and airway epithelium of mice with murine IFN-γ. Bacterial colony-forming units (CFU) in the lungs of mice infected with Mycobacterium tuberculosis (Mtb) reduced from about 106/g of tissue to ~104 after four doses given once a week. Nodular inflammatory lesions in the lungs reduced significantly in number. Immunohistochemistry of infected lung sections for LC3-1 and LAMP-1 indicated autophagy induction between 18 and 48 h after inhalation. ELISA on bronchoalveolar lavage (BAL) fluid showed differences in kinetics of IFN-γ concentrations in the epithelial lining fluid of healthy versus infected mice. Uninfected mice receiving DNA constructs expressing a fluorescent protein were live-imaged. The fluorescence signals from the intracellular protein peaked at about 36 h after inhalation and declined by 48 h. These results establish preclinical PoC of the efficacy of a DPI and dosing regimen as a host-directed and transient gene therapy of experimental pulmonary TB in mice, justifying preclinical development.

An Evaluation of Three Kinematic Methods for Gait Event Detection Compared to the Kinetic-Based 'Gold Standard'.

Video- and sensor-based gait analysis systems are rapidly emerging for use in 'real world' scenarios outside of typical instrumented motion analysis laboratories. Unlike laboratory systems, such systems do not use kinetic data from force plates, rather, gait events such as initial contact (IC) and terminal contact (TC) are estimated from video and sensor signals. There are, however, detection errors inherent in kinematic gait event detection methods (GEDM) and comparative study between classic laboratory and video/sensor-based systems is warranted. For this study, three kinematic methods: coordinate based treadmill algorithm (CBTA), shank angular velocity (SK), and foot velocity algorithm (FVA) were compared to 'gold standard' force plate methods (GS) for determining IC and TC in adults (n = 6), typically developing children (n = 5) and children with cerebral palsy (n = 6). The root mean square error (RMSE) values for CBTA, SK, and FVA were 27.22, 47.33, and 78.41 ms, respectively. On average, GED was detected earlier in CBTA and SK (CBTA: -9.54 ± 0.66 ms, SK: -33.41 ± 0.86 ms) and delayed in FVA (21.00 ± 1.96 ms). The statistical model demonstrated insensitivity to variations in group, side, and individuals. Out of three kinematic GEDMs, SK GEDM can best be used for sensor-based gait event detection.

PrediQt-Cx: post treatment health related quality of life prediction model for cervical cancer patients.

BACKGROUND: Cervical cancer is the third largest cause of cancer mortality in India. The objectives of the study were to compare the pre and the post treatment quality of life in cervical cancer patients and to develop a prediction model to provide an insight into the possibilities in the treatment modules. METHODOLOGY/PRINCIPAL FINDINGS: A total of 198 patients were assessed with two structured questionnaires of Health Related Quality of Life (The European Organisation for Research and Treatment of Cancer, EORTC QLQ C-30 and CX-24). The baseline observations were recorded when the patients first reported (T1) and second evaluation was done at 6 months post treatment (T2). The mean age of detection was 50.9 years with the literacy level being non-educated or less than high school. Majority of them were married/cohabiting 179 (90.4%). On histopathological examination (HPE) squamous cell carcinoma was found to be the most common cell type carcinoma 147 (74.2%) followed by Adenocarcinoma 31 (15.7%). Radical hysterectomy was the most common treatment modality 76 (38.4%), followed by Wertheims Hysterectomy 46 (23.2%) and Radiochemotherapy 59 (29.8%). The mean score of global health of cervical cancer patients post treatment was 77.90, which was significantly higher than the pre - treatment score (54.32). Mean "symptoms score" post treatment was 21.69 with an aggravation of 7.32 compared to pre treatment scores. Patients experienced substantial decrease in sexual activity post treatment. CONCLUSIONS/SIGNIFICANCE: The prediction model(PrediQt-Cx), based on Support Vector Machine(SVM) for predicting post treatment HRQoL in cervical cancer patients was developed and internally cross validated. After external validation PrediQt-Cx can be easily employed to support decision making by clinicians and patients from north India region, through openly made available for access at http://prediqt.org.