Visual-motor integration in children with unilateral cerebral palsy: application of the computer-aided measure of visual-motor integration.

BACKGROUND: Children with unilateral cerebral palsy (UCP) are encouraged to participate in the regular school curriculum. However, even when using the less-affected hand for handwriting, children with UCP still experience handwriting difficulties. Visual-motor integration (VMI) is a predictor of handwriting quality. Investigating VMI in children with UCP is important but still lacking. Conventional paper-based VMI assessments is subjective and use all-or-nothing scoring procedures, which may compromise the fidelity of VMI assessments. Moreover, identifying important shapes that are predictive of VMI performance might benefit clinical decision-making because different geometric shapes represent different developmental stepping stones of VMI. Therefore, a new computer-aided measure of VMI (the CAM-VMI) was developed to investigate VMI performance in children with UCP and to identify shapes important for predicting their VMI performance. METHODS: Twenty-eight children with UCP and 28 typically-developing (TD) children were recruited. All participants were instructed to complete the CAM-VMI and Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery-VMI). The test items of the CAM-VMI consisted of nine simple geometric shapes related to writing readiness. Two scores of the CAM-VMI, namely, Error and Effort, were obtained by image registration technique. The performances on the Beery-VMI and the CAM-VMI of children with UCP and TD children were compared by independent t-test. A series of stepwise regression analyses were used to identify shapes important for predicting VMI performance in children with UCP. RESULTS: Significant group differences were found in both the CAM-VMI and the Beery-VMI results. Furthermore, Error was identified as a significant aspect for predicting VMI performance in children with UCP. Specifically, the square item was the only significant predictor of VMI performance in children with UCP. CONCLUSIONS: This study was a large-scale study that provided direct evidence of impaired VMI in school-aged children with UCP. Even when using the less-affected hand, children with UCP could not copy the geometric shapes as well as TD children did. The copied products of children with UCP demonstrated poor constructional accuracy and inappropriate alignment. Furthermore, the predictive model suggested that the constructional accuracy of a copied square is an important predictor of VMI performance in children with UCP.

Prediction of methicillin-resistant Staphylococcus aureus and carbapenem-resistant Klebsiella pneumoniae from flagged blood cultures by combining rapid Sepsityper MALDI-TOF mass spectrometry with machine learning.

This study investigated combination of the Rapid Sepsityper Kit and a machine learning (ML)-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) approach for rapid prediction of methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Klebsiella pneumoniae (CRKP) from positive blood culture bottles. The study involved 461 patients with monomicrobial bloodstream infections. Species identification was performed using the conventional MALDI-TOF MS Biotyper system and the Rapid Sepsityper protocol. The data underwent preprocessing steps, and ML models were trained using preprocessed MALDI-TOF data and corresponding labels. The interpretability of the model was enhanced using SHapely Additive exPlanations values to identify significant features. In total, 44 S. aureus isolates comprising 406 MALDI-TOF MS files and 126 K. pneumoniae isolates comprising 1249 MALDI-TOF MS files were evaluated. This study demonstrated the feasibility of predicting MRSA among S. aureus and CRKP among K. pneumoniae isolates using MALDI-TOF MS and Sepsityper. Accuracy, area under the receiver operating characteristic curve, and F1 score for MRSA/methicillin-susceptible S. aureus were 0.875, 0.898 and 0.904, respectively; for CRKP/carbapenem-susceptible K. pneumoniae, these values were 0.766, 0.828 and 0.795, respectively. In conclusion, the novel ML-based MALDI-TOF MS approach enables rapid identification of MRSA and CRKP from flagged blood cultures within 1 h. This enables earlier initiation of targeted antimicrobial therapy, reducing deaths due to sepsis. The favourable performance and reduced turnaround time of this method suggest its potential as a rapid detection strategy in clinical microbiology laboratories, ultimately improving patient outcomes.

Let-7g Upregulation Attenuated the KRAS-PI3K-Rac1-Akt Axis-Mediated Bioenergetic Functions.

The aberrant activation of signaling pathways contributes to cancer cells with metabolic reprogramming. Thus, targeting signaling modulators is considered a potential therapeutic strategy for cancer. Subcellular fractionation, coimmunoprecipitation, biochemical analysis, and gene manipulation experiments revealed that decreasing the interaction of kirsten rat sarcoma viral oncogene homolog (KRAS) with p110α in lipid rafts with the use of naringenin (NGN), a citrus flavonoid, causes lipid raft-associated phosphatidylinositol 3-kinase (PI3K)-GTP-ras-related C3 botulinum toxin substrate 1 (Rac1)-protein kinase B (Akt)-regulated metabolic dysfunction of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), leading to apoptosis in human nasopharyngeal carcinoma (NPC) cells. The use of lethal-7g (let-7g) mimic and let-7g inhibitor confirmed that elevated let-7g resulted in a decrease in KRAS expression, which attenuated the PI3K-Rac1-Akt-BCL-2/BCL-xL-modulated mitochondrial energy metabolic functions. Increased let-7g depends on the suppression of the RNA-specificity of monocyte chemoattractant protein-induced protein-1 (MCPIP1) ribonuclease since NGN specifically blocks the degradation of pre-let-7g by NPC cell-derived immunoprecipitated MCPIP1. Converging lines of evidence indicate that the inhibition of MCPIP1 by NGN leads to let-7g upregulation, suppressing oncogenic KRAS-modulated PI3K-Rac1-Akt signaling and thereby impeding the metabolic activities of aerobic glycolysis and mitochondrial OXPHOS.

Assessment for Tactile Perception in Children With Cerebral Palsy.

IMPORTANCE: Impaired tactile perception frequently accompanies motor deficits in children with cerebral palsy (CP). Assessing tactile perception precisely for children with CP remains challenging because of a lack of assessments with robust psychometric evidence or standard procedures. OBJECTIVE: To develop a standardized assessment tool, the Tactile Perceptual Test (TPT), for measuring tactile perception in children with CP and to examine its psychometric properties. DESIGN: Observational study design. SETTING: University research laboratory and medical center. PARTICIPANTS: Children with CP (n = 100) and typical development (TD; n = 50). OUTCOMES AND MEASURES: The TPT includes four subtests measuring stereognosis, roughness, hardness, and heaviness. Three comparator instruments, Semmes-Weinstein monofilaments, Two-Point Discrimination, and the stereognosis subtest of the Revised Nottingham Sensory Assessment, were used for convergent validity. RESULTS: Good test-retest reliability was confirmed for all of the TPT subtests. The values of minimal detectable change were acceptable. Moderate correlations between the TPT and comparator instruments were found, as expected. For known-groups validity, the significant difference was confirmed between children with CP and those with TD. CONCLUSIONS AND RELEVANCE: The TPT is a reliable and valid measure for multiple subdomains of tactile perception in children with CP. This tactile assessment may help clarify tactile performance to provide appropriate, precise interventions. What This Article Adds: The TPT measures tactile perception in children with CP. It has four subdomains of tactile perception that could facilitate prioritization of tactile treatment of specific subdomains and thereby aid in the provision of appropriate interventions.

Efficacy of Constraint-Induced Movement Therapy Versus Bimanual Intensive Training on Motor and Psychosocial Outcomes in Children With Unilateral Cerebral Palsy: A Randomized Trial.

IMPORTANCE: Emerging research has demonstrated that constraint-induced movement therapy (CIMT) and bimanual intensive training (BIT) show promising effectiveness for children with unilateral cerebral palsy (UCP). Considering that neurorehabilitative programs have always been designed with long training periods, psychosocial outcomes have received scarce attention and thus have not been investigated sufficiently. OBJECTIVE: To compare the efficacy of CIMT and BIT with 36-hr interventional dosages for both motor and psychosocial outcomes. DESIGN: Randomized trial. SETTING: Community. PARTICIPANTS: Forty-eight children with UCP, ages 6 to 12 yr. INTERVENTION: Both CIMT and BIT delivered via individual intervention for 2.25 hr/day, twice a week, for 8 wk. OUTCOMES AND MEASURES: The Melbourne Assessment 2, Pediatric Motor Activity Log-Revised, Bruininks-Oseretsky Test of Motor Proficiency, ABILHAND-Kids measure, and Parenting Stress Index-Short Form were administrated at pretreatment, midterm, posttreatment, and 6 mo after intervention. An engagement questionnaire for investigating the child's engagement in the intervention was used to collect the perspectives of the children and the parents weekly. RESULTS: Children with UCP who received either CIMT or BIT achieved similar motor improvements. The only difference was that CIMT yielded larger improvements in frequency and quality of use of the more affected hand at the 6-mo follow-up. Similar child engagement and parental stress levels were found in the two groups. CONCLUSIONS AND RELEVANCE: This study comprehensively compared the efficacy of motor and psychosocial outcomes for 36-hr dosages of CIMT and BIT. The promising findings support the clinical efficacy and feasibility of the proposed protocols. What This Article Adds: The core therapeutic principle of CIMT (i.e., remind the child to use the more affected hand) may be more easily duplicated by parents. Parents may have overestimated their child's engagement and given relatively higher scores; therefore, occupational therapists should also consider the opinions of the children themselves.

Influence of antipsychotic medications on hyperlipidemia risk in patients with schizophrenia: evidence from a population-based cohort study and in vitro hepatic lipid homeostasis gene expression.

Introduction: Schizophrenia increases the risk of mortality and cardiovascular disease (CVD) risk. However, the correlation between antipsychotics (APs) and CVD remains controversial. Hyperlipidemia is a significant risk factor for CVD. Methods: We conducted a nationwide population-based retrospective cohort study to investigate the effects of APs on the risk of hyperlipidemia and lipid homeostasis gene expression. We used data from the Longitudinal Health Insurance Database of Taiwan on new-onset schizophrenia patients and a comparison cohort without schizophrenia. We used a Cox proportional hazards regression model to analyze the differences in hyperlipidemia development between the two cohorts. Furthermore, we examined the effects of APs on the hepatic expression of lipid homeostasis-related genes. Results: After adjusting for potential interrelated confounding factors, the case group (N = 4,533) was found to have a higher hyperlipidemia risk than the control cohort (N = 4,533) [adjusted hazard ratio (aHR), 1.30, p < 0.001]. Patients with schizophrenia without APs had a significantly higher risk of hyperlipidemia (aHR, 2.16; p < 0.001). However, patients receiving APs had a significantly lower risk of hyperlipidemia than patients not receiving APs (all aHR ≤ 0.42, p < 0.001). First-generation antipsychotics (FGAs) induce the expression of hepatic lipid catabolism genes in an in vitro model. Discussion: Patients with schizophrenia had a higher risk of hyperlipidemia than controls; however, compared with non-treated patients, AP users had a lower risk of hyperlipidemia. Early diagnosis and management of hyperlipidemia may help prevent CVD.

Association of epilepsy, anti-epileptic drugs (AEDs), and type 2 diabetes mellitus (T2DM): a population-based cohort retrospective study, impact of AEDs on T2DM-related molecular pathway, and via peroxisome proliferator-activated receptor γ transactivation.

Introduction: A potential association between epilepsy and subsequent type 2 diabetes mellitus (T2DM) has emerged in recent studies. However, the association between epilepsy, anti-epileptic drugs (AEDs), and the risk of T2DM development remains controversial. We aimed to conduct a nationwide, population-based, retrospective, cohort study to evaluate this relationship. Methods: We extracted data from the Taiwan Longitudinal Generation Tracking Database of patients with new-onset epilepsy and compared it with that of a comparison cohort of patients without epilepsy. A Cox proportional hazards regression model was used to analyze the difference in the risk of developing T2DM between the two cohorts. Next-generation RNA sequencing was used to characterize T2DM-related molecularchanges induced by AEDs and the T2DM-associated pathways they alter. The potential of AEDs to induce peroxisome proliferator-activated receptor γ (PPARγ) transactivation was also evaluated. Results: After adjusting for comorbidities and confounding factors, the case group (N = 14,089) had a higher risk for T2DM than the control group (N = 14,089) [adjusted hazards ratio (aHR), 1.27]. Patients with epilepsy not treated with AEDs exhibited a significantly higher risk of T2DM (aHR, 1.70) than non-epileptic controls. In those treated with AEDs, the risk of developing T2DM was significantly lower than in those not treated (all aHR ≤ 0.60). However, an increase in the defined daily dose of phenytoin (PHE), but not of valproate (VPA), increased the risk of T2DM development (aHR, 2.28). Functional enrichment analysis of differentially expressed genes showed that compared to PHE, VPA induced multiple beneficial genes associated with glucose homeostasis. Among AEDs, VPA induced the specific transactivation of PPARγ. Discussion: Our study shows epilepsy increases the risk of T2DM development, however, some AEDs such as VPA might yield a protective effect against it. Thus, screening blood glucose levels in patients with epilepsy is required to explore the specific role and impact of AEDs in the development of T2DM. Future in depth research on the possibility to repurpose VPA for the treatment of T2DM, will offer valuable insight regarding the relationship between epilepsy and T2DM.

Association of combination antiretroviral therapy with risk of neurological diseases in patients with HIV/AIDS in Taiwan: a nested case-control study.

Heterogeneous neurocognitive impairment remains an important issue, even in the era of combination antiretroviral therapy (cART), with an incidence ranging from 15% to 65%. Although ART drugs with higher penetration scores to the central nervous system (CNS) show better HIV replication control in the CNS, the association between CNS penetration effectiveness (CPE) scores and neurocognitive impairment remains inconclusive. To explore whether ART exposure is associated with the risk of neurological diseases among patients with HIV/AIDS, this study in Taiwan involved 2,571 patients with neurological diseases and 10,284 matched, randomly selected patients without neurological diseases between 2010 and 2017. A conditional logistic regression model was used in this study. The parameters for ART exposure included ART usage, timing of exposure, cumulative defined daily dose (DDD), adherence, and cumulative CPE score. Incident cases of neurological diseases, including CNS infections, cognitive disorders, vasculopathy, and peripheral neuropathy, were obtained from the National Health Insurance Research Database in Taiwan. Odds ratios (ORs) for the risk of neurological diseases were conducted using a multivariate conditional logistic regression model. Patients with a history of past exposure (OR: 1.68, 95% confidence interval [CI]:1.22-2.32), low cumulative DDDs (< 2,500) (OR: 1.28, 95% CI: 1.15-1.42), low adherence (0 < adherence (ADH) ≤ 0.8) (OR: 1.46, 95% CI: 1.30-1.64), or high cumulative CPE scores (>14) (OR: 1.34, 95% CI: 1.14-1.57) had a high risk of neurological diseases. When stratified by classes of ART drugs, patients with low cumulative DDDs or low adherence had a high risk of neurological diseases, including NRTIs, PIs, NNRTIs, INSTIs, and multi-drug tablets. Subgroup analyses also suggested that patients with low cumulative DDDs or low adherence had a high risk of neurological diseases when they had high cumulative CPE scores. Patients with high cumulative DDDs or medication adherence were protected against neurological diseases only when they had low cumulative CPE scores (≤ 14). Patients may be at risk for neurological diseases when they have low cumulative DDDs, low adherence, or usage with high cumulative CPE scores. Continuous usage and low cumulative CPE scores of ART drugs may benefit neurocognitive health in patients with HIV/AIDS.

Highly Mimetic Ex Vivo Lung-Cancer Spheroid-Based Physiological Model for Clinical Precision Therapeutics.

Lung cancer remains a major health problem despite the considerable research into prevention and treatment methods. Through a deeper understanding of tumors, patient-specific ex vivo spheroid models with high specificity can be used to accurately investigate the cause, metastasis, and treatment strategies for lung cancer. Biofabricate lung tumors are presented, consisting of patient-derived tumor spheroids, endothelial cells, and lung decellularized extracellular matrix, which maintain a radial oxygen gradient, as well as biophysicochemical behaviors of the native tumors for precision medicine. It is also demonstrated that the developed lung-cancer spheroid model reproduces patient responses to chemotherapeutics and targeted therapy in a co-clinical trial, with 85% accuracy, 86.7% sensitivity, and 80% specificity. RNA sequencing analysis validates that the gene expression in the spheroids replicates that in the patient's primary tumor. This model can be used as an ex vivo predictive model for personalized cancer therapy and to improve the quality of clinical care.

Direct prediction of carbapenem-resistant, carbapenemase-producing, and colistin-resistant Klebsiella pneumoniae isolates from routine MALDI-TOF mass spectra using machine learning and outcome evaluation.

The objective of this study was to develop a rapid prediction method for carbapenem-resistant Klebsiella pneumoniae (CRKP) and colistin-resistant K. pneumoniae (ColRKP) based on routine MALDI-TOF mass spectrometry (MS) results in order to formulate a suitable and rapid treatment strategy. A total of 830 CRKP and 1462 carbapenem-susceptible K. pneumoniae (CSKP) isolates were collected; 54 ColRKP isolates and 1592 colistin-intermediate K. pneumoniae (ColIKP) isolates were also included. Routine MALDI-TOF MS, antimicrobial susceptibility testing, NG-Test CARBA 5, and resistance gene detection were followed by machine learning (ML). Using the ML model, the accuracy and area under the curve for differentiating CRKP and CSKP were 0.8869 and 0.9551, respectively, and those for ColRKP and ColIKP were 0.8361 and 0.8447, respectively. The most important MS features of CRKP and ColRKP were m/z 4520-4529 and m/z 4170-4179, respectively. Of the CRKP isolates, MS m/z 4520-4529 was a potential biomarker for distinguishing KPC from OXA, NDM, IMP, and VIM. Of the 34 patients who received preliminary CRKP ML prediction results (by texting), 24 (70.6%) were confirmed to have CRKP infection. The mortality rate was lower in patients who received antibiotic regimen adjustment based on the preliminary ML prediction (4/14, 28.6%). In conclusion, the proposed model can provide rapid results for differentiating CRKP and CSKP, as well as ColRKP and ColIKP. The combination of ML-based CRKP with preliminary reporting of results can help physicians alter the regimen approximately 24 h earlier, resulting in improved survival of patients with timely antibiotic intervention.

Effects of Intensive Versus Distributed Constraint-Induced Movement Therapy for Children With Unilateral Cerebral Palsy: A Quasi-Randomized Trial.

BACKGROUND: Previous studies have compared the effectiveness of constraint-induced movement therapy (CIMT) by different training doses. However, whether the dosing schedule, that is, intensive or distributed, influences the effectiveness of CIMT in children with unilateral cerebral palsy (CP) is unknown. OBJECTIVE: To investigate the effectiveness of intensive and distributed CIMT for children with unilateral CP. METHODS: Fifty children with unilateral CP were assigned to intensive or distributed CIMT group with a total of 36 training hours. The intensive CIMT was delivered within 1 week, and the distributed CIMT was delivered twice a week for 8 weeks. The outcomes were the Melbourne Assessment 2, Box and Block Test, Pediatric Motor Activity Log-Revised (PMAL-R), Bruininks-Oseretsky test of motor proficiency 2, ABILHAND-Kids and Parenting Stress Index-Short Form. The intensive group was assessed at the initiation of treatment (week 0), at the end of 1 week treatment (week 1), and 8 weeks after the initiation of treatment (week 8). The distributed group was assessed at week 0 and week 8. RESULTS: The within-group analyses demonstrated significant differences on all motor outcomes. There were no significant between-group differences at post-treatment, while the intensive CIMT demonstrated larger improvements than the distributed CIMT did on quality of use of the more-affected hand, as rated by parents on the PMAL-R at week 8. CONCLUSIONS: The 2 dosing schedules of CIMT had similar effectiveness for children with unilateral CP. The intensive CIMT yielded additional improvement on parent rated motor quality of the more-affected hand at 8 weeks after the initiation of treatment. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT03128385).

Effect of Chinese herbal medicine therapy on risks of all-cause mortality, infections, parasites, and circulatory-related mortality in HIV/AIDS patients with neurological diseases.

Introduction: Long-term living with human immunodeficiency virus (HIV) and/or antiretroviral therapy (ART) is associated with various adverse effects, including neurocognitive impairment. Heterogeneous neurocognitive impairment remains an important issue, affecting between 15-65% of human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) patients and resulting in work performance, safety, and health-related outcomes that have a heavy economic burden. Methods: We identified 1,209 HIV/AIDS patients with neurological diseases during 2010-2017. The Kaplan-Meier method, log-rank test, and Cox proportional hazards model were used to analyze 308 CHM users and 901 non-CHM users within this population. Major CHM clusters were determined using association rule mining and network analysis. Results and Discussion: Results showed that CHM users had a 70% lower risk of all-cause mortality (adjusted hazard ratio (aHR) = 0.30, 95% confidence interval (CI):0.16-0.58, p < 0.001) (p = 0.0007, log-rank test). Furthermore, CHM users had an 86% lower risk of infections, parasites, and circulatory-related mortality (aHR = 0.14, 95% confidence interval (CI):0.04-0.46, p = 0.001) (p = 0.0010, log-rank test). Association rule mining and network analysis showed that two CHM clusters were important for patients with neurological diseases. In the first CHM cluster, Huang Qin (HQ; root of Scutellaria baicalensis Georgi), Gan Cao (GC; root of Glycyrrhiza uralensis Fisch.), Huang Lian (HL; root of Coptis chinensis Franch.), Jie Geng (JG; root of Platycodon grandiflorus (Jacq.) A.DC.), and Huang Bai (HB; bark of Phellodendron amurense Rupr.) were identified as important CHMs. Among them, the strongest connection strength was identified between the HL and HQ. In the second CHM cluster, Suan-Zao-Ren-Tang (SZRT) and Ye Jiao Teng (YJT; stem of Polygonum multiflorum Thunb.) were identified as important CHMs with the strongest connection strength. CHMs may thus be effective in treating HIV/AIDS patients with neurological diseases, and future clinical trials are essential for the prevention of neurological dysfunction in the population.

Specific recognition of cyclic oligonucleotides by Cap4 for phage infection.

Under selective pressure, bacteria have evolved diverse defense systems against phage infections. The SMODS-associated and fused to various effector domains (SAVED)-domain containing proteins were identified as major downstream effectors in cyclic oligonucleotide-based antiphage signaling system (CBASS) for bacterial defense. Recent study structurally characterizes a cGAS/DncV-like nucleotidyltransferase (CD-NTase)-associated protein 4 from Acinetobacter baumannii (AbCap4) in complex with 2'3'3'-cyclic AMP-AMP-AMP (cAAA). However, the homologue Cap4 from Enterobacter cloacae (EcCap4) is activated by 3'3'3'-cyclic AMP-AMP-GMP (cAAG). To elucidate the ligand specificity of Cap4 proteins, we determined the crystal structures of full-length wild-type and K74A mutant of EcCap4 to 2.18 and 2.42 Å resolution, respectively. The DNA endonuclease domain of EcCap4 shares similar catalytic mechanism with type II restriction endonuclease. Mutating the key residue K74 in the conserved DXn(D/E)XK motif completely abolishes its DNA degradation activity. The potential ligand-binding cavity of EcCap4 SAVED domain is located adjacent to its N-terminal domain, significantly differing from the centrally located cavity of AbCap4 SAVED domain which recognizes cAAA. Based on structural and bioinformatic analysis, we found that Cap4 proteins can be classified into two types: the type I Cap4, like AbCap4, recognize cAAA and the type II Cap4, like EcCap4, bind cAAG. Several conserved residues identified at the surface of potential ligand-binding pocket of EcCap4 SAVED domain are confirmed by ITC experiment for their direct binding roles for cAAG. Changing Q351, T391 and R392 to alanine abolished the binding of cAAG by EcCap4 and significantly reduced the anti-phage ability of the E. cloacae CBASS system constituting EcCdnD (CD-NTase in clade D) and EcCap4. In summary, we revealed the molecular basis for specific cAAG recognition by the C-terminal SAVED domain of EcCap4 and demonstrates the structural differences for ligand discrimination among different SAVED-domain containing proteins.

Development and Psychometric Evaluation of the Computer-Aided Measure of Chinese Handwriting Legibility (CAM-CHL) for School-Age Children.

IMPORTANCE: Handwriting legibility is the main criterion for determining whether a child has handwriting difficulties. A comprehensive assessment of handwriting legibility with sound psychometrics is essential to timely identification of handwriting difficulties and outcome measurement after handwriting interventions. OBJECTIVE: To evaluate the psychometrics of the Computer-Aided Measure of Chinese Handwriting Legibility (CAM-CHL) and to investigate Chinese handwriting legibility in school-age children using the CAM-CHL. DESIGN: Cross-sectional, repeated observation, test-retest. SETTING: Elementary schools in Taiwan. PARTICIPANTS: We recruited 25 lower-grade children for the examination of test-retest reliability, 75 children from all grade levels, and 10 senior schoolteachers for the examination of the CAM-CHL's convergent validity and the investigation of handwriting legibility. OUTCOMES AND MEASURES: Children were asked to copy a set of Chinese characters as legibly as possible. We used the CAM-CHL to assess handwriting legibility in four domains: Size, Orientation, Position, and Deformation. The schoolteachers were asked to subjectively assess the handwriting legibility using a 3-point Likert-type scale. RESULTS: The CAM-CHL demonstrated good to excellent test-retest reliability and acceptable random measurement error in all legibility domains. The CAM-CHL had fair to moderate convergent validity with schoolteachers' perceptions. Additionally, upper-grade children had better handwriting legibility in the Size and Position domains than lower-grade children. CONCLUSIONS AND RELEVANCE: The CAM-CHL, a comprehensive and objective method of assessing Chinese handwriting legibility, has sound reliability and acceptable validity, suggesting its potential as an outcome measure for school-age children. What This Article Adds: The CAM-CHL can be used in comprehensive evaluations of Chinese handwriting legibility in school-age children. The CAM-CHL has acceptable psychometrics for use as an outcome measure.

Comparative effects of kinect-based versus therapist-based constraint-induced movement therapy on motor control and daily motor function in children with unilateral cerebral palsy: a randomized control trial.

BACKGROUND: Constraint-induced movement therapy (CIMT) is a prominent neurorehabilitation approach for improving affected upper extremity motor function in children with unilateral cerebral palsy (UCP). However, the restraint of the less-affected upper extremity and intensive training protocol during CIMT may decrease children's motivation and increase the therapist's workload and family's burden. A kinect-based CIMT program, aiming to mitigate the concerns of CIMT, has been developed. The preliminary results demonstrated that this program was child-friendly and feasible for improving upper extremity motor function. However, whether the kinect-based CIMT can achieve better or at least comparable effects to that of traditional CIMT (i.e., therapist-based CIMT) should be further investigated. Therefore, this study aimed to compare the effects of kinect-based CIMT with that of therapist-based CIMT on upper extremity and trunk motor control and on daily motor function in children with UCP. METHODS: Twenty-nine children with UCP were recruited and randomly allocated to kinect-based CIMT (n = 14) or therapist-based CIMT (n = 15). The intervention dosage was 2.25 h a day, 2 days a week for 8 weeks. Outcome measures, namely upper extremity and trunk motor control and daily motor function, were evaluated before and after 36-h interventions. Upper extremity and trunk motor control were assessed with unimanual reach-to-grasp kinematics, and daily motor function was evaluated with the Revised Pediatric Motor Activity Log. Between-group comparisons of effectiveness on all outcome measures were analyzed by analysis of covariance (α = 0.05). RESULTS: The two groups demonstrated similar improvements in upper extremity motor control and daily motor function. In addition, the kinect-based CIMT group demonstrated greater improvements in trunk motor control than the therapist-based CIMT group did (F(1,28) > 4.862, p < 0.036). CONCLUSION: Kinect-based CIMT has effects comparable to that of therapist-based CIMT on UE motor control and daily motor function. Moreover, kinect-based CIMT helps decrease trunk compensation during reaching in children with UCP. Therefore, kinect-based CIMT can be used as an alternative approach to therapist-based CIMT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02808195. Registered on 2016/06/21, https://clinicaltrials.gov/ct2/show/NCT02808195 .

Crystal structure of the capsular polysaccharide-synthesis enzyme CapG from Staphylococcus aureus.

Bacterial capsular polysaccharides provide protection against environmental stress and immune evasion from the host immune system, and are therefore considered to be attractive therapeutic targets for the development of anti-infectious reagents. Here, we focused on CapG, one of the key enzymes in the synthesis pathway of capsular polysaccharides type 5 (CP5) from the opportunistic pathogen Staphylococcus aureus. SaCapG catalyses the 2-epimerization of UDP-N-acetyl-D-talosamine (UDP-TalNAc) to UDP-N-acetyl-D-fucosamine (UDP-FucNAc), which is one of the nucleotide-activated precursors for the synthesis of the trisaccharide repeating units of CP5. Here, the cloning, expression and purification of recombinant SaCapG are reported. After extensive efforts, single crystals of SaCapG were successfully obtained which belonged to space group C2 and exhibited unit-cell parameters a = 302.91, b = 84.34, c = 145.09 Å, ß = 110.65°. The structure was solved by molecular replacement and was refined to 3.2 Šresolution. The asymmetric unit revealed a homohexameric assembly of SaCapG, which was consistent with gel-filtration analysis. Structural comparison with UDP-N-acetyl-D-glucosamine 2-epimerase from Methanocaldococcus jannaschii identified α2, the α2-α3 loop and α10 as a gate-regulated switch controlling substrate entry and/or product release.

Mesenchymal stem cell therapy on top of triple therapy with remdesivir, dexamethasone, and tocilizumab improves PaO2/FiO2 in severe COVID-19 pneumonia.

Background: Despite patients with severe coronavirus disease (COVID-19) receiving standard triple therapy, including steroids, antiviral agents, and anticytokine therapy, health condition of certain patients continue to deteriorate. In Taiwan, the COVID-19 mortality has been high since the emergence of previous variants of this disease (such as alpha, beta, or delta). We aimed to evaluate whether adjunctive infusion of human umbilical cord mesenchymal stem cells (MSCs) (hUC-MSCs) on top of dexamethasone, remdesivir, and tocilizumab improves pulmonary oxygenation and suppresses inflammatory cytokines in patients with severe COVID-19. Methods: Hospitalized patients with severe or critical COVID-19 pneumonia under standard triple therapy were separated into adjuvant hUC-MSC and non-hUC-MSC groups to compare the changes in the arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio and biological variables. Results: Four out of eight patients with severe or critical COVID-19 received either one (n = 2) or two (n = 2) doses of intravenous infusions of hUC-MSCs using a uniform cell dose of 1.0 × 108. Both high-sensitivity C-reactive protein (hs-CRP) level and monocyte distribution width (MDW) were significantly reduced, with a reduction in the levels of interleukin (IL)-6, IL-13, IL-12p70 and vascular endothelial growth factor following hUC-MSC transplantation. The PaO2/FiO2 ratio increased from 83.68 (64.34-126.75) to 227.50 (185.25-237.50) and then 349.56 (293.03-367.92) within 7 days after hUC-MSC infusion (P < 0.001), while the change of PaO2/FiO2 ratio was insignificant in non-hUC-MSC patients (admission day: 165.00 [102.50-237.61]; day 3: 100.00 [72.00-232.68]; day 7: 250.00 [71.00-251.43], P = 0.923). Conclusion: Transplantation of hUC-MSCs as adjunctive therapy improves pulmonary oxygenation in patients with severe or critical COVID-19. The beneficial effects of hUC-MSCs were presumably mediated by the mitigation of inflammatory cytokines, characterized by the reduction in both hs-CRP and MDW.

Identification of a novel interaction site between the large hepatitis delta antigen and clathrin that regulates the assembly of genotype III hepatitis delta virus.

BACKGROUND: Hepatitis delta virus (HDV), a satellite virus of hepatitis B virus (HBV), is a small, defective RNA virus strongly associated with the most severe form of hepatitis and progressive chronic liver disease and cirrhosis. Chronic hepatitis D, resulting from HBV/HDV coinfection, is considered to be the most severe form of viral hepatitis and affects 12-20 million people worldwide. Involved in the endocytosis and exocytosis of cellular and viral proteins, clathrin contributes to the pathogenesis and morphogenesis of HDV. Previously, we demonstrated that HDV-I and -II large hepatitis delta antigens (HDAg-L) possess a putative clathrin box that interacts with clathrin heavy chain (CHC) and supports HDV assembly. METHODS: Virus assembly and vesicular trafficking of HDV virus-like particles (VLPs) were evaluated in Huh7 cells expressing HDV-I, -II and -III HDAg-L and hepatitis B surface antigen (HBsAg). To elucidate the interaction motif between HDAg-L and CHC, site-directed mutagenesis was performed to introduce mutations into HDAg-L and CHC and analyzed using coimmunoprecipitation or pull-down assays. RESULTS: Comparable to HDV-I virus-like particles (VLPs), HDV-III VLPs were produced at a similar level and secreted into the medium via clathrin-mediated post-Golgi vesicular trafficking. Mutation at F27 or E33 of CHC abolished the binding of CHC to the C-terminus of HDV-III HDAg-L. Mutation at W207 of HDV-III HDAg-L inhibited its association with CHC and interfered with HDV-III VLP formation. We elucidated mechanism of the binding of HDV-III HDAg-L to CHC and confirmed the pivotal role of clathrin binding in the assembly of genotype III HDV. CONCLUSIONS: A novel W box which was identified at the C terminus of HDV-III HDAg-L is known to differ from the conventional clathrin box but also interacts with CHC. The novel W box of HDAg-L constitutes a new molecular target for anti-HDV-III therapeutics.