Psychometric testing of the Chinese version of the International Classification of Functioning, Disability, and Health Measure of Participation and Activities Screener in people with stroke.

BACKGROUND: Clinicians need a validated measure to assess the activity and participation of Chinese people with stroke. OBJECTIVES: To culturally adapt and psychometrically test the Chinese (Cantonese) version of the International Classification of Functioning, Disability and Health Measure of Participation and Activities (C-IMPACT-S) in community-dwelling people with stroke. METHODS: We followed the standard translation procedures to culturally adapt the C-IMPACT-S. Then we administered the C-IMPACT-S to 100 people with stroke and 50 healthy counterparts for psychometric testing, including the ceiling and floor effects, internal consistency, test - retest, measurement error, minimal detectable change, correlations with other outcome measures, known-group validity and optimal cutoff scores. RESULTS: The C-IMPACT-S has no floor effects but ceiling effects in item 5. It has poor to excellent (Cronbach's α = 0.56-95) internal consistency and fair to excellent (Intraclass correlation coefficients = 0.58-1.00) test-retest reliability. The overall C-IMPACT-S mean score and activity and participation component mean scores had statistically significant no to weak correlations with the Fugl-Meyer Assessment, the Chinese versions of Geriatric Depression Scale, Fatigue Assessment Scale, Lawton Instrumental Activities of Daily Living Scale and Community Integration Measure. The stroke participants had lower C-IMPACT-S scores then their health counterparts. The optimal cutoff scores of the overall C-IMPACT-S and activity and participation domains were 88.02% (sensitivity 72%, specificity 80%), 80.56% (sensitivity 86%, specificity 68%) and 91.67% (sensitivity 68%, specificity 80%), respectively. CONCLUSIONS: C-IMPACT-S is a reliable and valid measure for assessing the levels of activity and participation of people with chronic stroke.

Community integration and its predictors in people with stroke: a multicenter longitudinal study.

OBJECTIVE: To investigate the community integration of patients following stroke and determine the predictors of their level of community integration at 1-year follow-up. DESIGN: A multicenter, longitudinal, and observational study. SUBJECTS: Sixty-five inpatients (41 men) with a mean age of 56.9 (standard deviation = 17.0) years, who had their first stroke at least 1 month prior to this study were recruited from 4 rehabilitation inpatient wards in China. METHODS: In the initial assessment, the participants were evaluated using the Community Integration Questionnaire, the Fugl-Meyer Assessment, the Berg Balance Scale, the Modified Barthel Index, the Mini Mental State Examination, and the Modified Ashworth Scale. In the follow-up assessments, which were conducted via telephone no less than 1 year after discharge, the participants were evaluated using the Community Integration Questionnaire and also assessed for other disease-related conditions. RESULTS: The participants' scores on the Community Integration Questionnaire in the follow-up assessment were significantly greater than those at the initial assessment (p < 0.05). In addition, the participants' Community Integration Questionnaire scores in the follow-up assessment were significantly correlated with their ages, numbers of years of education, and Modified Barthel Index, Berg Balance Scale, Mini Mental State Examination scores in the initial assessment (p < 0.05), and marginally significantly correlated with their scores on Fugl-Meyer Assessment in the initial assessment (p = 0.058). The participants' ages, numbers of years of education, and Modified Barthel Index, Berg Balance Scale, Mini Mental State Examination, Fugl-Meyer Assessment of the lower extremity, and Fugl-Meyer Assessment scores in the initial assessment were predictive of their Community Integration Questionnaire scores at follow-up, with coefficients of determination ranging from 0.254 to 0.056 (p < 0.05). CONCLUSIONS: The level of community integration of the participants was generally low, but it was greater at 1-year follow-up than it was initially. Balance function and daily living ability may be key predictors of community integration of patients following stroke.

Reliability and validity of the supine-to-stand test in people with stroke.

OBJECTIVE: To investigate the psychometric properties of the supine-to-stand test in people with stroke. DESIGN: Cross-sectional design. SUBJECTS: Fifty-two people with stroke (mean (standard deviation) age 63.13 (6.09) years; time post-stroke 93.13 (61.36) months) and 49 healthy older adults (61.90 (7.29) months). METHODS: Subjects with stroke were recruited from the community dwelling in Hong Kong and  assessed with the supineto- stand test, Fugl-Meyer Motor Assessment, ankle muscle strength test, Berg Balance Scale, limit of stability test, Timed Up-and-Go Test, Six-Minute Walk Test, Chinese version of Activities-specific Balance Confidence scale, Community Integration Measure (CIM-C), and 12-item Short-Form Health Survey (SF-12) in a university-based rehabilitation laboratory. RESULTS: The supine-to-stand test completion time demonstrated excellent intra-rater, inter-rater and test-retest reliability (intraclass correlation coefficient 0.946-1.000) for the people with stroke. The completion time was significantly negatively correlated with Berg Balance Scale, Six-Minute Walk Test, limit of stability - maximal excursion, and limit of stability - endpoint excursion results (r = -0.391 to -0.507), whereas it was positively correlated with the Timed Up-and-Go test results (r = 0.461). The optimal cut-off supine-to-stand test completion time of 5.25 s is feasible for a clinical measure to distinguish the performance of people with stroke from healthy older adults (area under the curve = 0.852, sensitivity = 81.1%, specificity = 84.0%). CONCLUSION: The supine-to-stand test is a reliable, sensitive, specific and easy-to-administer clinical test for assessing the supine-to-stand ability of people with stroke.

Translation and concurrent validity, sensitivity and specificity of Chinese version of Short Orientation Memory Concentration Test in people with a first cerebral infarction.

Purpose: This study aimed to translate the English version of the Short Orientation-Memory-Concentration (SOMC) test into a Chinese version, denoted the C-SOMC test, and to investigate the concurrent validity, sensitivity, and specificity of the C-SOMC test against a longer and widely used screening instrument in people with a first cerebral infarction. Methods: An expert group translated the SOMC test into Chinese using a forward-backward procedure. Eighty-six participants (67 men and 19 women, mean age = 59.31 ± 11.57 years) with a first cerebral infarction were enrolled in this study. The validity of the C-SOMC test was determined using the Chinese version of Mini Mental State Examination (C-MMSE) as the comparator. Concurrent validity was determined using Spearman's rank correlation coefficients. Univariate linear regression was used to analyze items' abilities to predict the total score on the C-SOMC test and the C-MMSE score. The area under the receiver operating characteristic curve (AUC) was used to demonstrate the sensitivity and specificity of the C-SOMC test at various cut-off values distinguishing cognitive impairment from normal cognition. Results: The total score for the C-SOMC test and the score for item 1 on this test exhibited moderate-to-good correlations with the C-MMSE score, with respective ρ-values of 0.636 and 0.565 (P < 0.001). The scores for each of items 2, 4, 5, 6, and 7 yielded fair correlations with C-MMSE score, with ρ-value from 0.272 to 0.495 (P < 0.05). The total score on the C-SOMC test and the item score were good predictors (adjusted R2 = 0.049 to 0.615) of the C-MMSE score, and six items were good predictors (adjusted R2 = 0.134 to 0.795) of the total score. The AUC was 0.92 for the C-SOMC test. A cut-off of 17/18 on the C-SOMC test gave optimal performance: correct classification of 75% of participants, with 75% sensitivity and 87.9% specificity. Conclusion: The C-SOMC test demonstrated good concurrent validity, sensitivity and specificity in a sample of people with a first cerebral infarction, demonstrating that it could be used to screen for cognitive impairment in stroke patients.

Structural Transformation by Crystal Engineering Endows Aqueous Zinc-Ion Batteries with Ultra-long Cyclability.

Manganese oxide is a promising cathode material for aqueous zinc batteries. However, its weak structural stability, low electrical conductivity, and sluggish reaction kinetics lead to rapid capacity fading. Herein, a crystal engineering strategy is proposed to construct a novel MnO2 cathode material. Both experimental results and theoretical calculations demonstrate that Al-doping plays a crucial role in phase transition and doping-superlattice structure construction, which stabilizes the structure of MnO2 cathode materials, improves conductivity, and accelerates ion diffusion dynamics. As a result, 1.98% Al-doping MnO2 (AlMO) cathode shows an incredible 15 000 cycle stability with a low capacity decay rate of 0.0014% per cycle at 4 A g-1 . Additionally, it provides superior specific capacity of 311.2 mAh g-1 at 0.1 A g-1 and excellent rate performance (145.2 mAh g-1 at 5.0 A g-1 ). To illustrate the potential of 1.98%AlMO to be applied in actual practice, flexible energy storage devices are fabricated and measured. These discoveries provide a new insight for structural transformation via crystal engineering, as well as a new avenue for the rational design of electrode material in other battery systems.

Psychometric properties of Upper-body Dressing Scale in people with stroke.

OBJECTIVES: To investigate the psychometric properties of the Upper-Body Dressing Scale (UBDS), a tool for evaluating upper-body dressing performance in stroke patients. DESIGN: Cross-sectional study. SUBJECTS: Seventy-six chronic stroke patients and 49 healthy older adults. METHODS: UBDS, Fugl-Meyer Assessment (FMA), Wolf Motor Function Test (WMFT), Berg Balance Scale (BBS), Timed Up-and-Go Test (TUGT), Limit of Stability (LOS) test, Motor Activity Log (MAL-30), Arm Activity Measure (AAM), 12-item Short Form Health Survey, and Community Integration Measure - Cantonese version were assessed Results: UBDS time and UBDS score demonstrated good to excellent inter-rater and test-retest reliabilities for chronic stroke patients (intraclass correlation coefficient 0.759-1.000). UBDS time correlated significantly with FMA Upper and Lower Extremity, WMFT, and BBS scores, TUGT time, LOS Movement Velocity (affected side), LOS Maximal Excursion (composite), MAL-30 Amount of Use and Quality of Movement (affected side), and AAM (section B) scores (r = -0.61 to 0.63). The minimal detectable changes in UBDS time and UBDS score were 28.67 s and 0, respectively. The cut-off UBDS time and UBDS score were 37.67 s and 7.50, respectively. CONCLUSION: UBDS time is a reliable, sensitive, and specific measurement for assessing upper-body dressing performance in chronic stroke patients.

Reliability, Concurrent Validity, and Minimal Detectable Change of Timed Up and Go Obstacle Test in People With Stroke.

OBJECTIVE: The aims of this study were to investigate the psychometric property of the timed Up and Go Obstacle (TUGO) test in people with stroke. DESIGN: Cross-sectional design. SETTING: University based neurorehabilitation laboratory. PARTICIPANTS: Twenty-eight people with stroke and 30 healthy older adults. INTERVENTION: Not Applicable. OUTCOME MEASURES: The TUGO (obstacle heights: 0, 5, 17 cm) test completion times, Fugl-Meyer Assessment (FMA) score, ankle dorsiflexor and plantarflexor muscle strength, Berg Balance Scale (BBS) score, Narrow Corridor Walking Test (NCWT) completion time, timed Up and Go (TUG) test completion time, and Community Integrated Measure. RESULTS: Excellent inter-rater (intraclass correlation coefficient [ICC]=0.999-1.000) and test-retest reliabilities (ICC=0.917-0.975) were found for TUGO test completion times for all obstacle heights. The TUGO test completion times for all obstacle heights were significantly correlated with NCWT and TUG test completion times (r=0.817-0.912). Only TUGO test completion times for 0 and 5 cm obstacle heights showed significant correlations with BBS scores (r=-0.518 to -0.534), while the TUGO test completion time for the 17 cm obstacle height correlated significantly with FMA scores. The minimal detectable change and optimal cut-off values for TUGO test completion times for the 0, 5, and 17 cm obstacle heights were 2.54, 3.60, and 3.07 s, and 14.69, 14.76, and 16.10 s, respectively. CONCLUSION: The TUGO test is a reliable, valid, and easy-to-administer clinical measure to discriminate between people with stroke and healthy older adults.

Loaded and unloaded timed stair tests as tools for assessing advanced functional mobility in people with stroke.

BACKGROUND: The Timed Stair Test (TST) was originally designed to measure advanced functional mobility in patients who have undergone a total hip replacement. Its psychometric properties have not been examined systematically in people with stroke. AIM: The aims of this study were to: 1) determine the intra-rater reliability of TST under loaded and unloaded condition; 2) identify the minimal detectable changes (MDCs) in TST completion times; 3) investigate the concurrent validity between TST completion times and stroke-specific outcome measures; and 4) determine the cut-off TST completion time to differentiate the performance between people with stroke and healthy older adults. DESIGN: Cross-sectional study. SETTING: A university-based rehabilitation center. POPULATION: Ninety-four people with stroke and 34 healthy older adults. METHODS: TSTs were conducted under loaded and unloaded conditions. Two trials of the TST for each of the two conditions were performed on the same day. The Fugl-Meyer Assessment of Lower Extremity (FMA-LE), lower-limb muscle strength test assessed by a hand held dynamometer, Berg Balance Scale (BBS), Limit of Stability (LOS) Test, Timed Up and Go (TUG) Test, and the Cantonese version of the Community Integration Measure (CIM) were also used to assess the subjects. RESULTS: Excellent intra-rater reliability was demonstrated for TST completion times under loaded (intraclass correlation coefficient [ICC2,1]=0.991) and unloaded (ICC2,1=0.985) conditions. The MDCs in TST completion times were 6.55 seconds and 7.25 seconds under loaded and unloaded conditions, respectively. FMA-LE scores, mean strength of the affected-side dorsiflexors and plantar flexors, BBS scores, and LOS movement velocity and maximum excursion scores demonstrated fair to excellent negative correlations with TST completion times under both loaded (r=-0.314 to -0.786) and unloaded (r=-0.296 to -0.794) conditions. TUG results demonstrated good to excellent positive correlations with TST completion times under both loaded (r=0.875, P<0.001) and unloaded (r=0.872, P<0.001) conditions. The TST completion times of 26.3 seconds and 23.4 seconds under loaded and unloaded conditions, respectively, differentiated between people with stroke and healthy older adults. CONCLUSIONS: The TST is a reliable clinical tool for evaluating advanced functional mobility in people with stroke. CLINICAL REHABILITATION IMPACT: TST is a fast and simple test that does not require sophisticated equipment, making it suitable for busy hospital and rehabilitation settings.

Assessing the Turning Ability during Walking in People with Stroke Using L Test.

BACKGROUND: The L Test of Functional Mobility (L Test) was developed to assess the advanced mobility, which includes both turning and walking ability. This study aimed to evaluate (1) the intra-rater reliability of the L Test in four turning conditions, (2) the correlation with other stroke-specific impairment for community-dwelling older adults with stroke, and (3) the optimal cut-off completion time of the L Test to distinguish the difference of performance between healthy older adults and people with stroke. METHODS: This is a cross-sectional design. Thirty older adults with stroke and healthy older adults were included. The subjects were assessed by L Test along with other stroke-specific outcomes. RESULTS: The L Test showed excellent intra-rater reliability (ICC = 0.945-0.978) for the four turning conditions. There were significant correlations between L Test completion times and Fugl-Meyer Assessment-Lower Extremity (FMA-LE) scores, Fugl-Meyer Assessment-Upper Extremity (FMA-UE) scores, Berg Balance Scale (BBS) score, and Timed Up and Go (TUG) Test scores. The cut-off of the L Test was established as 23.41-24.13 s. CONCLUSION: The L Test is an easy-to-administer clinical test for assessing the turning ability of people with stroke.

Ultrasmall Folate Receptor Alpha Targeted Enzymatically Cleavable Silica Nanoparticle Drug Conjugates Augment Penetration and Therapeutic Efficacy in Models of Cancer.

To address the key challenges in the development of next-generation drug delivery systems (DDS) with desired physicochemical properties to overcome limitations regarding safety, in vivo efficacy, and solid tumor penetration, an ultrasmall folate receptor alpha (FRα) targeted silica nanoparticle (C'Dot) drug conjugate (CDC; or folic acid CDC) was developed. A broad array of methods was employed to screen a panel of CDCs and identify a lead folic acid CDC for clinical development. These included comparing the performance against antibody-drug conjugates (ADCs) in three-dimensional tumor spheroid penetration ability, assessing in vitro/ex vivo cytotoxic efficacy, as well as in vivo therapeutic outcome in multiple cell-line-derived and patient-derived xenograft models. An ultrasmall folic acid CDC, EC112002, was identified as the lead candidate out of >500 folic acid CDC formulations evaluated. Systematic studies demonstrated that the lead formulation, EC112002, exhibited highly specific FRα targeting, multivalent binding properties that would mediate the ability to outcompete endogenous folate in vivo, enzymatic responsive payload cleavage, stability in human plasma, rapid in vivo clearance, and minimal normal organ retention organ distribution in non-tumor-bearing mice. When compared with an anti-FRα-DM4 ADC, EC112002 demonstrated deeper penetration into 3D cell-line-derived tumor spheroids and superior specific cytotoxicity in a panel of 3D patient-derived tumor spheroids, as well as enhanced efficacy in cell-line-derived and patient-derived in vivo tumor xenograft models expressing a range of low to high levels of FRα. With the growing interest in developing clinically translatable, safe, and efficacious DDSs, EC112002 has the potential to address some of the critical limitations of the current systemic drug delivery for cancer management.

Translation and Initial Validation of the Chinese (Cantonese) Brief 2-Way Social Support Scale for Use in People with Chronic Stroke.

Background: Social support is important for stroke rehabilitation. Conventionally, social support is evaluated from the level of support received. However, the bidirectional support hypothesis postulated that self-perceived social support is optimized if individuals provide and receive social support in a balanced manner. The Brief 2-Way Social Support Scale (Brief 2-Way SSS) is a social support instrument measuring the reciprocity of receiving and giving emotional and instrumental social support. Objective: (1) To translate and culturally adapt the English version of the Brief 2-Way SSS into Chinese (Cantonese) (Brief 2-Way SSS-C), (2) to report the results of validation of the Brief 2-Way SSS-C, and (3) to investigate the level of social support in people with stroke in Hong Kong. Methods: The Brief 2-Way SSS-C was produced following the standard forward-backward translation model. People with stroke (n = 109) and age-matched controls (n = 53) were recruited through a university-affiliated neurorehabilitation laboratory. Results: The Brief 2-Way SSS-C demonstrated excellent content validity, acceptable to good internal consistency (Cronbach's alpha of 0.74-0.88), and good test-retest reliability (intraclass correlation coefficient of 0.76-0.81). There were no ceiling or floor effects, and the MDC95 across all subscales was 4. The Brief 2-Way SSS-C subscales had significant correlations with various health-related outcome measures. People with stroke had a lower level of social support than the age-matched healthy controls. Conclusions: The Brief 2-Way SSS-C is a culturally relevant, reliable, and valid outcome measure for the level of social support in community-dwelling people with stroke.

The Predictive Role of Hand Section of Fugl-Meyer Assessment and Motor Activity Log in Action Research Arm Test in People With Stroke.

Background: Recent findings of clinical studies have demonstrated a significant positive relationship between Fugl-Meyer Assessment of upper extremity score and the action research arm test (ARAT) score in people with stroke. Although the motor activity log (MAL) can assess the self-perception of motor performance, which can affect the performance of the upper limb, the relationship between MAL score and ARAT score still remains unclear. The objective of this study is to quantify the independent contribution of MAL score and FMA-hand score on the ARAT score in people with stroke. Methods: This is a cross-sectional study. There were a total of 87 subjects (50 males, 37 females; mean age = 61.12 ± 6.88 years, post-stroke duration=6.31 ± 2.84 years) included in this study. Self-perceived performance in using the paretic limb was measured by MAL, including subscale of the amount of usage (MAL-AOU) and quality of movement (MAL-QOM). Functional performance of the upper limb was measured by action research arm test (ARAT). Upper limb motor control of the hand was measured by hand section of Fugl-Meyer assessment (FMA-hand). Results: The result showed that MAL-QOM (r = 0.648, p < 0.001), MAL-AOU (r = 0.606, p < 0.001), FMA-hand scores (r = 0.663, p < 0.001), and the use of a walking aid (r = -0.422, p < 0.001) were significantly correlated with the ARAT scores. A total 66.9% of the variance in the ARAT scores was predicted by the final regression model including MAL-QOM, MAL-AOU, FMA-hand scores, and walking aid. The FMA-hand score was the best predictor of ARAT scores, which can predict a 36.4% variance of ARAT scores in people with stroke, which controlled the effect of using a walking aid. After controlling for use of a walking aid and FMA-hand scores, the multiple linear regression modeling showed that MAL-QOM and MAL-AOU scores could also independently predict an additional 10.4% of the variance in ARAT scores. Conclusion: In addition to the FMA-hand score, the MAL score was significantly correlated with the ARAT score. Improving self-perceived performance should be one goal of rehabilitation in people with stroke. Further work developing and testing techniques to do so is clearly warranted.

Ultrasmall Nanoparticle Delivery of Doxorubicin Improves Therapeutic Index for High-Grade Glioma.

PURPOSE: Despite dramatic growth in the number of small-molecule drugs developed to treat solid tumors, durable therapeutic options to control primary central nervous system malignancies are relatively scarce. Chemotherapeutic agents that appear biologically potent in model systems have often been found to be marginally effective at best when given systemically in clinical trials. This work presents for the first time an ultrasmall (<8 nm) multimodal core-shell silica nanoparticle, Cornell prime dots (or C' dots), for the efficacious treatment of high-grade gliomas. EXPERIMENTAL DESIGN: This work presents first-in-kind renally clearable ultrasmall (<8 nm) multimodal C' dots with surface-conjugated doxorubicin (DOX) via pH-sensitive linkers for the efficacious treatment in two different clinically relevant high-grade glioma models. RESULTS: Optimal drug-per-particle ratios of as-developed nanoparticle-drug conjugates were established and used to obtain favorable pharmacokinetic profiles. The in vivo efficacy results showed significantly improved biological, therapeutic, and toxicological properties over the native drug after intravenous administration in platelet-derived growth factor-driven genetically engineered mouse model, and an EGF-expressing patient-derived xenograft (EGFR PDX) model. CONCLUSIONS: Ultrasmall C' dot-drug conjugates showed great translational potential over DOX for improving the therapeutic outcome of patients with high-grade gliomas, even without a cancer-targeting moiety.

Psychometric Properties of the Trail Walking Test for People With Stroke.

Objective: To investigate (i) the inter-rater and test-retest reliability of the trail walking test (TWT) and the minimum detectable change in the TWT completion time; (ii) the correlations between the TWT completion time and stroke-specific impairments; and (iii) the cutoff TWT completion time to distinguish between people with stroke and healthy older adults according to dual-tasking ambulation ability. Design: Cross-sectional study. Setting: University-based rehabilitation center. Participants: In total, 104 people with stroke and 53 healthy older adults. Main Outcome Measures: The TWT, the Fugl-Meyer Assessment of Lower Extremity (FMA-LE), the ankle muscle strength test, the limit of stability (LOS) test, the Berg Balance Scale (BBS), the Timed Up and Go test (TUG), and the Community Integration Measure (CIM). Results: The mean TWT completion time in subjects with stroke was 124.906 s. The TWT demonstrated excellent inter-rater reliability [intraclass correlation (ICC) = 0.999] and good test-retest reliability (ICC = 0.876) in people with stroke. The TWT performance demonstrated significant negative correlations with the FMA-LE scores (r = -0.409), LOS movement velocity (affected and unaffected sides; r = -0.320 and -0.388, respectively), and LOS endpoint excursion (affected and unaffected sides; r = -0.357 and -0.394, respectively); a significant positive correlation with the LOS reaction time (affected side; r = 0.256); a moderate negative correlation with the BBS scores (r = -0.72); and an excellent positive correlation with the TUG completion time (r = 0.944). The receiver operating characteristic curve analysis revealed that an optimal cutoff of 69.61 s for the TWT completion time had an outstanding diagnostic power to distinguish between people with stroke and healthy older adults (area under the curve = 0.919) with high sensitivity (88.5%) and specificity (83.0%). Conclusion: Results of our preliminary study demonstrated that the TWT is a reliable, valid, sensitive, and specific clinical test for evaluating dual-tasking ambulation ability in people with stroke aged 45 years or above and without cognitive impairments. It can differentiate the dual-tasking ambulation ability between people with stroke and healthy older adults.

Bilateral Transcutaneous Electrical Nerve Stimulation Improves Upper Limb Motor Recovery in Stroke: A Randomized Controlled Trial.

BACKGROUND: Recent evidence has shown bilateral transcutaneous electrical nerve stimulation (Bi-TENS) combined with task-oriented training (TOT) to be superior to unilateral transcutaneous electrical nerve stimulation (Uni-TENS)+TOT in improving lower limb motor functioning following stroke. However, no research explored the effect of Bi-TENS+TOT in improving upper limb motor recovery. This study aimed to compare Bi-TENS+TOT with Uni-TENS+TOT, Placebo transcutaneous electrical nerve stimulation (Placebo-TENS)+TOT, and no treatment (Control) groups in upper limb motor recovery. METHODS: This is a 4-group parallel design. One hundred and twenty subjects were given either Bi-TENS+TOT, Uni-TENS+TOT, Placebo-TENS+TOT, or Control without treatment in this randomized controlled trial. Twenty 60-minute sessions were administered 3× per week for 7 weeks. The outcome measure was the Fugl-Meyer Assessment of Upper Extremity, which was assessed at baseline, after 10 sessions (mid-intervention) and 20 sessions (post-intervention) of intervention, and at 1- and 3-month follow-up. RESULTS: Patients in the Bi-TENS+TOT group showed greater improvement in the Fugl-Meyer Assessment of Upper Extremity scores than Uni-TENS+TOT (mean difference, 2.13; P=0.004), Placebo-TENS+TOT (mean difference, 2.63; P<0.001), and Control groups (mean difference, 3.11; P<0.001) at post-intervention. Both Bi-TENS+TOT (mean difference, 3.39; P<0.001) and Uni-TENS+TOT (mean difference, 1.26; P=0.018) showed significant within-group improvement in the Fugl-Meyer Assessment of Upper Extremity scores. Patients in the Bi-TENS+TOT group showed earlier within-group improvement in the Fugl-Meyer Assessment of Upper Extremity scores at mid-intervention than Uni-TENS+TOT. These improvements were maintained at the 3-month follow-up assessment. CONCLUSIONS: Bi-TENS combined with TOT is an effective therapy for improving upper limb motor recovery following stroke. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03112473.

Molecular Engineering of Ultrasmall Silica Nanoparticle-Drug Conjugates as Lung Cancer Therapeutics.

PURPOSE: Small-molecule inhibitors have had a major impact on cancer care. While treatments have demonstrated clinically promising results, they suffer from dose-limiting toxicities and the emergence of refractory disease. Considerable efforts made to address these issues have more recently focused on strategies implementing particle-based probes that improve drug delivery and accumulation at target sites, while reducing off-target effects. EXPERIMENTAL DESIGN: Ultrasmall (<8 nm) core-shell silica nanoparticles, C' dots, were molecularly engineered to function as multivalent drug delivery vehicles for significantly improving key in vivo biological and therapeutic properties of a prototype epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib. Novel surface chemical components were used to conjugate gefitinib-dipeptide drug-linkers and deferoxamine (DFO) chelators for therapeutic delivery and PET imaging labels, respectively. RESULTS: Gefitinib-bound C' dots (DFO-Gef-C' dots), synthesized using the gefitinib analogue, APdMG, at a range of drug-to-particle ratios (DPR; DPR = 11-56), demonstrated high stability for DPR values≤ 40, bulk renal clearance, and enhanced in vitro cytotoxicity relative to gefitinib (LD50 = 6.21 nmol/L vs. 3 µmol/L, respectively). In human non-small cell lung cancer mice, efficacious Gef-C' dot doses were at least 200-fold lower than that needed for gefitinib (360 nmoles vs. 78 µmoles, respectively), noting fairly equivalent tumor growth inhibition and prolonged survival. Gef-C' dot-treated tumors also exhibited low phosphorylated EFGR levels, with no appreciable wild-type EGFR target inhibition, unlike free drug. CONCLUSIONS: Results underscore the clinical potential of DFO-Gef-C' dots to effectively manage disease and minimize off-target effects at a fraction of the native drug dose.

A Novel Bivalent Mannosylated Targeting Ligand Displayed on Nanoparticles Selectively Targets Anti-Inflammatory M2 Macrophages.

Persistent activation of macrophages (MP)s into a proinflammatory M1 or anti-inflammatory M2 phenotype plays a role in several pathological conditions, including autoimmune diseases, fibrosis, infections, atherosclerosis and tumor development. The mannose receptor (MR, CD206), expressed at low levels on resting MPs and absent on M1 MPs, is highly expressed on M2 MPs, making it a potential target and drug delivery portal. Recently, we developed a novel, highly selective MR targeting ligand (MRTL), consisting of two mannose molecules separated by a monodisperse 12 unit poly(ethylene glycol) linker, to enhance the cellular uptake of polymeric nanocarriers. The feasibility of using the MRTL ligand for selectively targeting M2 MPs for intracellular delivery of nanoparticles (NPs) was investigated. Rat peritoneal MPs were differentiated into an M1 or M2 phenotype using IFN-γ and IL-4/IL-13, respectively. Expression of the M1 marker, inducible nitric oxide synthase (iNOS), and the M2 markers arginase (Arg)-1 and MR (at both the mRNA and protein levels) confirmed MP phenotypic activation. Resting, M1 and M2 MPs were treated with fluorescein isothiocyanate (FITC)-labeled MRTL or NPs displaying FITC-labeled MRTL at two surface densities (1 and 10%) and examined by confocal microscopy. Intracellular fluorescence was also quantified. Uptake of the MRTL was 2.4- and 11.8-fold higher in M2 MPs when compared to resting or M1 MPs, respectively, consistent with marker expression levels. Mannan, a competitive inhibitor of the MR, abrogated MRTL uptake. MRTL also co-localized with a fluid-phase endocytosis marker, further suggesting that uptake was mediated by MR-mediated endocytosis. Intracellular NP fluorescence was confirmed by flow cytometry and by confocal microscopy. MRTL-NPs accumulated intracellularly with no significant cell surface binding, suggesting efficient translocation. NPs displaying a low surface density (1%) of the MRTL exhibited significantly higher (2.3-fold) uptake into M2 MPs, relative to resting and M1 MPs. The 10% MRTL-NPs displayed greater uptake by M2 MPs when compared to resting and M1 MPs, but less uptake than 1% MRTL-NPs into M2 MPs. Control FITC-labeled plain NPs did not exhibit selective MP uptake. These studies demonstrate that M2 MPs are selectively targeted by NPs displaying a novel bivalent ligand that utilizes the MR as a target/portal for cell entry. This study also establishes the feasibility of the approach allowing for further investigation in vivo.

Ultrasmall Core-Shell Silica Nanoparticles for Precision Drug Delivery in a High-Grade Malignant Brain Tumor Model.

PURPOSE: Small-molecule inhibitors have revolutionized treatment of certain genomically defined solid cancers. Despite breakthroughs in treating systemic disease, central nervous system (CNS) metastatic progression is common, and advancements in treating CNS malignancies remain sparse. By improving drug penetration across a variably permeable blood-brain barrier and diffusion across intratumoral compartments, more uniform delivery and distribution can be achieved to enhance efficacy. EXPERIMENTAL DESIGN: Ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots), were functionalized with αv integrin-binding (cRGD), or nontargeting (cRAD) peptides, and PET labels (124I, 89Zr) to investigate the utility of dual-modality cRGD-C' dots for enhancing accumulation, distribution, and retention (ADR) in a genetically engineered mouse model of glioblastoma (mGBM). mGBMs were systemically treated with 124I-cRGD- or 124I-cRAD-C' dots and sacrificed at 3 and 96 hours, with concurrent intravital injections of FITC-dextran for mapping blood-brain barrier breakdown and the nuclear stain Hoechst. We further assessed target inhibition and ADR following attachment of dasatinib, creating nanoparticle-drug conjugates (Das-NDCs). Imaging findings were confirmed with ex vivo autoradiography, fluorescence microscopy, and p-S6RP IHC. RESULTS: Improvements in brain tumor delivery and penetration, as well as enhancement in the ADR, were observed following administration of integrin-targeted C' dots, as compared with a nontargeted control. Furthermore, attachment of the small-molecule inhibitor, dasatinib, led to its successful drug delivery throughout mGBM, demonstrated by downstream pathway inhibition. CONCLUSIONS: These results demonstrate that highly engineered C' dots are promising drug delivery vehicles capable of navigating the complex physiologic barriers observed in a clinically relevant brain tumor model.

Molecular phenotyping and image-guided surgical treatment of melanoma using spectrally distinct ultrasmall core-shell silica nanoparticles.

Accurate detection and quantification of metastases in regional lymph nodes remain a vital prognostic predictor for cancer staging and clinical outcomes. As intratumoral heterogeneity poses a major hurdle to effective treatment planning, more reliable image-guided, cancer-targeted optical multiplexing tools are critically needed in the operative suite. For sentinel lymph node mapping indications, accurately interrogating distinct molecular signatures on cancer cells in vivo with differential levels of sensitivity and specificity remains largely unexplored. To address these challenges and demonstrate sensitivity to detecting micrometastases, we developed batches of spectrally distinct 6-nm near-infrared fluorescent core-shell silica nanoparticles, each batch surface-functionalized with different melanoma targeting ligands. Along with PET imaging, particles accurately detected and molecularly phenotyped cancerous nodes in a spontaneous melanoma miniswine model using image-guided multiplexing tools. Information afforded from these tools offers the potential to not only improve the accuracy of targeted disease removal and patient safety, but to transform surgical decision-making for oncological patients.

Inter-rater and Intra-rater Reliability of the Chinese Version of the Action Research Arm Test in People With Stroke.

Purpose: To detect the inter-rater and intra-rater reliability of the Chinese version of the Action Research Arm Test (C-ARAT) in patients recovering from a first stroke. Methods: Fifty-five participants (45 men and 10 women) with a mean age of 58.67 ± 12.45 (range: 22-80) years and a mean post-stroke interval of 6.47 ± 12.00 (0.5-80) months were enrolled in this study. To determine the inter-rater reliability, the C-ARAT was administered to each participant by two raters (A and B) with varying levels of experience within 1 day. To determine intra-rater reliability, rater A re-administered the C-ARAT to 33 of the 55 participants on the second day. Intra-class correlation coefficients (ICCs) and Bland-Altman plots were used to analyse the inter-rater and intra-rater reliability. Results: Regarding inter-rater reliability, the total, grasping, gripping, pinching, and gross movement scores received respective ICCs of 0.998, 0.997, 0.995, 0.997, and 0.960 (all p < 0.001), indicating excellent inter-rater reliability in stroke patients. Regarding intra-rater reliability, the corresponding ICCs were 0.987, 0.980, 0.975, 0.944, and 0.954 (all p < 0.001), again indicating excellent intra-rater reliability. The Bland-Altman plots yielded a mean difference of 0.15 with 95% limits of agreement (95%LOA) ranging from -2.16 to 2.46 for the inter-rater measurements and a mean difference of -1.06 with 95%LOA ranging from -6.43 to 4.31 for the intra-rater measurement. The C-ARAT thus appeared to be a stable scoring method. Conclusions: The C-ARAT yielded excellent intra-rater and inter-rater reliability for evaluating the paretic upper extremities of stroke patients. Therefore, our results supported the use of the C-ARAT in this population.