Clinical study on low-frequency repetitive transcranial magnetic stimulation for the treatment of walking dysfunction following stroke through three-dimensional gait analysis.

BACKGROUND: The recovery of walking capacity is of great significance in stroke rehabilitation. We evaluated changes in post-stroke gait function after low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) treatment. METHODS: Stroke patients were randomly assigned to control (conventional treatment)/LF-rTMS (LF-rTMS treatment based on conventional treatment) groups. Gait spatiotemporal parameters/affected side joint motion angle/affected side dynamic parameters were analyzed by 3D gait analyses. Motor evoked potential (MEP)/central motor conduction time (CMCT) changes were detected. Correlations between MEP latency/CMCT and gait parameters after LF-rTMS were analyzed by Pearson analysis. RESULTS: The two groups exhibited boosted stride speed/frequency/length, affected side stride length/swing phase percentage/hip/knee/ankle joint plantar flexion angle, and affected side ahead ground reaction force/ upward ground reaction force (AGRF/UGRF)/ankle joint plantar flexion moment, along with reduced affected side gait period/stance phase percentage after treatment, and the LF-rTMS group manifested better efficacy. MEP latency/CMCT of stroke patients treated with LF-rTMS was adversely linked to stride speed, affected side stride length/swing phase percentage/knee flexion angle, AGRF and UGRF, and positively correlated with affected side stance phase percentage. CONCLUSION: LF-rTMS significantly improved gait spatiotemporal parameters/affected joint motion angles/neurophysiologic parameters (MEP latency/CMCT) in patients with post-stroke walking dysfunction. MEP latency/CMCT after LF-rTMS treatment were prominently correlated with gait parameters. Relative to the traditional scale assessment, we provided a more accurate, objective and reliable evaluation of the effects of LF-rTMS on lower limb mobility and functional recovery effects in stroke patients from the perspective of 3D gait analysis and neurophysiology, which provided more evidence to support the clinical application of LF-rTMS in post-stroke walking dysfunction treatment.

Bimetal-bridging Nitrogen Coordination in Carbon-based Electrocatalysts for pH-universal Oxygen Reduction.

Electrocatalysts with atomically dispersed metal sites (e.g., metal-nitrogen-carbon) have been deemed as promising alternatives for noble-metal catalysts in couples of electrocatalytic reactions. However, the modulation of such atomic sites and the understanding of their interactions are still highly challenging. Herein, we propose a unique supermolecule assembly-profile coating strategy to prepare a series of diatomic electrocatalysts by profile coating of eight Prussian blue analogues (PBAs) on supramolecular supports respectively as bimetallic sources. The detailed microstructure analysis revealed that the metal-nitrogen-carbon sites with four- (Zn-N4 ) and five-coordination (Fe-N5 ) via the nitrogen coordination are similar to the cytochrome c oxidases. For promising electrocatalysis, such unique microstructure is able to activate oxygen molecules due to nitrogen-bonding coordination with bimetal sites, thus leading to efficient four-electron oxygen reduction in alkaline, neutral, and acid electrolytes. Especially, zinc group elements (e.g., Zn and Cd) with d10 electron configuration would significantly boost the nitrogen-bonding coordination with bimetal sites to enhance electrocatalytic activity. The proof-of-concept for the general synthesis of advanced electrocatalysts with controllable bimetal active sites and the mechanistic understanding will promote the promising electrocatalysis by applying the similar principles.

Intermittent theta burst stimulation combined with cognitive training improves cognitive dysfunction and physical dysfunction in patients with post-stroke cognitive impairment.

OBJECTIVE: Post-stroke cognitive impairment (PSCI) is a common complication of stroke. Intermittent theta burst stimulation (iTBS) can inducing motor learning. We observed the effects of combination of iTBS with cognitive training on physical/cognitive dysfunctions in PSCI patients. METHODS: PSCI patients treated with basic treatment & cognitive training (Control group)/iTBS & cognitive training (iTBS group) were enrolled, with Mini-mental State Examination (MMSE)/Montreal Cognitive Assessment (MoCA)/Frontal Assessment Battery (FAB)/barthel index (BI)/Upper Limb Fugl-Meyer Assessment (U-FMA)/Action Research Arm Test (ARAT) scores compared. Gait spatiotemporal parameters/dynamic parameters were analyzed by 3D gait analysis. Correlations between MMSE/MoCA scores and gait parameters in PSCI patients after iTBS & cognitive training were analyzed by Spearman analysis. RESULTS: Increased MMSE/MoCA/FAB/BI/U-FMA/ARAT scores, step speed, step frequency, stride length, step width, step length on the affected side, percentage of swing phase on the affected side, hip joint flexion angle on the affected side, knee joint flexion angle on the affected side, and ankle plantar flexion angle on the affected side and reduced gait period on the affected side and percentage of stance phase on the affected side were found in patients of both groups after treatment, with the effects in the iTBS group more profound. CONCLUSION: iTBS & cognitive training obviously improved the cognitive function scores/upper limb function scores/gait parameters in PSCI patients versus cognitive training treatment. After combination therapy, the MMSE/MoCA scores of PSCI patients were significantly correlated with gait parameters. This provided more data support for iTBS & cognitive training application in the rehabilitation treatment of PSCI patients.

Three-Dimensional Gait Analysis and sEMG Measures for Robotic-Assisted Gait Training in Subacute Stroke: A Randomized Controlled Trial.

Background: The efficacy of robotic-assisted gait training (RAGT) should be considered versatilely; among which, gait assessment is one of the most important measures; observational gait assessment is the most commonly used method in clinical practice, but it has certain limitations due to the deviation of subjectivity; instrumental assessments such as three-dimensional gait analysis (3DGA) and surface electromyography (sEMG) can be used to obtain gait data and muscle activation during walking in stroke patients with hemiplegia, so as to better evaluate the rehabilitation effect of RAGT. Objective: This single-blind randomized controlled trial is aimed at analyzing the impact of RAGT on the 3DGA parameters and muscle activation in patients with subacute stroke and evaluating the clinical effect of improving walking function of RAGT. Methods: This randomized controlled trial evaluated the improvement of 4-week RAGT on patients with subacute stroke by 3DGA and surface electromyography (sEMG), combined with clinical scales: experimental group (n = 18, 20 sessions of RAGT) or control group (n = 16, 20 sessions of conventional gait training). Gait performance was evaluated by the 3DGA, and clinical evaluations based on Fugl-Meyer assessment for lower extremity (FMA-LE), functional ambulation category (FAC), and 6-minute walk test (6MWT) were used. Of these patients, 30 patients underwent sEMG measurement synchronized with 3DGA; the cocontraction index in swing phase of the knee and ankle of the affected side was calculated. Results: After 4 weeks of intervention, intragroup comparison showed that walking speed, temporal symmetry, bilateral stride length, range of motion (ROM) of the bilateral hip, flexion angle of the affected knee, ROM of the affected ankle, FMA-LE, FAC, and 6MWT in the experimental group were significantly improved (p < 0.05), and in the control group, significant improvements were observed in walking speed, temporal symmetry, stride length of the affected side, ROM of the affected hip, FMA-LE, FAC, and 6MWT (p < 0.05). Intergroup comparison showed that the experimental group significantly outperformed the control group in walking speed, temporal symmetry of the spatiotemporal parameters, ROM of the affected hip and peak flexion of the knee in the kinematic parameters, and the FMA-LE and FAC in the clinical scale (p < 0.05). In patients evaluated by sEMG, the experimental group showed a noticeable improvement in the cocontraction index of the knee (p = 0.042), while no significant improvement was observed in the control group (p = 0.196), and the experimental group was better than the control group (p = 0.020). No noticeable changes were observed in the cocontraction index of the ankle in both groups (p > 0.05). Conclusions: Compared with conventional gait training, RAGT successfully improved part of the spatiotemporal parameters of patients and optimized the motion of the affected lower limb joints and muscle activation patterns during walking, which is crucial for further rehabilitation of walking ability in patients with subacute stroke. This trial is registered with ChiCTR2200066402.

Fe-Ni Alloy Nanoclusters Anchored on Carbon Aerogels as High-Efficiency Oxygen Electrocatalysts in Rechargeable Zn-Air Batteries.

In this work, Fe-Ni alloy nanoclusters (Fe-Ni ANCs) anchored on N, S co-doped carbon aerogel (Fe-Ni ANC@NSCA catalysts) are successfully prepared by the optimal pyrolysis of polyaniline (PANI) aerogels derived from the freeze-drying of PANI hydrogel obtained by the polymerization of aniline monomers in the co-presence of tannic acid (TA), Fe3+ , and Ni2+ ions. In addition, the optimal molar ratio of the TA, Fe3+ , and Ni2+ ions for synthesis of Fe-Ni ANC@NSCA catalysts are 1:2:5, which can guarantee the formation of carbon aerogel composed of quasi-2D porous carbon sheets and the formation of high-density Fe-Ni ANCs with an ultrasmall size between 2 to 2.8 nm. These Fe-Ni ANCs consisting of N4 -Fe-O-Ni-N4 moiety are proposed as a new type of active species for the first time, to the best of the authors' knowledge. Thanks to their unique features, the Fe-Ni ANC@NSCA catalysts show excellent performance in oxygen reduction reaction with a half-wave potential (E1/2 ) of 0.891 V and oxygen evolution reaction (260 mV @ 10 mA cm-2 ) in alkaline media as bifunctional catalysts, which are better than the state-of-the-art commercial Pt/C catalysts and RuO2 catalysts. Moreover, Zn-air battery assembled with the Fe-Ni ANC@NSCA catalysts also shows a remarkable performance and exceptionally high stability over 500 h at 5 mA cm-2 .

Toward Flexible Zinc-Air Batteries with Self-Supported Air Electrodes.

The compelling demand for higher energy performance, flexibility, and miniaturization is the main driving force of the energy storage and conversion industry's quest for flexible devices based on new integration and fabrication process. Herein, the recent advances on the development of flexible zinc-air batteries based on self-supported air electrodes are summarized, focusing on the multiscale and systematic design principles for the design of flexible air electrodes. With the electrocatalytic activity regulation and structural engineering strategies, the rational design of self-supported air electrodes is discussed in integrated devices to underpin the good flexibility for wearable requirement. The perspectives on promising developments of flexible zinc-air batteries and the accumulated knowledge from other flexible devices are also addressed for promoting the advances on flexible zinc-air batteries.

Time-varying feature selection for longitudinal analysis.

We propose time-varying coefficient model selection and estimation based on the spline approach, which is capable of capturing time-dependent covariate effects. The new penalty function utilizes local-region information for varying-coefficient estimation, in contrast to the traditional model selection approach focusing on the entire region. The proposed method is extremely useful when the signals associated with relevant predictors are time-dependent, and detecting relevant covariate effects in the local region is more scientifically relevant than those of the entire region. Our simulation studies indicate that the proposed model selection incorporating local features outperforms the global feature model selection approaches. The proposed method is also illustrated through a longitudinal growth and health study from National Heart, Lung, and Blood Institute.

Pembrolizumab Plus Pegylated Interferon alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib KEYNOTE-029 Study.

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC.Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review.Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 µg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 µg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC.Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805-15. ©2018 AACR.

Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial.

BACKGROUND: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab. METHODS: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity. FINDINGS: Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8-18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93). INTERPRETATION: Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway. FUNDING: Merck & Co, Inc.

Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study.

Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm, phase II KEYNOTE-055 study, we evaluated pembrolizumab, an anti-programmed death 1 receptor antibody, in this platinum- and cetuximab-pretreated population with poor prognosis. Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment. Patients received pembrolizumab 200 mg every 3 weeks. Imaging was performed every 6 to 9 weeks. Primary end points: overall response rate (Response Evaluation Criteria in Solid Tumors v1.1, central review) and safety. Efficacy was assessed in all dosed patients and in subgroups on the basis of programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status. Results Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive, and 22% were HPV positive. At the time of analysis, 109 patients (64%) experienced a treatment-related adverse event; 26 patients (15%) experienced a grade ≥ 3 event. Seven patients (4%) discontinued treatment, and one died of treatment-related adverse events. Overall response rate was 16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 12+ months); 75% of responses were ongoing at the time of analysis. Response rates were similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1 months, and median overall survival was 8 months. Conclusion Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.