The Efficacy of Early Rehabilitation Combined with Virtual Reality Training in Patients with First-Time Acute Stroke: A Randomized Controlled Trial.

Early rehabilitation has beneficial impacts on functional outcomes for patients with acute stroke. However, whether the addition of virtual reality (VR) training could further improve these patients' muscle strength, functional recovery, and psychological health is unknown. A randomized controlled trial was conducted on 33 patients with first-time acute ischemic stroke. The patients were randomly assigned using a 1:1 randomization ratio to either the experimental group (EG) or the comparison group (CG). Both groups received early rehabilitation, and the EG received extra VR training during their stay in the hospital. Muscle strength, functional status, and psychological health were assessed before the intervention and at discharge. Generalized estimating equations were used to examine the intervention effects via the interaction of time and group. After adjusting for potential covariates, the EG showed a more significant decrease in depression at discharge than the CG (ß = 3.77, p = 0.011). There were no differences in muscle strength and functional recovery between groups after intervention. Adding VR training into early rehabilitation facilitates substantial positive effects on psychological health, specifically depression, but not muscle strength and functional recovery, compared to receiving early rehabilitation alone in patients with first-time acute stroke during their hospitalized period.

Determinants of moderate-to-high physical activity levels in hemodialysis patients: A multicenter cross-sectional study.

Moderate physical activity is related to reduced mortality in hemodialysis patients. However, most hemodialysis patients have low physical activity levels for complex reasons. This study investigated the determinants of moderate-to-high physical activity levels and whether psychosocial correlates are associated with engagement in moderate-to-high physical activity among hemodialysis patients. A cross-sectional survey was conducted with 134 hemodialysis outpatients, aged 64.7 years, in three hemodialysis centers in Taiwan. Data on sociodemographics, comorbidities, lifestyles, and psychosocial correlates, including perceived benefits, barriers, and self-efficacy of physical activity, were collected. Multiple logistic regression analyses were performed. Results showed that patients with moderate-to-high physical activity levels constituted a significantly lower proportion of current smokers and had fewer perceived physical activity barriers and higher self-efficacy of physical activity compared with those with low levels. After adjusting for potential sociodemographic covariates, current employment, nonsmoking status, and high self-efficacy of physical activity were significantly associated with moderate-to-high physical activity levels. Developing strategies to improve the self-efficacy of physical activity, support employment, and enhance anti-smoking campaigns in hemodialysis patients can help them engage in moderate-to-high levels of physical activity.

Inhibition of DNMTs increases neoantigen-reactive T-cell toxicity against microsatellite-stable colorectal cancer in combination with radiotherapy.

The therapeutic efficacy of immunotherapy is limited in the majority of colorectal cancer patients due to the low mutational and neoantigen burdens in this immunogenically "cold" microsatellite stability-colorectal cancer (MSS-CRC) cohort. Here, we showed that DNA methyltransferase (DNMT) inhibition upregulated neoantigen-bearing gene expression in MSS-CRC, resulting in increased neoantigen presentation by MHC class I in tumor cells and leading to increased neoantigen-specific T-cell activation in combination with radiotherapy. The cytotoxicity of neoantigen-reactive T cells (NRTs) to DNMTi-treated cancer cells was highly cytotoxic, and these cells secreted high IFNγ levels targeting MSS-CRC cells after ex vivo expansion of NRTs with DNMTi-treated tumor antigens. Moreover, the therapeutic efficacy of NRTs further increased when NRTs were combined with radiotherapy in vivo. Administration of DNMTi-augmented NRTs and radiotherapy achieved an ∼50 % complete response and extended survival time in an immunocompetent MSS-CRC animal model. Moreover, remarkably, splenocytes from these mice exhibited neoantigen-specific T-cell responses, indicating that radiotherapy in combination with DNMTi-augmented NRTs prolonged and increased neoantigen-specific T-cell toxicity in MSS-CRC patients. In addition, these DNMTi-augmented NRTs markedly increase the therapeutic efficacy of cancer vaccines and immune checkpoint inhibitors (ICIs). These data suggest that a combination of radiotherapy and epi-immunotherapeutic agents improves the function of ex vivo-expanded neoantigen-reactive T cells and increases the tumor-specific cytotoxic effector population to enhance therapeutic efficacy in MSS-CRC.

Effectiveness of a 12-week telerehabilitation training in people with long COVID: A randomized controlled trial.

BACKGROUND: Telerehabilitation has been developed and applied for years for cardiac and pulmonary diseases with good clinical outcomes. However, its application to participants with long COVID remains limited. OBJECTIVES: To investigate the effectiveness of a 12-week telerehabilitation training program in participants with long COVID. The primary outcome was cardiorespiratory fitness (CRF), and secondary outcomes were physical activity (PA) amounts, exercise self-efficacy, sleep quality, and health-related quality of life (HRQOL). METHODS: A parallel-group, randomized controlled trial was conducted. Eligible participants with long COVID (n = 182) were randomly assigned in a 1:1 ratio to either the experimental group (EG) or the control group (CG). The EG received 12 weeks of telerehabilitation training with weekly remote monitoring for exercise maintenance and support. The CG received PA counseling only. CRF, PA amounts, exercise self-efficacy, sleep quality, and HRQOL were assessed at baseline and 12 weeks. Generalized estimating equations were used to analyze the intervention effects by examining the interaction between time and group. RESULTS: One hundred twenty-two participants (67 %) completed the study, and 182 were included in the intention-to-treat analysis. The EG had greater walking behavior (ß = -763.3, p < 0.001), total amount of PA (ß= -711, p = 0.003), exercise self-efficacy (ß = -1.19, p < 0.001), and better sleep quality (ß = 1.69, p = 0.012) after the 12-weeks of telerehabilitation training than the CG. However, there were no significant differences in any CRF parameters or HRQOL at 12 weeks between the EG and CG. CONCLUSION: Telerehabilitation training offers a personalized and convenient approach that can increase exercise willingness and PA amounts and improve sleep quality. These findings underscore the potential benefits of telerehabilitation training for promoting healthier lifestyles and improving overall health outcomes. CLINICAL TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (NCT05205460) on January 25, 2022.

Association Between Physical Activity Amount and Cardiorespiratory Fitness, Sleep Quality, and Health-Related Quality of Life in Patients With Long COVID: A Cross-sectional Study.

OBJECTIVE: To investigate the association between physical activity (PA) amount and gender differences on cardiorespiratory fitness (CRF), sleep quality, and health-related quality of life (HRQoL) in individuals with long COVID. DESIGN: Cross-sectional study. SETTING: An integrated outpatient clinic for post-COVID-19 at a medical center. PARTICIPANTS: Convenience sample of patients (N=264) diagnosed with long COVID. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: PA amounts, sleep quality, and HRQoL were measured by the International Physical Activity Questionnaire, Pittsburgh Sleep Quality Index, and the World Health Organization Questionnaire on Quality of Life: Short Form, respectively. CRF was evaluated through graded exercise testing. RESULTS: The participants had a mean age of 42.5±13.5 years and a mean duration of post-COVID-19 symptoms of 12.7±6.8 weeks. More than half (n=149, 56.5%) were female patients. Female participants had significantly lower CRF than male participants (P<.05). Older age and higher body mass index were associated with worse CRF and HRQoL (P<.05). Less sitting behavior and greater amounts of vigorous-intensity PA (VPA) or total PA were associated with better CRF (P<.05). In addition, greater total PA and moderate-intensity PA (MPA) were associated with better sleep quality and HRQoL (P<.05), respectively. CONCLUSIONS: Gender differences were found in CRF among patients with long COVID. Greater self-reported VPA or total PA was associated with better CRF, whereas greater total PA and MPA were associated with better sleep quality and HRQoL, respectively, in patients with long COVID. Further research is needed to explore these associations in longitudinal studies.

Neoantigen-augmented iPSC cancer vaccine combined with radiotherapy promotes antitumor immunity in poorly immunogenic cancers.

Although irradiated induced-pluripotent stem cells (iPSCs) as a prophylactic cancer vaccine elicit an antitumor immune response, the therapeutic efficacy of iPSC-based cancer vaccines is not promising due to their insufficient antigenicity and the immunosuppressive tumor microenvironment. Here, we found that neoantigen-engineered iPSC cancer vaccines can trigger neoantigen-specific T cell responses to eradicate cancer cells and increase the therapeutic efficacy of RT in poorly immunogenic colorectal cancer (CRC) and triple-negative breast cancer (TNBC). We generated neoantigen-augmented iPSCs (NA-iPSCs) by engineering AAV2 vector carrying murine neoantigens and evaluated their therapeutic efficacy in combination with radiotherapy. After administration of NA-iPSC cancer vaccine and radiotherapy, we found that ~60% of tumor-bearing mice achieved a complete response in microsatellite-stable CRC model. Furthermore, splenocytes from mice treated with NA-iPSC plus RT produced high levels of IFNγ secretion in response to neoantigens and had a greater cytotoxicity to cancer cells, suggesting that the NA-iPSC vaccine combined with radiotherapy elicited a superior neoantigen-specific T-cell response to eradicate cancer cells. The superior therapeutic efficacy of NA-iPSCs engineered by mouse TNBC neoantigens was also observed in the syngeneic immunocompetent TNBC mouse model. We found that the risk of spontaneous lung and liver metastasis was dramatically decreased by NA-iPSCs plus RT in the TNBC animal model. Altogether, these results indicated that autologous iPSC cancer vaccines engineered by neoantigens can elicit a high neoantigen-specific T-cell response, promote tumor regression, and reduce the risk of distant metastasis in combination with local radiotherapy.

Volume Effect of Nerve Hydrodissection for Carpal Tunnel Syndrome: A Prospective, Randomized, and Single-Blind Study.

OBJECTIVES: This study compared ultrasound-guided nerve hydrodissection (HD) outcomes using two commonly used injectate volumes (10 and 5 mL) of normal saline to explore if there is a volume effect of HD for patients with moderate carpal tunnel syndrome (CTS). METHODS: Twenty-four participants were randomly assigned to treatment with HD using ultrasound-guidance and either 10 mL or 5 mL of normal saline (HD-10 and HD-5 groups respectively). Our primary outcome measures were the change scores of the two subscales of the Boston Carpal Tunnel Syndrome Questionnaire: The Symptom Severity Scale (SSS) and Functional Status Scale (FSS). We conducted a one-way repeated analysis of variance for 3 time points (4, 12, and 24 weeks) for both SSS and FSS, respectively, for change scores from time 0, and percentage change from time 0. RESULTS: All participants (n = 12 per group) completed the study. From 0 to 24 weeks the HD-10 group outperformed the HD-5 group for improvement in SSS (median ± IQR; -0.8 ± 0.4 versus -0.5 ± 0.5; P = .024) and FSS scores (mean ± SD; -0.8 ± 0.2 versus -0.5 ± 0.5; P = .011). The HD-10 group improvement in FSS subtest significantly exceeded the MCID percentage-change-based threshold of 27% (34%; P = .039). CONCLUSIONS: Despite the limitations of small study size, a largely inert injectate, and a single injection approach, these findings in favor of the 10 mL group suggest that the volume used for ultrasound-guided HD in moderate CTS matters, and a higher volume is more effective.

Dysfunctional TLR1 reduces the therapeutic efficacy of chemotherapy by attenuating HMGB1-mediated antitumor immunity in locally advanced colorectal cancer.

Regional lymph node metastasis is an important predictor for survival outcome and an indicator for postoperative adjuvant chemotherapy in patients with colorectal cancer. Even with advances in adjuvant chemotherapeutic regimens, 5-year distant metastasis and survival rates are still unsatisfactory. Here, we evaluate the clinical significance of polymorphisms in receptors for HMGB1, which is the hallmark of chemotherapy-induced immunogenic cell death, in patients with stage II-III colon carcinoma (COAD). We found that high cytosolic HMGB1 is elicited in stage III COAD patients who received adjuvant chemotherapy. Patients with the TLR1-N248S polymorphism (rs4833095), which causes loss-of-function in HMGB1-mediated TLR1-TLR2 signaling, may influence the therapeutic efficacy of adjuvant chemotherapy, leading to a high risk of distant metastasis within 5 years [HR = 1.694, 95% CI = 1.063-2.698, p = 0.027], suggesting that TLR1-N248S is an independent prognostic factor for locally advanced colon carcinoma patients. We found that defective TLR1 impaired TLR1/2 signaling during dendritic cell (DC) maturation for the antitumor immune response under immunogenic chemotherapy oxaliplatin (OXP) treatment. Defective TLR1 on DCs impaired their maturation ability by HMGB1 and reduced the secretion of IFNγ from T cells to eradicate tumor cells in vitro. Moreover, systemic inhibition of TLR1/2 dramatically reduced the tumor-infiltrating immune cells by OXP treatment, leading to poor therapeutic response to OXP. In contrast, administration of a TLR1/2 agonist synergistically increased the benefit of OXP treatment and triggered a high density of tumor-infiltrating immune cells. We also observed that fewer tumor-infiltrating cytotoxic T lymphocytes were located within the tumor microenvironment in patients bearing the TLR1-N248S polymorphism. Overall, our results suggest that dysfunctional TLR1 may reduce the therapeutic response to adjuvant chemotherapy by impairing HMGB1-mediated DC maturation and attenuating the antitumor immune response in locally advanced colon carcinoma patients.

A Novel Engineered AAV-Based Neoantigen Vaccine in Combination with Radiotherapy Eradicates Tumors.

The potency of tumor-specific antigen (TSA) vaccines, such as neoantigen (neoAg)-based cancer vaccines, can be compromised by host immune checkpoint inhibitory mechanisms, such as programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1), that attenuate neoAg presentation on dendritic cells (DC) and hinder T cell-mediated cytotoxicity. To overcome PD-1/PD-L1 inhibition in DCs, we developed a novel adeno-associated virus (meAAV) neoAg vaccine, modified with TLR9 inhibitory fragments, PD-1 trap, and PD-L1 miRNA, which extend the persistence of meAAV and activate neoAg-specific T-cell responses in immune-competent colorectal and breast cancer murine models. Moreover, we found that in combination with radiotherapy, the meAAV-based neoAg cancer vaccine not only elicited higher antigen presentation ability, but also maintained neoAg-specific cytotoxic T lymphocyte (CTL) responses. These functional PD-1 traps and PD-L1 miRNAs overcome host PD-1/PD-L1 inhibitory mechanisms and boost the therapeutic efficacy of radiotherapy. More importantly, combined radiotherapy and meAAV neoAg cancer vaccines significantly enhanced neoAg-specific CTL responses, increased CTL infiltration in tumor microenvironment, and decreased tumor-associated immunosuppression. This process led to the complete elimination of colorectal cancer and delayed tumor growth of breast cancer in tumor-bearing mice. Taken together, our results demonstrated a novel strategy that combines neoAg cancer vaccine and radiotherapy to increase the therapeutic efficacy against colorectal and breast cancers.

Novel Motor-Sparing Ultrasound-Guided Neural Injection in Severe Carpal Tunnel Syndrome: A Comparison of Four Injectates.

Nerve hydrodissection uses fluid injection under pressure to selectively separate nerves from areas of suspected entrapment; this procedure is increasingly viewed as potentially useful in treating carpal tunnel syndrome (CTS). The usage of normal saline (NS), 5% dextrose water (D5W), platelet-rich plasma (PRP), and hyaluronic acid (HA) as primary injectates for hydrodissection without an anesthetic can limit anesthetic-related toxicity and preserve the motor functions of the median nerve. Here, we describe a novel motor-sparing neural injection and compare the effect of these four injectates for severe CTS. We retrospectively reviewed the outcomes of 61 severe CTS cases after a single neural injection with NS, D5W, PRP, or HA. Outcomes were evaluated on the 1st and 6th months postinjection, including the Boston Carpal Tunnel Questionnaire (BCTQ) scores and the nerve cross-sectional area (CSA). The results revealed that PRP, D5W, and HA were more efficient than NS at all measured time points (p < 0.05), except for CSA at the 1st month between the NS and D5W groups. Single-injections of PRP and D5W seemed more effective than that of HA within 6 months postinjection for symptom and functional improvement (6th-month BCTQ-symptom, D5W vs. HA, p = 0.047; 1st-month BCTQ-symptom, PRP vs. HA, p = 0.018; 1st- and 6th-month BCTQ-function, D5W vs. HA, p = 0.002 and 0.016, respectively; 1st-month BCTQ-function, PRP vs. HA, p < 0.001). For reducing CSA, PRP and HA seemed more effective than D5W (HA > PRP > D5W on the 1st month and HA vs. D5W, p = 0.001; PRP > HA > D5W on the 6th month and PRP vs. D5W, p = 0.012).

The Long-Term Analgesic Effectiveness of Platelet-Rich Plasma Injection for Carpal Tunnel Syndrome: A Cross-Sectional Cohort Study.

OBJECTIVE: Interest in perineural platelet-rich-plasma (PRP) injections for the treatment of carpal tunnel syndrome (CTS) has increased in recent years. However, evidence supporting the long-term effectiveness of PRP is lacking. Therefore, the aim of our cross-sectional cohort study was to investigate the long-term results of PRP injections for CTS. METHODS: Eighty-one patients diagnosed with CTS of any grade who received a single PRP injection at least 2 years prior were enrolled. Through structured telephone interviews, all patients were asked of their post-injection outcomes compared to their pre-injection condition. Symptom relief ≥50%, compared to the pre-injection condition, was considered an effective outcome. Binary logistic regression was applied to analyze each baseline variable as a regressor for determining the prognostic outcome factors. RESULTS: In total, 70% of patients reported positive outcomes ≥2 years post-injection. Shorter duration of symptoms before treatment (odds ratio: 0.991; 95% confidence interval [CI] 0.983-0.999; P = .023) and lower electrodiagnostic severity of CTS were the main prognostic factors for an effective outcome (mild grade vs severe grade, odds ratio: 17.652; 95% CI 1.43-221.1; P = .025). Although there was a trend toward positive outcomes at longer follow-up durations (2-3 years vs 3-4 years vs 4-5 years), the difference was not statistically significant. CONCLUSIONS: A single perineural PRP injection has a long-term analgesic effect on CTS, especially in mild-to-moderate cases.