The effect of early initiation of gait training using hybrid assistive limb (HAL) remains unclear. This observational study aimed to investigate whether early initiation of gait training using HAL ...improves functional outcomes in patients with stroke.
We retrospectively analyzed patients with acute stroke admitted to our facility. HAL was used for exoskeletal robotic gait training. Study participants were median split into an early group and a late group based on the days from stroke onset to initiation of gait training using HAL. The functional outcomes, defined by the Brunnstrom recovery stage (BRS), modified Rankin Scale (mRS), and Functional Independence Measure (FIM) at discharge, were compared using propensity score-matched analysis.
We performed a propensity score-matched analysis in 63 patients with stroke (31 from the early group and 32 from the late group), and 17 pairs were matched. There were no significant differences in discharge in the BRS of the upper limb and finger in the post-matched cohort. On the other hand, the BRS of the lower limb in the early group was significantly higher than that in the late group. In addition, the mRS, but not FIM scores, was significantly better in the early group than that in the late group.
In conclusion, early initiation of gait training using HAL might improve the motor function of the paralyzed lower limb and disability in patients with stroke.
Instruction set randomization (ISR) is a cost-effective obfuscation technique that modifies or enhances the relationship between instructions and machine languages. An Instruction Register File ...(IRF), a list of frequently used instructions, can be used for ISR by providing the way of indirect access to them. This study examines the IRF that integrates a positional register, which was proposed as a supplementary unit of the IRF, for the sake of tamper resistance. According to our evaluation, with a new design for the contents of the positional register, the measure of tamper resistance was increased by 8.2% at a maximum, which corresponds to a 32.2% increase in the size of the IRF. The number of logic elements increased by the addition of the positional register was 3.5% of its baseline processor.
The number of studies on the characteristics of patients with stroke who would benefit from robot-assisted upper limb rehabilitation is limited, and there are no clear criteria for determining which ...individuals should receive such treatment. The current study aimed to develop a clinical prediction rule using machine learning to identify the characteristics of patients with stroke who can the achieve minimal clinically important difference of the Fugl-Meyer Upper Extremity Evaluation (FMA-UE) after single-joint hybrid assistive limb (HAL-SJ) rehabilitation.
This study included 71 patients with subacute stroke who received HAL-SJ rehabilitation. The chi-square automatic interaction detector (CHAID) model was applied to predict improvement in upper limb motor function. Based the analysis using CHAID, age, sex, days from stroke onset to the initiation of HAL-SJ rehabilitation, and upper limb motor and cognitive functions were used as independent variables. Improvement in upper limb motor function was determined based on the minimal clinically important difference of the FMA-UE, which was used as a dependent variable.
According to the CHAID model, the FMA-UE score during the initiation of HAL-SJ rehabilitation was the most significant predictive factor for patients who are likely to respond to the intervention. Interestingly, this therapy was more effective in patients with moderate upper limb motor dysfunction and early initiation of HAL-SJ rehabilitation. The accuracy of the CHAID model was 0.89 (95% confidence interval: 0.81–0.96).
We developed a clinical prediction rule for identifying the characteristics of patients with stroke whose upper limb motor function can improve with HAL-SJ rehabilitation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose:
Fragility hip fractures (FHFs) are associated with a high risk of mortality, but the relative contribution of various factors remains controversial. This study aimed to evaluate predictive ...factors of mortality at 1 year after discharge in Japan.
Methods:
A total of 497 patients aged 60 years or older who sustained FHFs during follow-up were included in this study. Expected variables were finally assessed using multivariable Cox proportional hazards models.
Results:
The 1-year mortality rate was 9.1% (95% confidence interval: 6.8–12.0%, n = 45). Log-rank test revealed that previous fractures (p = 0.003), Barthel index (BI) at discharge (p = 0.011), and place-to-discharge (p = 0.004) were significantly associated with mortality for male patients. Meanwhile, body mass index (BMI; p = 0.023), total Charlson comorbidity index (TCCI; p = 0.005), smoking (p = 0.007), length of hospital stay (LOS; p = 0.009), and BI (p = 0.004) were the counterparts for females. By multivariate analyses, previous vertebral fractures (hazard ratio (HR) 3.33; p = 0.044), and BI <30 (HR 5.42, p = 0.013) were the predictive variables of mortality for male patients. BMI <18.5 kg/m2 (HR 2.70, p = 0.023), TCCI ≥5 (HR 2.61, p = 0.032), smoking history (HR 3.59, p = 0.018), LOS <14 days (HR 13.9; p = 0.007), and BI <30 (HR 2.76; p = 0.049) were the counterparts for females.
Conclusions:
Previous vertebral fractures and BI <30 were the predictive variables of mortality for male patients, and BMI <18.5 kg/m2, TCCI ≥5, smoking history, LOS <14 days, and BI <30 were those for females. Decreased BI is one of the independent and preventable risk factors. A comprehensive therapeutic approach should be considered to prevent deterioration of activities of daily living and a higher risk of mortality.
Background
We attempted to determine the preferences of women regarding the benefits they considered necessary to make adjuvant therapy worthwhile, and to compare preferences for adjuvant endocrine ...therapy, chemotherapy, and trastuzumab therapy. We also investigated the effect of information about cost on women’s treatment preferences.
Patients and methods
Consecutive women who had a medical examination at the Breast Clinic, Ota General Hospital, were included in our study. We collected a questionnaire from a total of 365 women; 297 completed responses were included in the study.
Results
Among 297 women, 105 had breast cancer that had been treated and 192 did not have breast cancer; 38% of women judged that a 5% or less gain in the probability of survival was sufficient to make endocrine therapy worthwhile; 28% of participants judged that chemotherapy was worthwhile; 24% of participants judged that trastuzumab therapy was worthwhile. Women indicated that they were more likely to receive adjuvant endocrine therapy than chemotherapy or trastuzumab therapy, for the same gains in the probability of survival. Cost information about treatments did not affect women’s treatment preferences. Younger women tended to judge improvements in survival sufficient to make adjuvant endocrine and chemotherapy worthwhile, as compared to older women. The comparisons were statistically significant in the 10 and 20% categories for endocrine therapy and chemotherapy.
Conclusion
Women prefer endocrine therapy to chemotherapy or trastuzumab therapy, given the same projected treatment benefits. Younger women prefer both chemotherapy and endocrine therapy as compared with older woman.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Intratumor bacteria modify the tumor immune microenvironment and influence outcomes of various tumors. Periodontal pathogen Fusobacterium nucleatum has been detected in pancreatic cancer tissues and ...is associated with poor prognosis. However, it remains unclear how F. nucleatum affects pancreatic cancer. Here, we compared clinical features with F. nucleatum colonization in pancreatic cancer tissues. F. nucleatum was detected in 15.5% (13/84) of pancreatic cancer patients. The tumor size was significantly larger in the F. nucleatum‐positive group than in the negative group. To clarify the biological effect of intratumor F. nucleatum on pancreatic cancer progression, we performed migration/invasion assays and cytokine array analysis of cancer cells cocultured with F. nucleatum. F. nucleatum promoted CXCL1 secretion from pancreatic cancer cells, leading to cancer progression through autocrine signaling. Intratumor F. nucleatum suppressed tumor‐infiltrating CD8+ T cells by recruiting myeloid‐derived suppressor cells (MDSCs) to the tumor in an F. nucleatum‐injected subcutaneous pancreatic cancer mouse model, resulting in tumor progression. Furthermore, tumor growth accelerated by F. nucleatum was suppressed by MDSC depletion or cytokine inhibitors. Intratumor F. nucleatum promoted pancreatic cancer progression through autocrine and paracrine mechanisms of the CXCL1‐CXCR2 axis. Blockade of the CXCL1‐CXCR2 axis may be a novel therapeutic approach for patients with intratumor F. nucleatum‐positive pancreatic cancer.
Fusobacterium nucleatum, a periodontal pathogen, stimulated pancreatic cancer cells to secrete CXCL1, leading to cancer progression. In an autocrine manner, F. nucleatum promoted the migration of pancreatic cancer cells. In a paracrine manner, F. nucleatum suppressed CD8+ T cells by recruiting myeloid‐derived suppressor cells to the tumor.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
1504 Background: Trastuzumab deruxtecan (T-DXd) is a highly effective agent for HER2-positive metastatic breast cancer (MBC), but is associated with adverse events such as nausea, fatigue, and ...interstitial lung disease. Based on recent studies showing that symptom monitoring and alert notifications via ePROs could improve patient quality of life (QoL) and prognosis, we hypothesized that employing this method may diminish the treatment burden for patients receiving T-DXd. Methods: In this multicenter, randomized controlled exploratory study (jRCTs031200387), we randomized patients with HER2-positive MBC eligible for T-DXd to either the ePRO monitoring (ePROm) group or the usual care (UC) group. ePROm involved weekly symptom and daily body temperature/SpO 2 reports via a smartphone or computer at home. If any symptoms exceeded the predetermined thresholds, an email alert was sent to the medical staff, the ePRO was evaluated, and, if necessary, a phone consultation was provided. The primary endpoint was the change in the Global QoL score of EORTC QLQ-C30 from baseline at week 24. Secondary endpoints included score changes in the functional and symptom scales of EORTC QLQ-C30, and the time to deterioration of Global QoL (defined as a 10-point decrease from baseline). For a score difference between groups of 10 points and a standard deviation of 24, the required number of patients was 55 in each group, with a two-sided alpha error of 10% and a power of 87%. We analyzed the primary endpoint using a mixed-effects model for repeated measures. Results: Between March 2021 and January 2023, 111 patients were enrolled at 38 hospitals in Japan, with 56 assigned to ePROm and 55 to UC; the full-analysis set for QoL assessment included 54 and 52 patients, respectively. During the 24-week period, there were 1223 ePRO reports (95% compliance rate) in the ePROm group, including 427 alert notifications (7.9 per patient) to healthcare providers. Overall compliance with the questionnaire for QoL was 97%. Mean changes from baseline scores in Global QoL at week 24 showed that ePROm was significantly better than UC (mean difference 8.0 90% CI 0.2, 15.8; p=0.091). Role, cognitive, and social functioning were better in ePROm, with mean differences of 10.0 (95% CI 1.1, 18.9; p=0.028), 6.3 (1.1, 11.5; p=0.017), and 10.9 (3.9, 18.0; p=0.003), respectively. There was no difference in nausea/vomiting (0.5 - 6.2, 7.1; p=0.889), while fatigue was significantly better in ePROm (-8.4 -16.1, -0.6; p=0.034). Median time to first deterioration in Global QoL score was 3.9 months (95% CI 2.5, 13.9) in ePROm and 3.0 months (95% CI 1.6, 6.7) in UC (hazard ratio 0.73 95% CI 0.45, 1.17; p=0.159). Conclusions: ePROm systems, especially for symptom and SpO 2 tracking in HER2-positive MBC patients treated with T-DXd, are promising to enhance patient QoL. Clinical trial information: jRCTs031200387 .
Background
We have previously identified APP669‐711 (a.k.a. Aβ(‐3)‐40) in human plasma using immunoprecipitation combined with matrix‐assisted laser desorption ionization time‐of‐flight mass ...spectrometry (IP‐MALDI‐MS) (Kaneko et al., Proc Jpn Acad Ser B Phys Biol Sci. 2014). Our assay has revealed that the composite biomarker, which is a combination of APP669‐711/Aβ1‐42 ratio and Aβ1‐40/ Aβ1‐42 ratio in human plasma, correlates with amyloid PET status (Nakamura et al., Nature 2018). However, the significance of these peptide ratios in an APP/PS1 mouse model of Alzheimer's disease has been unclear. In this study, we investigated the levels of Aβ‐related peptides including APP669‐711 in plasma samples from the model mouse.
Method
We prepared plasma samples from young (2 months of age) and old (23–25 months of age) APP/PS1 mice expressing both APP bearing the Swedish mutation and PSEN1 harboring ΔE9 mutation, and cultured supernatants of HEK293 cells. Mouse plasma samples and cultured supernatants were measured by IP‐MALDI‐MS.
Result
Human APP669‐711 was detected in cultured supernatant of HEK293 cells overexpressing human wild‐type APP but not human APP with the Swedish mutation. This result indicated that two amino acid substitutions (i.e., Swedish mutation) near the APP669 site inhibited the APP669 cleavage and the production of APP669‐711 from the transgene of APP/PS1 mice. Then we focused on mouse endogenous murine Aβ‐related peptides in the evaluation of plasma biomarker for the amyloid deposition in the brains of APP/PS1 mice. The analysis of APP/PS1 mouse plasma showed that murine APP669‐711/Aβ1‐42 and APP669‐711/Aβ1‐40 ratios were increased in old mice with plaques compared to young mice without them. However, the murine Aβ1‐40/Aβ1‐42 ratio was not changed between old and young mice.
Conclusion
These results suggested that the APP669‐711/Aβ1‐42 ratio is a common biomarker for the amyloid plaque pathology in humans and APP/PS1 mice. Also, we revealed the possibility that the APP669‐711/Aβ1‐40 ratio is a biomarker specific for the brain Aβ deposition in APP/PS1 mice. These biomarkers can be useful tools to study lifestyle intervention and drug development for the prevention of amyloid deposition using the model mouse.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Neurogranin (Ng) is a cerebrospinal fluid (CSF) biomarker for synaptic dysfunction at early stage of Alzheimer’s disease (AD). It has been reported that a variety of truncated peptides ...from Ng is increased in AD brain tissue. However, the clinical significance of Ng peptides in plasma has remained unclear. We have developed a simultaneous detection method of a plurality of amyloid βpeptides in plasma by using immunoprecipitation combined with matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (IP‐MALDI‐MS) (Kaneko et al., Proc Jpn Acad Ser B Phys Biol Sci. 2014). In this study, we applied the IP‐MALDI‐MS technique to Ng measurement.
Method
Ng peptides and proteins were immunoprecipitated from human plasma or standard sample spiked by stable isotope‐labeled (SIL) Ng50‐78 using magnetic beads coupled with anti‐Ng monoclonal antibody. After the IP was performed two times consecutively, Ng proteins and peptides eluted from antibody beads were applied on the MALDI plate. SIL‐Ng50‐78 was used as an internal standard for normalizing an intensity of each Ng peptide.
Result
We optimized the condition such as a kind of detergent and an amount of antibody beads in IP for enhancing Ng signal intensity in MS. In the examination of detergents, UDM showed the highest sensitivity among six tested detergents. Using IP‐MALDI‐MS, we tried to detect Ng peptides and proteins in human plasma. As a result, some peaks corresponding to a variety of Ng peptides (m/z m/z > 5000.0) were detected in a plasma sample. To evaluate our semi‐quantitative assay using the internal standard, we selected some Ng peptides with low and high mass (m/z 2331.5–4084.7) to examine a linearity of the normalized intensity of Ng peptides. The accuracy in linear regression model showed within 80‐120% over a range of 5–160 pM in Ng48‐75 and 10‐160 pM in Ng50–78 and Ng33–75. Intra assay precision of Ng peptides in plasma was less than 20%CV.
Conclusion
IP‐MALDI‐MS enable the highly sensitive and simultaneous semi‐quantitative measurement of multiple Ng peptides levels. It could be helpful in the analysis of plasma Ng peptides for AD biomarker.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We previously evaluated Wilms’ tumor gene 1 (WT1) peptide vaccination in a large number of patients with leukemia or solid tumors and have reported that HLA‐A*24:02 restricted, 9‐mer WT1‐235 peptide ...(CYTWNQMNL) vaccine induces cellular immune responses and elicits WT1‐235‐specific cytotoxic T lymphocytes (CTLs). However, whether this vaccine induces humoral immune responses to produce WT1 antibody remains unknown. Thus, we measured IgG antibody levels against the WT1‐235 peptide (WT1‐235 IgG antibody) in patients with glioblastoma multiforme (GBM) receiving the WT1 peptide vaccine. The WT1‐235 IgG antibody, which was undetectable before vaccination, became detectable in 30 (50.8%) of a total of 59 patients during 3 months of WT1 peptide vaccination. The dominant WT1‐235 IgG antibody subclass was Th1‐type, IgG1 and IgG3. WT1‐235 IgG antibody production was significantly and positively correlated with both progression‐free survival (PFS) and overall survival (OS). Importantly, the combination of WT1‐235 IgG antibody production and positive delayed type‐hypersensitivity (DTH) to the WT1‐235 peptide was a better prognostic marker for long‐term OS than either parameter alone. These results suggested that WT1‐235 peptide vaccination induces not only WT1‐235‐specific CTLs as previously described but also WT1‐235‐specific humoral immune responses associated with antitumor cellular immune response. Our results indicate that the WT1 IgG antibody against the WT1 peptide may be a useful predictive marker, with better predictive performance in combination with DTH to WT1 peptide, and provide a new insight into the antitumor immune response induction in WT1 peptide vaccine‐treated patients.
What's new?
The Wilms' tumor gene 1 (WT1) antigen is a promising target for immunotherapeutic strategies against glioblastoma multiforme (GBM), a brain tumor with poor survival rates. The present study shows that vaccination with WT1‐235 peptide can induce WT1‐235‐specific humoral immune responses in GBM patients. WT1‐235 IgG antibody production was significantly associated with prolonged progression‐free survival and overall survival. Survival times were significantly longer in GBM patients with positive delayed‐type hypersensitivity (DTH) responses to WT1 peptide. Thus, in WT1 vaccine‐treated GBM patients, especially those exhibiting positive DTH responses, WT1‐235 IgG antibody production can predict long‐term survival.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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