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Recurrent disability progression endpoints in multiple sclerosis clinical trials

Mult Scler. 2022 Sep 30:13524585221125382. doi: 10.1177/13524585221125382. Online ahead of print.

ABSTRACT

BACKGROUND: The current standard endpoint to assess disability accumulation in multiple sclerosis (MS) clinical trials is the time to the first confirmed disability progression, which excludes subsequent progression events. Including recurrent progression events may permit a more comprehensive assessment of treatment effects on disability progression.

OBJECTIVE: To propose a definition of recurrent disability progression events and to compare time-to-first and recurrent event analysis.

METHODS: Recurrent disability progression events were defined by expanding the recommended first event definition. Marginal recurrent event methods (negative binomial model, Lin-Wei-Yang-Ying model) were compared with Cox regression in data from three randomized controlled trials in relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS), and in simulated randomized controlled trial data.

RESULTS: The recurrent event analyses included a substantially larger number of progression events compared with the time-to-first-event analyses (+7.5% and +9.9% in the RMS trials and +22.7% in the PPMS trial). The increase in the number of events resulted in more precise treatment effect estimates and a corresponding gain in statistical power.

CONCLUSION: Our results support the use of recurrent event data analysis, especially in progressive MS trials, to improve estimates of treatment effects, increase statistical power, and better capture the clinically meaningful long-term disability progression experience.

PMID:36177953 | DOI:10.1177/13524585221125382

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Comparative study of the protective effect of Xuebijing injection and Sivelestat sodium on acute lung injury/acute respiratory distress syndrome rats

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2022 Aug;34(8):837-841. doi: 10.3760/cma.j.cn121430-20220401-00334.

ABSTRACT

OBJECTIVE: To compare the protective effect of Xuebijing injection versus Sivelestat sodium on acute lung injury/acute respiratory distress syndrome (ALI/ARDS) rats.

METHODS: A total of 71 male Sprague-Dawley (SD) rats were randomly divided into the blank control group (n = 8), ALI/ARDS model group (n = 21), Xuebijing injection group (n = 21) and Sivelestat sodium group (n = 21). Rats in the blank control group were injected with normal saline while the other three groups were intravenously injected 25 mg/kg lipopolysaccharide (LPS) via the tail vein to establish ALI/ARDS model. After induction of ALI/ARDS model, the blank control group and ALI/ARDS model group were given intraperitoneal injection of an equal volume of normal saline twice a day. Rats in the Xuebijing injection group were given tail vein injection of 8 mL/kg Xuebijing injection twice a day, and those in the Sivelestat sodium group were given intraperitoneal injection of 100 mg/kg Sivelestat sodium three times a day. All rats were administered continuously for five days. During the experiment, the general status of rats was observed, and the weight and survival were recorded. At the end of the experiment, bronchoalveolar lavage fluid (BALF) of rats was collected for the detection of inflammatory cells and inflammatory factors. Histopathological changes of rats lung tissue were observed.

RESULTS: Compared with the ALI/ARDS model group, the Xuebijing injection group and Sivelestat sodium group had significantly decreased white blood cell (WBC) count and percent of neutrophil (NEU%) [WBC (×109/L): 55.86±6.68, 49.96±6.76 vs. 73.13±7.35, NEU%: 0.459±0.077, 0.315±0.047 vs. 0.709±0.067, all P < 0.05], significantly increased percent of lymphocytes (LYM%: 0.412±0.067, 0.517±0.051 vs. 0.232±0.057, both P < 0.05), and reduced interleukin-6 (IL-6) level (ng/L: 295.2±39.7, 281.9±33.1 vs. 469.6±77.0) in BALF. However, there were no significant differences in these parameters between the Xuebijing injection group and Sivelestat sodium injection group (all P > 0.05). Survival rate at the end of experiment was higher in the Xuebijing group than that in the Sivelestat sodium injection group and ALI/ARDS model group [52.4% (11/21) vs. 28.6% (6/21), 14.3% (3/21)], and survival rate at the end of experiment was higher in the Sivelestat sodium injection group than that in the ALI/ARDS model group, but the differences were not statistically significant (P > 0.05). In addition, weight and weight growth rate in the Xuebijing injection group were higher than the Sivelestat sodium group at the end of the experiment [weight (g): 217.1±6.4 vs. 207.1±7.0, weight growth rate: (-0.9±2.8)% vs. (-4.3±3.5)%], there were no significant difference between the two groups (both P > 0.05). Lung histopathology in the ALI/ARDS model group revealed high level of inflammatory exudate and inflammatory cells infiltrated in the alveoli of rats, along with damage of local alveolar epithelial cell and alveolar structure. However, these histological changes were improved in the Xuebijing injection group and in the Sivelestat sodium group.

CONCLUSIONS: Xuebijing injection can alleviate ALI/ARDS-induced lung injury and systemic damage and improve the survival of rats by inhibiting inflammation. The protective effect of Xuebijing injection is essentially consistent with that of Sivelestat sodium.

PMID:36177927 | DOI:10.3760/cma.j.cn121430-20220401-00334

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Comparison of the predictive performance of Logistic regression, BP neural network and support vector machine model for the risk of acute exacerbation of readmission in elderly patients with chronic obstructive pulmonary disease within 30 days

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2022 Aug;34(8):819-824. doi: 10.3760/cma.j.cn121430-20220303-00198.

ABSTRACT

OBJECTIVE: To compare the effectiveness of Logistic regression, BP neural network and support vector machine models in the prediction of 30-day risk of readmission in elderly patients with an exacerbation of chronic obstructive pulmonary disease (COPD) and to provide a scientific basis for the screening and prevention of high-risk patients with readmission.

METHODS: The COPD patient survey questionnaire was made, including the general data questionnaire, modified Medical Research Council dyspnea scale (mMRC), activities of daily living (ADL), the geriatric depression scale, the mini nutritional assessment-short form (MNA-SF) and COPD assessment test (CAT). Elderly COPD patients were selected from the department of respiratory medicine of 13 general hospitals in Ningxia from April 2019 to August 2020 by convenience sampling method, and they were followed up 30 days after discharge. To explore the risk factors of patient readmission, Logistic regression model, BP neural network model and support vector machine models were constructed based on the risk factors. According to the ratio of the training set to the testing set of 7:3, the model was divided into the training set sample and the testing set sample. The prediction efficiency of the model was compared by the precision rate, recall rate and accuracy rate, F1 index and the area under the receiver operator characteristic curve (AUC).

RESULTS: A total of 1 120 patients were investigated, including 879 non-readmission patients and 241 readmission patients. Univariate regression analysis showed that there were statistically significant differences in age, education level, smoking status, proportion of diabetes and coronary heart disease, hospitalization times of acute exacerbation of COPD in the past 1 year, seasonal factors and long-term home oxygen therapy, regular medication, proportion of rehabilitation exercise, course of disease, ADL, depression status, mMRC, nutritional status between non-readmission patients and readmission patients. Binary Logistic regression analysis showed that education level, smoking status, coronary heart disease, hospitalization times of acute exacerbation of COPD in the past 1 year, seasonal factors, whether long-term home oxygen therapy, whether regular medication, nutritional status were the risk factors for 30-day acute exacerbation of readmission in elderly patients with COPD. The training set showed that the accuracy rate of Logistic regression model, BP neural network model and support vector machine models were 70.95%, 76.51% and 84.78%, respectively. The recall rates were 79.55%, 86.36% and 88.64%, respectively. The accuracy rates were 87.81%, 90.81% and 93.82%, respectively. F1 indexes were 0.75, 0.81 and 0.87, respectively. The AUC were 0.850, 0.893 and 0.921, respectively. The testing set showed that the precision rate of Logistic regression model, BP neural network model and support vector machine model were 78.38%, 80.65% and 88.57%, respectively. The recall rates were 70.73%, 60.98% and 75.61%, respectively. The accuracy rates were 85.82%, 84.40% and 90.07%, respectively. F1 indexes were 0.74, 0.69 and 0.82, respectively. The AUC were 0.814, 0.775 and 0.858, respectively.

CONCLUSIONS: Comparing with Logistic regression and BP neural network, support vector machine model has better prediction effect, and can effectively predict the risk of acute exacerbation of readmission in elderly patients with COPD within 30 days.

PMID:36177924 | DOI:10.3760/cma.j.cn121430-20220303-00198

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Real-world experience of consolidation durvalumab after concurrent chemoradiotherapy in stage III non-small cell lung cancer

Thorac Cancer. 2022 Sep 30. doi: 10.1111/1759-7714.14667. Online ahead of print.

ABSTRACT

BACKGROUND: Durvalumab consolidation is associated with improved survival following concurrent chemoradiotherapy (CCRT) in patients with stage III non-small cell lung cancer (NSCLC). Given the heterogeneity of stage III NSCLC patients, in this study we evaluated the efficacy and safety of durvalumab in the real-world setting.

METHOD: Unresectable stage III NSCLC patients were retrospectively studied: one cohort received CCRT, another had CCRT-durvalumab. Primary endpoints were progression-free survival (PFS) and overall survival (OS), secondary endpoints were relapse rate and safety. In CCRT-durvalumab cohort, association between blood markers with survival and pneumonitis risk were analyzed.

RESULTS: A total of 84 patients were enrolled: 45 received CCRT, and 39 received CCRT-durvalumab. Median PFS was 17.5 months for CCRT-durvalumab and 8.9 months for CCRT-alone (HR 0.47, p = 0.038). Median OS was not-reached for CCRT-durvalumab and 22.3 months for CCRT-alone (HR 0.35, p = 0.024). Both EGFR-positive and wild-type (WT) patients had numerically improved PFS with durvalumab consolidation compared to CCRT-alone, 17.5 versus 10.9 months and 11.8 versus 6.63 months, respectively (interaction p-value = 0.608). Grade 2+ pneumonitis was detected in 25% of patients in the durvalumab cohort. Most pneumonitis occurred at 3.5 weeks after durvalumab initiation. Baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 3 and ≥5 were associated with shorter PFS with durvalumab. Week 6 platelet-lymphocyte-ratio ≥ 180 was associated with a lower risk of pneumonitis.

CONCLUSION: In this real-world study, durvalumab consolidation post CCRT was associated with a statistically significant improvement in PFS and OS. Effect of durvalumab on PFS was not modified by EGFR status. Active surveillance for pneumonitis is crucial. Baseline NLR may help to predict the benefit of treatment with durvalumab.

PMID:36177913 | DOI:10.1111/1759-7714.14667

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Galectin‑1 binds GRP78 to promote the proliferation and metastasis of gastric cancer

Int J Oncol. 2022 Nov;61(5):141. doi: 10.3892/ijo.2022.5431. Epub 2022 Sep 30.

ABSTRACT

The present study aimed to investigate the potential molecular mechanisms by which galectin‑1 (Gal‑1) and glucose‑regulated protein 78 (GRP78) influence the development of malignant gastric cancer (GC). Immunohistochemistry and western blotting were used to map the expression and location of the Gal‑1 gene in the 80 paraffin‑embedded GC samples, 16 fresh samples and surrounding tissues. Gal‑1 was overexpressed and knocked down using lentiviral vectors in the human GC cell lines HGC‑27 and AGS. Through the use of the Cell Counting Kit‑8 assay, clone formation assay, wound healing assay, invasion assay and tumor xenograft, the possible biological roles of Gal‑1 were further evaluated. The downstream interacting proteins were predicted by the BioGRID database, and GRP78 was chosen for further investigation. Immunofluorescence labeling and Co‑IP were used to confirm the connection. The statistical tests utilized were the two‑tailed paired Student’s t‑test, χ2 test, Kaplan‑Meier and Cox regression analysis, and Spearman’s rank correlation coefficients. In GC, Gal‑1 is extensively expressed and has the potential to interact with GRP78. Poor prognosis is linked to high levels of GRP78 and Gal‑1 expression in patients with GC. According to the functional study, Gal‑1 knockdown prevented cells from thriving and pushed Gal‑1 expression, which aided in the proliferation, migration and invasion of GC. Gal‑1 overexpression additionally aided the development of subcutaneous xenograft tumors. The mechanistic investigation proved that GRP78 and Gal‑1 interacted, accelerating the course of GC. Gal‑1 silencing had an inhibitory effect on the proliferation of HGC‑27 cells that was removed by ectopic GRP78 expression, whereas the stimulating effects of Gal‑1 overexpression in AGS cells were inhibited by GRP78 knockdown. In conclusion, Gal‑1 interacts with GRP78 to facilitate the advancement of GC. The Gal‑1/GRP78 axis is supported by the functional data of the present study as a possible GC treatment target.

PMID:36177897 | DOI:10.3892/ijo.2022.5431

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Differences in genetic correlations between posttraumatic stress disorder and alcohol-related problems phenotypes compared to alcohol consumption-related phenotypes

Psychol Med. 2022 Sep 30:1-11. doi: 10.1017/S0033291722002999. Online ahead of print.

ABSTRACT

BACKGROUND: Posttraumatic Stress Disorder (PTSD) tends to co-occur with greater alcohol consumption as well as alcohol use disorder (AUD). However, it is unknown whether the same etiologic factors that underlie PTSD-alcohol-related problems comorbidity also contribute to PTSD- alcohol consumption.

METHODS: We used summary statistics from large-scale genome-wide association studies (GWAS) of European-ancestry (EA) and African-ancestry (AA) participants to estimate genetic correlations between PTSD and a range of alcohol consumption-related and alcohol-related problems phenotypes.

RESULTS: In EAs, there were positive genetic correlations between PTSD phenotypes and alcohol-related problems phenotypes (e.g. Alcohol Use Disorders Identification Test (AUDIT) problem score) (rGs: 0.132-0.533, all FDR adjusted p < 0.05). However, the genetic correlations between PTSD phenotypes and alcohol consumption -related phenotypes (e.g. drinks per week) were negatively associated or non-significant (rGs: -0.417 to -0.042, FDR adjusted p: <0.05-NS). For AAs, the direction of correlations was sometimes consistent and sometimes inconsistent with that in EAs, and the ranges were larger (rGs for alcohol-related problems: -0.275 to 0.266, FDR adjusted p: NS, alcohol consumption-related: 0.145-0.699, FDR adjusted p: NS).

CONCLUSIONS: These findings illustrate that the genetic associations between consumption and problem alcohol phenotypes and PTSD differ in both strength and direction. Thus, the genetic factors that may lead someone to develop PTSD and high levels of alcohol consumption are not the same as those that lead someone to develop PTSD and alcohol-related problems. Discussion around needing improved methods to better estimate heritabilities and genetic correlations in diverse and admixed ancestry samples is provided.

PMID:36177877 | DOI:10.1017/S0033291722002999

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Body mass index and comorbidities are associated with the duration of COVID-19 symptoms in non-hospitalized patients

J Int Med Res. 2022 Sep;50(9):3000605221127520. doi: 10.1177/03000605221127520.

ABSTRACT

OBJECTIVE: Evidence indicates that people with a high body mass index (BMI) tend to develop more severe forms of coronavirus disease 2019 (COVID-19). In this study, we aimed to determine the association between the duration of COVID-19 symptoms and variables such as BMI, age, presence of comorbidities, and smoking in non-hospitalized patients.

METHODS: In this observational cross-sectional analytical study, we analyzed the data of patients with COVID-19 but without severe manifestations. We conducted descriptive statistics, non-parametric tests, and multivariate quasi-Poisson regression in the analysis. The quasi-Poisson regression model was configured with the duration of COVID-19 symptoms as the response variable, and BMI and the presence of comorbidities as the explanatory variables.

RESULTS: Among 302 non-hospitalized patients, we found a significant difference in COVID-19 symptom duration between the overweight group and the group with normal weight. Multivariate quasi-Poisson regression analysis showed that BMI and the presence of comorbidities were associated with the duration of COVID-19 symptoms. On the contrary, sex, age, and smoking status were not related to COVID-19 symptom duration.

CONCLUSIONS: BMI and comorbidities were associated with the duration of COVID-19 symptoms in non-hospitalized patients.

PMID:36177839 | DOI:10.1177/03000605221127520

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Relationship between DHX15 expression and survival prognosis in colorectal cancer

Rev Esp Enferm Dig. 2022 Sep 30. doi: 10.17235/reed.2022.8838/2022. Online ahead of print.

ABSTRACT

Objective To explore the relationship between the expression of DEAH-box RNA helicase 15 (DHX15) in colorectal cancer (CRC), its clinical pathological features and survival prognosis. Method DHX15 expression data with clinic pathological features from the Cancer Gene Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), were statistically analyzed for the association between DHX15 expression and overall survival of CRC. The expression of DHX15 was performed by immunohistochemical staining (IHC) using tumor and the adjacent normal tissues mounted in tissue microarrays. The significance of DHX15 expression in predicting the survival and prognosis of CRC were analyzed using Kaplan-Meier method, Univariate and Multivariate Cox regression analysis. Results Low expression of DHX15 mRNA and DHX15 protein in CRC were both negative factors for survival prognosis. Overall survival of patients with low-expression of DHX15 was significantly lower (χ2=8.452, p=0.004) by Kaplan-Meier evaluation. Low expression of DHX15 in CRC tissues was correlated with distal lymph node metastasis (χ²=7.120, p=0.008), TNM stage (χ²=3.935, p=0.047) and disease recurrence (χ²=9.524, p=0.002) of CRC patients. Low expression of DHX15, (HR=4.012, 95%CI: 1.462~11.013, p=0.007), late TNM stage (HR=0.067, 95%CI: 0.029~0.156, p<0.001) and recurrence (HR=0.008, 95%CI: 0.002~0.034, p<0.001) were risk factors related to the prognosis of CRC patients by Univariate Cox regression analysis. Conclusion Our findings reveal a key role for DHX15 in the progress of CRC metastasis and recurrence. DHX15 may be a potential biomarker for CRC targeted therapy.

PMID:36177832 | DOI:10.17235/reed.2022.8838/2022

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Target temperature management versus normothermia without temperature feedback systems for out-of-hospital cardiac arrest survivors

J Int Med Res. 2022 Sep;50(9):3000605221126880. doi: 10.1177/03000605221126880.

ABSTRACT

OBJECTIVE: The clinical benefit of automatic temperature control devices remains unclear. We investigated the outcomes of out-of-hospital cardiac arrest (OHCA) survivors who had undergone either target temperature management (TTM) with a temperature feedback system (TFS) or maintenance of normothermia without a TFS during post-resuscitation care.

METHODS: This study was a retrospective analysis of a multicenter prospective cohort of OHCA survivors who had received postcardiac arrest care from August 2014 to December 2018. The overlap propensity score weighting method was applied for adjustment between groups.

RESULTS: A total of 405 OHCA survivors were included. TTM with a TFS and normothermia without a TFS were applied to 318 and 87 patients, respectively. Fever events were more common in patients with normothermia without a TFS. After propensity score matching, no statistically significant differences were observed in the 1-month good neurologic outcome (odds ratio 0.99, 95% confidence interval [CI] 0.56-1.25) or survival rate (odds ratio 1.25, 95% CI 0.88-1.78).

CONCLUSION: No significant differences in the 1-month neurologic outcome were observed between patients receiving TTM with a TFS and those undergoing normothermia without a TFS.

PMID:36177833 | DOI:10.1177/03000605221126880

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Comparison of Preoperative Computed Tomography and Intraoperative Estimation in Predicting the Version of a Single-Wedge Femoral Stem

Orthop Surg. 2022 Sep 30. doi: 10.1111/os.13524. Online ahead of print.

ABSTRACT

OBJECTIVE: Early prediction of stem version aids in optimization of combined version during total hip arthroplasty (THA). This study aimed to analyze the discrepancy between stem version and native femoral version measured by different methods, and to explore which method can better predict the stem version.

METHODS: We retrospectively reviewed 26 patients (39 hips) treated with robot-assisted THA in our hospital between September 2019 and December 2019. A straight, single-wedge, cementless stem (Accolade II) was used in all cases. Preoperative femoral version was measured at three levels on computerized tomography (CT) scan from the top to the middle level of femoral neck (Level 1 to Level 3). During THA, the version on cutting surface was measured prior to femoral broaching based on two reference lines: mid-cortical line and T line (trochanteric fossa to the middle of medial cortex). After femoral broaching, stem version was measured based on the femoral neck trial using Mako system (Stryker). In the statistical analysis, the difference and absolute discrepancy between stem version and femoral version measured with various methods were examined using paired t-test, and the relationship between stem version and various femoral versions were examined using correlation analysis.

RESULTS: Mean femoral neck version (Level 1) was 9.5° ± 2.6° (range, -16.8°-42.5°), while mean stem version measured by Mako system was 19.9° ± 2.0° (range, -8.0°-49.0°). Femoral version measured with each method showed a moderate correlation with stem version (p < 0.05). There was a significant difference between stem version and femoral version except at Level 3, with a mean difference of 0.8° ± 13.6° (p = 0.729). With regard to the intraoperative estimation, stem version significantly increased compared to the value based on mid-cortical line, with a mean difference of 8.4° ± 13.1° (p < 0.001). However, the mean value of stem version was a little smaller than that of femoral version measured by reference to T line, but without statistical significance (p = 0.156). No postoperative dislocations occurred during the study period. No revision was required for any component.

CONCLUSIONS: The middle level of femoral neck on CT scan and T line on cutting surface are better references to measure femoral version for predicting postoperative stem version. However, the relationship between stem version and predictive value was flexible. Therefore, further three-dimensional studies of postoperative CT are needed to validate the press-fit fixation and rotational freedom of the single-wedge stem.

PMID:36177805 | DOI:10.1111/os.13524