Single-cell transcriptomic analyses of mouse idh1 mutant growth plate chondrocytes reveal distinct cell populations responsible for longitudinal growth and enchondroma formation.

Enchondromas are a common tumor in bone that can occur as multiple lesions in enchondromatosis, which is associated with deformity of the effected bone. These lesions harbor mutations in IDH and driving expression of a mutant Idh1 in Col2 expressing cells in mice causes an enchondromatosis phenotype. In this study we compared growth plates from E18.5 mice expressing a mutant Idh1 with control littermates using single cell RNA sequencing. Data from Col2 expressing cells were analyzed using UMAP and RNA pseudo-time analyses. A unique cluster of cells was identified in the mutant growth plates that expressed genes known to be upregulated in enchondromas. There was also a cluster of cells that was underrepresented in the mutant growth plates that expressed genes known to be important in longitudinal bone growth. Immunofluorescence showed that the genes from the unique cluster identified in the mutant growth plates were expressed in multiple growth plate anatomic zones, and pseudo-time analysis also suggested these cells could arise from multiple growth plate chondrocyte subpopulations. This data identifies subpopulations of cells in control and mutant growth plates, and supports the notion that a mutant Idh1 alters the subpopulations of growth plate chondrocytes, resulting a subpopulation of cells that become enchondromas at the expense of other populations that contribute to longitudinal growth.

The clinical features and prognostic factors of miliary tuberculosis in a high tuberculosis burden area.

BACKGROUND: Miliary Tuberculosis (TB) remains an important infectious disease that threatens human health. The clinical characteristics and prognostic factors of miliary TB are summarized in this study. METHODS: The clinical information of miliary TB patients between 2010 and 2022 was retrospectively analyzed. Patients with miliary TB were characterized and compared to adverse outcomes cases. Factors independently associated with adverse outcomes were determined via multivariate logistic regression analysis. RESULTS: A total of 288 patients were analyzed, including 181 with adverse outcomes. The clinical manifestations are atypical. 88.54% Of them experienced systemic symptoms, whilst 69.79% manifested respiratory symptoms. 40.97% Presented with neurologic symptoms, while 35.07% reported gastrointestinal symptoms. The major comorbidities were pharmacological immunosuppression (21.53%), pneumoconiosis (15.28%), diabetes (10.76%), and pregnancy or postpartum (7.29%). Regarding microbiology, most patients were diagnosed via sputum or Bronchoalveolar Lavage Fluid (BALF), pleural effusion, ascites, cerebrospinal fluid, urine TB-DNA, and tuberculosis culture. Meanwhile, 2.43% of patients were diagnosed via cerebrospinal fluid NGS. Independent risk factors predictive of adverse outcomes were current smoking, leukocytosis, elevated alanine aminotransferase (ALT) levels, and the combination of lymphopenia with bone marrow tuberculosis or tuberculous lymphadenitis. The accuracy of the model was validated by an area under the ROC curve of 0.753 (95% IC 0.697-0.810). CONCLUSIONS: The clinical manifestations of miliary TB are atypical, and early diagnosis is challenging. The major comorbidities in miliary TB patients were pharmacological immunosuppression, pneumoconiosis, diabetes, pregnancy, and postpartum. Regarding etiological detection, multi-site and multi-type specimens should be collected for a timely diagnosis. Cerebrospinal fluid mNGS test may be a viable choice in some cases. Finally, current smoking, leukocytosis, elevated ALT levels, and the combination of lymphopenia with bone marrow tuberculosis or tuberculous lymphadenitis were identified as independent risk factors for adverse outcomes.

The clinical manifestations of miliary TB are atypical, and early diagnosis is challenging. The major comorbidities in miliary TB patients were pharmacological immunosuppression, pneumoconiosis, diabetes, pregnancy, and postpartum. Current smoking, leukocytosis, elevated ALT levels, and the combination of lymphopenia with bone marrow tuberculosis or tuberculous lymphadenitis were identified as independent risk factors for adverse outcomes.

List prices and clinical value of anticancer drugs in China, Japan, and South Korea: a retrospective comparative study.

Background: High prices of anticancer drugs have raised concerns due to their financial impact on patients and healthcare systems. This study aimed to assess the initial and latest list prices and clinical value of reimbursed anticancer drugs in China, Japan, and South Korea. Methods: We identified anticancer drugs newly approved by the National Medical Products Administration of China from January 2012 to June 2022, and by the Pharmaceuticals and Medical Devices Agency of Japan and the Ministry of Food and Drug Safety of South Korea up until June 2022. We compared initial and latest treatment prices between countries and assessed clinical value using patients' survival, quality of life (QoL), and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). We calculated Spearman rank correlation coefficients of treatment prices with clinical value for individual countries and employed regression analyses to investigate whether the relationship between prices and clinical value was modified by the country setting. Findings: Our cohort included 91 anticancer drug indications, with 60 listed for reimbursement in China, 91 in Japan, and 87 in South Korea. Median treatment prices were highest in Japan, followed by South Korea, and lowest in China, both for initial prices (US$64082 vs. US$45529 vs. US$19144, p < 0.0001) and latest prices (US$50859 vs. US$31611 vs. US$18666, p < 0.0001). Over time, China (ß = -0.047, p < 0.0001) and South Korea (ß = -0.049, p < 0.0001) witnessed more significant price reductions compared to Japan (ß = -0.013, p = 0.011). The correlations between both initial and latest treatment prices and clinical value (QoL and ESMO-MCBS) were more significant and stronger in China and South Korea than in Japan, although Japan exhibited slightly stronger correlations in terms of survival compared to China and South Korea. The relationship between clinical value and treatment prices may not be modified by the country setting. Interpretation: In comparison, South Korea's list prices and their correlations with clinical value appear reasonable. Policymakers in Japan could enhance efficiency by controlling prices and aligning them with clinical value, while China would need to take substantial steps to expand anticancer drug coverage. Funding: National Natural Science Foundation of China (72374149 and 72074163), and China Center for South Asian Studies, Sichuan University.

Nuclear isoform of RAPH1 interacts with FOXQ1 to promote aggressiveness and radioresistance in breast cancer.

Radioresistance limits the efficacy of radiotherapy against breast cancer, especially the most lethal subtype of breast cancer, triple-negative breast cancer (TNBC). Epithelial-to-mesenchymal transition (EMT) is closely related to tumor radioresistance. In this work, we attempted to identify the key EMT-related transcription factor(s) that can induce radioresistance in breast cancer cells. A set of 44 EMT transcription factors were analyzed in parental and radioresistant TNBC cell lines. The function of FOXQ1, a differentially expressed transcription factor, was determined in TNBC radioresistance. FOXQ1-interacting proteins were identified by co-immunoprecipitation and mass spectrometry. Compared with parental cells, FOXQ1 was significantly upregulated in radioresistant TNBC cells. Silencing of FOXQ1 increased the radiosensitiviy of radioresistant TNBC cells both in vitro and in vivo. FOXQ1 associated with a nuclear isoform of RAPH1 (named RAPH1-i3) in radioresistant TNBC cells. Overexpression of RAPH1-i3 enhanced TNBC cell proliferation and migration, and most interestingly, induced radioresistance in parental TNBC cells when co-expressed with FOXQ1. Similar findings were observed in estrogen receptor-positive breast cancer cell lines that had co-expression of RAPH1-i3 and FOXQ1. Mechanistically, co-expression of RAPH1-i3 and FOXQ1 activated STAT3 signaling and increased the expression of CCND1, MCL1, Bcl-XL, and MMP2. Depletion of RAPH1-i3 impaired the radioresistance of radioresistant TNBC cells. Additionally, RAPH1-i3 upregulation was associated with advanced tumor stage and reduced disease-free survival in TNBC patients. These results collectively show that RAPH1-i3 interacts with FOXQ1 to promote breast cancer progression and radioresistance. RAPH1-i3 and FOXQ1 represent therapeutic targets for the treatment of breast cancer including TNBC.

Skeletal muscle regeneration failure in ischemic-damaged limbs is associated with pro-inflammatory macrophages and premature differentiation of satellite cells.

BACKGROUND: Chronic limb-threatening ischemia (CLTI), a severe manifestation of peripheral arterial disease (PAD), is associated with a 1-year limb amputation rate of approximately 15-20% and substantial mortality. A key feature of CLTI is the compromised regenerative ability of skeletal muscle; however, the mechanisms responsible for this impairment are not yet fully understood. In this study, we aim to delineate pathological changes at both the cellular and transcriptomic levels, as well as in cell-cell signaling pathways, associated with compromised muscle regeneration in limb ischemia in both human tissue samples and murine models of CLTI. METHODS: We performed single-cell transcriptome analysis of ischemic and non-ischemic muscle from the same CLTI patients and from a murine model of CLTI. In both datasets, we analyzed gene expression changes in macrophage and muscle satellite cell (MuSC) populations as well as differential cell-cell signaling interactions and differentiation trajectories. RESULTS: Single-cell transcriptomic profiling and immunofluorescence analysis of CLTI patient skeletal muscle demonstrated that ischemic-damaged tissue displays a pro-inflammatory macrophage signature. Comparable results were observed in a murine CLTI model. Moreover, integrated analyses of both human and murine datasets revealed premature differentiation of MuSCs to be a key feature of failed muscle regeneration in the ischemic limb. Furthermore, in silico inferences of intercellular communication and in vitro assays highlight the importance of macrophage-MuSC signaling in ischemia induced muscle injuries. CONCLUSIONS: Collectively, our research provides the first single-cell transcriptome atlases of skeletal muscle from CLTI patients and a murine CLTI model, emphasizing the crucial role of macrophages and inflammation in regulating muscle regeneration in CLTI through interactions with MuSCs.

[High-intensity laser therapy combined with targeted hand function training for the treatment of grade 1-2 thumb carpometacarpal osteoarthritis].

OBJECTIVE: To explore clinical effect of high-intensity laser therapy(HILT) combined with targeted hand function training on pain and lateral pinch force in grade 1-2 thumb carpometacarpal(CMC) osteoarthritis(OA). METHODS: From April 2020 and April 2022, 42 female patients with thumb CMC OA grade 1 to 2, aged from 58 to 80 years old with an everage of (68.90±7.58) years old were divided into observation group of 21 patients who received HILT and targeted hand function training for 4 weeks, and 21 patients in control group who received ultrashort wave therapy combined with using of an orthosis for 4 weeks. Visual analogue scale(VAS) was applied to evaluate degree of pain, function of finger was evaluated by dynamometer to measure lateral pinch force at baseline, immediately following intervention at 4 and 12 weeks following intervention. RESULTS: VAS and lateral pinch force at immediately and 12 weeks after intervention betwwen two groups were better than that of before intervention(P<0.05). Compared with control group, the degree of pain in observation group improved more(immediately after intervention t=3.37, P<0.05, 12 weeks after intervention t=9.05, P<0.05), lateral pinch force higher than that of control group (immediately after intervention t=-2.55, P<0.05, 12 weeks after intervention t=9.51, P<0.05). CONCLUSION: High-intensity laser therapy combined with targeted hand function training is more effective than traditional methods in improving pain and lateral pinch force in grade 1-2 thumb carpometacarpal osteoarthritis.

The effects of the mirror therapy on shoulder function in patients with breast cancer following surgery: a randomized controlled trial.

PURPOSE: Shoulder dysfunction is one of the most bothersome questions for breast cancer survivors. Studies show that mirror therapy can improve shoulder function in patients with a limited shoulder range of motion and shoulder pain. Here, this article reports the results of a randomized controlled trial investigating the effects of the mirror therapy on shoulder function in patients with breast cancer following surgical treatments. METHODS: Totally, 79 participants were divided to two groups receiving active range-of-motion upper limb exercise based on the mirror therapy or active range-of-motion upper limb exercise respectively for 8 weeks. Shoulder range of motion, Constant-Murley Score, Disabilities of Arm, Shoulder, and Hand Questionnaire, Tampa Scale of Kinesiophobia, Visual analog scale, and grip strength were measured at baseline (T0), 2 weeks (T1), 4 weeks (T2), and 8 weeks (T3). The effects of the intervention on shoulder function were analyzed in generalized estimation equation, from group, time, and the interactions between group and time based on the data from participants who completed at least one post-baseline observation RESULTS: At least one post-baseline observation was performed by 69 participants (n=34 mirror group, n=35 control group). 28(82.35%) participants in the mirror group adhered to the exercise compared to 30(85.71%) in the control group. Generalized estimation equation model showed group had main effects on forward flexion (Waldχ²=6.476, P=0.011), with the Cohen's d=0.54. The effects of the group on abduction, Constant-Murley Score, and Disabilities of Arm, Shoulder, and Hand Questionnaire were significant when fix the effects of the time. At 8 weeks, participants in the mirror group showed an improvement in abduction compared to the control group (P=0.005), the Cohen's d was 0.70. At 8 weeks, participants in the mirror group had a higher Constant-Murley Score than control group (P=0.009), with Cohen's effect size value of d=0.64. The mirror group showed a greater improvement on the Disability of Arm, Shoulder, and Hand Questionnaire than control group at 2 weeks, 4 weeks, and 8 weeks (P≤0.032), but with a weak effect size value of all (r≤0.32). Group had main effects on Tampa Scale of Kinesiophobia (Waldχ²=6.631, P=0.010), with the Cohen's effect size value of d=0.56. CONCLUSIONS: Mirror therapy improved shoulder flexion, abduction, shoulder function in daily life, and arm function and symptom of the affected shoulder in patients with breast cancer following surgical treatment, while decreasing fear of movement/(re)injury. Mirror configuration needs to be improved in further research to increase its feasibility. IMPLICATIONS FOR CANCER SURVIVORS: Breast cancer survivors can try mirror therapy as a practical and effective method in shoulder rehabilitation for a promotion on effects. TRIAL REGISTRATION: ClinicalTrial.gov Identifier: ChiCTR2000033080.

Single-cell chromatin accessibility profiling reveals a self-renewing muscle satellite cell state.

A balance between self-renewal and differentiation is critical for the regenerative capacity of tissue-resident stem cells. In skeletal muscle, successful regeneration requires the orchestrated activation, proliferation, and differentiation of muscle satellite cells (MuSCs) that are normally quiescent. A subset of MuSCs undergoes self-renewal to replenish the stem cell pool, but the features that identify and define self-renewing MuSCs remain to be elucidated. Here, through single-cell chromatin accessibility analysis, we reveal the self-renewal versus differentiation trajectories of MuSCs over the course of regeneration in vivo. We identify Betaglycan as a unique marker of self-renewing MuSCs that can be purified and efficiently contributes to regeneration after transplantation. We also show that SMAD4 and downstream genes are genetically required for self-renewal in vivo by restricting differentiation. Our study unveils the identity and mechanisms of self-renewing MuSCs, while providing a key resource for comprehensive analysis of muscle regeneration.

Association of Tumor Cell Metabolic Subtype and Immune Response With the Clinical Course of Hepatocellular Carcinoma.

AIM: Tumor metabolism plays an important role in tumorigenesis and tumor progression. This study evaluated the potential association of tumor cell metabolism and immune cell tumor infiltration with the clinical course of hepatocellular carcinoma (HCC). METHODS: Gene-wise normalization and principal component analysis were performed to evaluate the metabolic system. A tumor microenvironment score system of tumor immune cell infiltration was constructed to evaluate its association with metabolic subtypes. Finally, we analyzed the impact of metabolism and immune cell infiltration on the clinical course of HCC. RESULTS: A total of 673 HCC patients were categorized into cholesterogenic (25.3%), glycolytic (14.6%), mixed (10.4%), and quiescent (49.8%) types based on glycolysis and cholesterol biosynthesis gene expression. The subgroups including the glycolytic genotyping expression (glycolytic and mixed types) showed a higher mortality rate. The glycolytic, cholesterogenic, and mixed types were positively correlated with M0 macrophage, resting mast cell, and naïve B-cell infiltration (P = .013, P = .019, and P = .006, respectively). In TCGA database, high CD8+ T cell and low M0 macrophage infiltration were associated with prolonged overall survival (OS, P = .0017 and P < .0001, respectively). Furthermore, in glycolytic and mixed types, patients with high M0 macrophage infiltration had a shorter OS (P = .03 and P = .013, respectively), and in quiescent type, patients with low naïve B-cell infiltration had a longer OS (P = .007). CONCLUSIONS: Tumor metabolism plays a prognostic role and correlates with immune cell infiltration in HCC. M0 macrophage and CD8+ T cell appear to be promising prognostic biomarker for HCC. Finally, M0 macrophages may represent a useful immunotherapeutic target in patients with HCC.

The impacts of the National Medication Price-Negotiated Policy on the financial burden of cancer patients in Shandong province, China: an interrupted time series analysis.

BACKGROUND: In order to further regulate the price of anticancer medication and alleviate the financial burden of cancer patients, the Chinese government implemented the National Medication Price-Negotiated Policy (NMPNP) in 2017. This study aims to assess the impacts of implementation of the NMPNP on the access of anticancer medication and the financial burden for cancer patients in Shandong province, and to provide evidence to inform the design of similar policies in other developing countries. METHODS: A quasi-experiment design of an interrupt time series analysis was conducted. The month of September 2017 was taken as the intervention point when the Shandong Provincial Reimbursement Drug Lists was updated based on the result of the NMPNP in 2017. The data used were the aggregated monthly claim data of cancer patients from 2016 to 2021, which were obtained from four cities in Shandong province. The outpatient and inpatient care visits per capita, proportion of OOP expenditure and medication costs in outpatient and inpatient medical costs were used as outcome variables. A segmented regression model was used to analyze the change of the access of anticancer medication and the financial burden for cancer patients. RESULTS: The outpatient care visits per capita significantly decreased after the intervention. Compared to preintervention trend, the proportion of OOP expenditure in outpatient medical costs decreased by average 0.25 percentage point per month (p <  0.0001) after the intervention, however the proportion of OOP expenditure in inpatient medical costs increased by 0.02 percentage point per month (p = 0.76). Since the intervention, the proportion of medication costs in outpatient medical costs averagely rose by 0.28 percentage point (p <  0.0001), and its implementation caused the proportion of medication costs in inpatient medical costs averagely decreased 0.2 percentage point (p <  0.0001). CONCLUSIONS: The NMPNP improved the access of anticancer medication, and relieved the financial burden of outpatient care. However, it did not effectively alleviate the financial burden of inpatient care. Additionally, the NMPNP impacted the behavior of the healthcare providers. The policymakers should closely monitor the change of providers behaviors, and dynamically adjust financial incentives policies of healthcare providers during the implementation of similar medication price negotiated policies.

ZNF33A Promotes Tumor Progression and BET Inhibitor Resistance in Triple-Negative Breast Cancer.

Overexpression of ZNF33A (Krüppel-type zinc finger 33A) promotes carcinogenesis in several malignant tumors. However, the biochemical role and clinical importance of ZNF33A in triple-negative breast cancer (TNBC) still need to be explored. In this study, overexpression of ZNF33A in TNBC patient tissues and cell lines led to a worse prognosis. ZNF33A promoted cell growth and facilitated the resistance of cancer cells to inhibitors of bromodomain and extraterminal domain (BET) in TNBC. ZNF33A also promoted the induction of c-Myc, the primary player for the resistance to BET inhibitors in TNBC. In conclusion, ZNF33A may be a tumor growth-promoting factor associated with TNBC prognosis, and ZNF33A repression may sensitize TNBC cells to BET inhibitors.

Primary or metastatic lung cancer? Sebaceous carcinoma of the thigh: A case report.

BACKGROUND: Sebaceous carcinoma (SC), a malignancy primarily characterized by aggressive growth, affects cutaneous tissues of the periocular region. Extraocular SC is extremely rare, especially in the extremities, as evidenced by only a handful of reported cases. CASE SUMMARY: A 65-year-old man presented with a rapidly enlarging swelling on the left inner thigh, which was initially misdiagnosed as a subcutaneous abscess. The lesion had appeared two months prior to admission. Clinical examination revealed a cauliflower-like swollen content, with an ulcerated and infected mass located on his left thigh. At the same time, we observed solitary nodular lesions in his lungs and brain, with biopsy pathology of the lung lesions found to be consistent with the mass in the thigh. The patient received chemotherapy comprising cis-platinum with fluorouracil, followed by targeted therapy with anlotinib hydrochloride and chemotherapy with vinorelbine, implantation of iodine-125 seeds in the thigh and pulmonary tumor. The initial stage intervention achieved partial remission. The efficacy of maintenance treatment was evaluated as stable disease after the first 5 cycles; however, the patient developed a new brain lesion after the sixth cycle of treatment, which resulted in progressive disease and he received whole brain gamma knife radiotherapy. CONCLUSION: We analyzed the clinical presentation, imaging features, pathology and treatment of a rare case of lung, brain and lymph node metastasis of SC located in the thigh. It is evident that cis-platinum combined with fluorouracil, vinorelbine combined with anlotinib hydrochloride may be an effective therapeutic regimen in advanced SC. However, brain metastatic lesions should receive early radiotherapy.

Effects of Baduanjin exercise on cognitive function and cancer-related symptoms in women with breast cancer receiving chemotherapy: a randomized controlled trial.

PURPOSE: Cognitive decline is one of the main side effects of breast cancer patients after relevant treatment, but there is a lack of clear measures for prevention and management without definite mechanism. Moreover, postoperative patients also have a need for limb rehabilitation. Whether the cognitive benefits of Baduanjin exercise can improve the overall well-being of breast cancer patients remains unknown. METHODS: This randomized controlled trial was conducted on 70 patients with breast cancer receiving chemotherapy who were randomly assigned and allocated to (1:1) a supervised Baduanjin intervention group (5 times/week, 30 min each time) or a control group for 3 months. The effects of Baduanjin exercise intervention were evaluated by outcome measures including subjective cognitive function, symptoms (fatigue, depression, and anxiety), and health-related quality of life at pre-intervention (T0), 4 weeks (T1), 8 weeks (T2), and 12 weeks (T3). The collected data were analyzed by using an intention-to-treat principle and linear mixed-effects modeling. RESULTS: Participants in the Baduanjin intervention group had a significantly greater improvement in terms of FACT-Cog (F = 14.511; p < 0.001), PCI (F = 15.789; p < 0.001), PCA (F = 6.261; p = 0.015), and FACT-B scores (F = 8.900; p = 0.004) compared with the control group over the time. The exercise-cognition relationship was significantly mediated through the reduction of fatigue (indirect effect: ß = 0.132; 95% CI 0.046 to 0.237) and the improvement of anxiety (indirect effect: ß = - 0.075; 95% CI - 0.165 to -0.004). CONCLUSIONS: This pilot study revealed the benefits of Baduanjin exercise for subjective cognition and health-related quality of life of Chinese breast cancer patients receiving chemotherapy and outlined the underlying mediating mechanism of exercise-cognition. The findings provided insights into the development of public health initiatives to promote brain health and improve quality of life among breast cancer patients. TRIAL REGISTRATION NUMBER: ChiCTR 2,000,033,152.

Mcl-1 inhibition overcomes BET inhibitor resistance induced by low FBW7 expression in breast cancer.

While the promise of bromodomains and extraterminal (BET) protein inhibitors (BETis) is emerging in breast cancer (BC) therapy, resistance in these cells to BETis conspicuously curbs their therapeutic potential. FBW7 is an important tumour suppressor. However, the role of FBW7 in BC is not clear. In the current study, our data indicated that the low expression of FBW7 contributes to the drug resistance of BC cells upon JQ1 treatment. shRNA-mediated FBW7 silencing in FBW7 WT BC cells suppressed JQ1-induced apoptosis. Mechanistically, it was revealed that this diminished FBW7 level leads to Mcl-1 stabilization, while Mcl-1 upregulation abrogates the killing effect of JQ1. Mcl-1 knockdown or inhibition resensitized the BC cells to JQ1-induced apoptosis. Moreover, FBW7 knockdown in MCF7 xenografted tumours demonstrated resistance to JQ1 treatment. The combination of JQ1 with a Mcl-1 inhibitor (S63845) resensitized the FBW7 knockdown tumours to JQ1 treatment in vivo. Our study paves the way for a novel therapeutic potential of BETis with Mcl-1 inhibitors for BC patients with a low FBW7 expression.

Effects of free range-of-motion upper limb exercise based on mirror therapy on shoulder function in patients after breast cancer surgery: study protocol for a randomized controlled trial.

BACKGROUND: Shoulder function complications are common after treatment for breast cancer. Quite a few survivors still report a limited shoulder range of motion, even though the free range-of-motion upper limb exercise is helpful to restore shoulder function. Mirror therapy (MT) is a classical and effective rehabilitation technique to recover motor and sensory function for the limbs; in addition, studies have reported that MT has an influence on patients with shoulder functional dysfunction including increasing shoulder range of motion, improving shoulder function scores, and decreasing pain scores. Here, we describe a protocol of a randomized controlled trial to explore if free range-of-motion upper limb exercise based on MT has efficacy on shoulder function in survivors after surgery of breast cancer. METHODS/DESIGN: This is a prospective, single-blind, two-arm randomized controlled trial. An estimated 70 participants will be randomly allocated to (1) the MT group or (2) the control group. The participants in the control group receive free range-of-motion upper limb exercise, and participants in the MT group will engage in free range-of-motion upper limb exercise based on MT. The intervention will start on the first day after surgery and be completed at 8 weeks after surgery. The primary outcome in this protocol is shoulder range of motion (ROM), while the Constant-Murley Score (CMS); Disability of the Arm, Shoulder, and Hand Questionnaire (DASH); Tampa Scale of Kinesiophobia (13-item TSK); visual analog scale (VAS); grip strength; arm circumference; and lymphedema are the secondary outcomes. Assessment will be conducted before allocation (baseline) and at 2 weeks, 4 weeks, and 8 weeks after surgery. DISCUSSION: Based on the results that MT has an influence on shoulder function immediately after intervention in patients without nerve injury, this randomized controlled trial is to observe the efficacy of MT on shoulder function after a long-term intervention in breast cancer survivors. We look forward to the innovation of this study for both breast cancer rehabilitation and MT. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( ChiCTR ) ChiCTR2000033080. Registered on 19 May 2020.

Association of pre-existing comorbidities with mortality and disease severity among 167,500 individuals with COVID-19 in Canada: A population-based cohort study.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) has infected 1.9% of the world population by May 2, 2021. Since most previous studies that examined risk factors for mortality and severity were based on hospitalized individuals, population-based cohort studies are called for to provide evidence that can be extrapolated to the general population. Therefore, we aimed to examine the associations of comorbidities with mortality and disease severity in individuals with COVID-19 diagnosed in 2020 in Ontario, Canada. METHODS AND FINDINGS: We conducted a retrospective cohort study of all individuals with COVID-19 in Ontario, Canada diagnosed between January 15 and December 31, 2020. Cases were linked to health administrative databases maintained in the ICES which covers all residents in Ontario. The primary outcome is all-cause 30-day mortality after the first COVID-19 diagnosis, and the secondary outcome is a composite severity index containing death and hospitalization. To examine the risk factors for the outcomes, we employed Cox proportional hazards regression models and logistic regression models to adjust for demographic, socio-economic variables and comorbidities. Results were also stratified by age groups. A total of 167,500 individuals were diagnosed of COVID-19 in 2020 and included in the study. About half (43.8%, n = 73,378) had at least one comorbidity. The median follow-up period were 30 days. The most common comorbidities were hypertension (24%, n = 40,154), asthma (16%, n = 26,814), and diabetes (14.7%, n = 24,662). Individuals with comorbidity had higher risk of mortality compared to those without (HR = 2.80, 95%CI 2.35-3.34; p<0.001), and the risk substantially was elevated from 2.14 (95%CI 1.76-2.60) to 4.81 (95%CI 3.95-5.85) times as the number of comorbidities increased from one to five or more. Significant predictors for mortality included comorbidities such as solid organ transplant (HR = 3.06, 95%CI 2.03-4.63; p<0.001), dementia (HR = 1.46, 95%CI 1.35-1.58; p<0.001), chronic kidney disease (HR = 1.45, 95%CI 1.34-1.57; p<0.001), severe mental illness (HR = 1.42, 95%CI%, 1.12-1.80; p<0.001), cardiovascular disease (CVD) (HR = 1.22, 95%CI, 1.15-1.30), diabetes (HR = 1.19, 95%, 1.12-1.26; p<0.001), chronic obstructive pulmonary disease (COPD) (HR = 1.19, 95%CI 1.12-1.26; p<0.001), cancer (HR = 1.17, 95%CI, 1.09-1.27; p<0.001), hypertension (HR = 1.16, 95%CI, 1.07-1.26; p<0.001). Compared to their effect in older age groups, comorbidities were associated with higher risk of mortality and severity in individuals under 50 years old. Individuals with five or more comorbidities in the below 50 years age group had 395.44 (95%CI, 57.93-2699.44, p<0.001) times higher risk of mortality compared to those without. Limitations include that data were collected during 2020 when the new variants of concern were not predominant, and that the ICES databases do not contain detailed individual-level socioeconomic and racial variables. CONCLUSION: We found that solid organ transplant, dementia, chronic kidney disease, severe mental illness, CVD, hypertension, COPD, cancer, diabetes, rheumatoid arthritis, HIV, and asthma were associated with mortality or severity. Our study highlights that the number of comorbidities was a strong risk factor for deaths and severe outcomes among younger individuals with COVID-19. Our findings suggest that in addition of prioritizing by age, vaccination priority groups should also include younger population with multiple comorbidities.

[Clinical results of critical rehabilitation pathway after total knee arthroplasty].

OBJECTIVE: To investigate the clinical results of the application of critical rehabilitation pathway in the rehabilitation after total knee arthroplasty. METHODS: From March 2015 to December 2019, 67 patients with total knee arthroplasty (TKA) were included. There were 49 females and 18 males, 42 cases on the left and 25 cases on the right, with an average age of 60 to 81(70.72±5.92) years old. Critical rehabilitation paths included intensive strength and gait rehabilitation exercises. All patients were evaluated before operation and 3, 12 months after operation. The evaluation indexes included stair climbing test (SCT), six minute walk test (6MWT), quadriceps and hamstring strength, range of motion, visual pain scale (VAS), Western Ontario McMasterUniversity Osteoarthritis score(WOMAC). RESULTS: All the patients completed the entire pathway and the assessment. The results of pre-operative, 3 months after surgery and 12 months after surgery were as follows respectively. SCT-up: (16.32±3.58) s, (18.16±2.46) s, (11.00±1.29) s, F=193.448, P<0.05;SCT-down:(17.40±2.94) s, (18.96±2.61) s, (12.16± 1.91) s, F=208.028, P<0.05;6MWT:(276.00±57.70) m, (318.00±46.18) m, (435.12±57.36) m, F=326.408, P<0.05;Quadriceps strength: (70.08±8.17) N, (52.40±6.67) N, (78.84±4.56) N, F=286.375, P<0.05;Hamstring muscle strength: (44.88± 7.53) N, (44.28 ±4.63) N, (47.04 ±4.77) N, F =3.620, P <0.05;Knee flexion angle: (115.56 ±13.04) ° , (113.16 ±8.84) ° , (120.28±5.23) °, F=11.228, P<0.05;Knee extension angle:(2.16±3.51) °, (-0.28±2.05) °, (-0.72±1.21) °, F=45.460, P< 0.05;VAS 7.52±1.26, 3.44±0.87, 1.76±0.60, F=723.110, P<0.05;WOMAC pain index:7.88±1.05, 3.60±0.65, 1.96±0.54, F=1 186.196, P<0.05;WOMAC stiffindex:3.00±0.50, 2.20±0.50, 1.68±0.56, F=177.944, P<0.05;WOMAC function index: 30.24±1.76, 26.16±2.08, 13.52±1.53, F=2 227.287, P<0.05. CONCLUSION: Critical rehabilitation path is safe and effective. The knee function of patients who receive critical rehabilitation path after TKA is significantly improved in the first 12 months after operation.

Effect of Baduanjin exercise intervention on cognitive function and quality of life in women with breast cancer receiving chemotherapy: study protocol of a randomized controlled trial.

BACKGROUND: More than 50% cognitive impairment was reported by cancer patients before and after medical treatment. However, there are no effective interventions to manage the cognitive problem in women with breast cancer. This pilot study was designed to evaluate the protective effect of Baduanjin exercise on cognitive function and cancer-related symptoms in women with early-stage breast cancer undergoing chemotherapy. METHOD: A single-blinded, randomized control trial was designed. The trial will recruit 70 patients with early-stage breast cancer scheduled to receive chemotherapy from Shanghai in China. All participants will be randomly assigned to (1:1) the supervised Baduanjin group (5 times/week, 30 min each time) or the wait-list control group for 3 months. The effect of Baduanjin exercise intervention will be evaluated by outcome measures including subjective and objective cognitive function, symptoms (fatigue, depression, and anxiety), and health-related quality of life at pre-intervention (T0), 8 weeks (T1), and 12 weeks (T2). The PCI score in the FACT-Cog as the primary cognitive outcome will be reported descriptively, while effect sizes and 95% confidence intervals (CIs) will be calculated. The collected data will be analyzed by using an intention-to-treat principle and linear mixed-effects modeling. DISCUSSION: This is the first randomized clinical trial to investigate whether Baduanjin exercise will have a positive role in improving cognitive function in women with breast cancer receiving chemotherapy. If possible, Baduanjin exercise will be a potential non-pharmacological intervention to manage cognitive dysfunction and promote survivorship care among breast cancer survivors. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR) ChiCTR2000033152 . Registered on 22 May 2020.

Bacterial Profile and Antibiotic Resistance among Cancer Patients with Urinary Tract Infection in a National Tertiary Cancer Hospital of Nepal.

Cancer patients are at high risk of antibiotic resistant bacterial urinary tract infections (UTIs). In this study, we assessed the bacterial profile and antibiotic resistance among cancer patients suspected of UTI in B.P. Koirala Memorial Cancer Hospital in Nepal through a cross-sectional study with routinely collected data. All cancer patients who had a recorded urine culture between July 2018-June 2019 were included in the study. Out of 308 patients who had undergone culture, 73 (24%) of samples had bacterial growth. The most common organisms isolated were E. coli (58%), Staphylococcus (11%) and Klebsiella (10%). These bacteria had undergone susceptibility testing to 27 different antibiotics in various proportions. Of the limited antibiotic testing levels, nitrofurantoin (54/66, 82%) and amikacin (30/51, 59%) were the most common. Among those tested, there were high levels of resistance to antibiotics in the "Access" and "Watch" groups of antibiotics (2019 WHO classification). In the "Reserve" group, both antibiotics showed resistance (polymyxin 15%, tigecycline 8%). Multidrug resistance was seen among 89% of the positive culture samples. This calls for urgent measures to optimize the use of antibiotics in UTI care at policy and health facility levels through stewardship to prevent further augmentation of antibiotic resistance among cancer patients.

Administration of glycyrrhetinic acid reinforces therapeutic effects of mesenchymal stem cell-derived exosome against acute liver ischemia-reperfusion injury.

Recent studies have shown that mesenchymal stem cell-derived exosome could attenuate ischaemia-reperfusion (I/R) injury by suppressing inflammatory response in the liver. Glycyrrhetinic acid was also shown to be capable of repressing the TLR4 signalling pathway. However, it remains to be explored as whether the combined administration of mesenchyma stem cell (MSC)-derived exosome and glycyrrhetinic acid (GA) could increase their therapeutic effects on I/R injury. Western blot was performed to evaluate the expression of proteins associated with inflammatory response in THP-1 cells and I/R rat models treated under different conditions. Flow cytometry was carried out to analyse the proportions of different subtypes of peripheral blood cells in I/R rats. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured to assess the liver injury in I/R rats. Combined treatment with MSC-derived exosome and GA effectively maintained the expression of key proteins involved in inflammatory response in LPS stimulated THP-1 cells and THP-1 cells treated under hypoxia conditions. In the established of I/R rat models, GA administration reinforced the therapeutic efficiency of MSC-derived exosomes by maintaining the proportion of different subgroups of peripheral blood cells, decreasing the concentration of ALT and AST, and restoring the expression of dysregulated proteins associated with inflammation. Our results demonstrated that treatment with exosomes derived from mesenchymal stem cells (MSCs) attenuated liver I/R injury, while the pre-treatment with GA may further promote the therapeutic effect of mesenchymal stem cell-derived exosome against acute liver ischaemia-reperfusion injury.