Effects of radial extracorporeal shock wave therapy on flexor spasticity of the upper limb in post-stroke patients: A randomized controlled trial.

OBJECTIVE: This study aimed to assess the efficacy of radial extracorporeal shock wave therapy in treating upper limb spasticity after a stroke. DESIGN: Randomized controlled trial. SETTING: Zhujiang Hospital of Southern Medical University. SUBJECTS: This study included 95 people with stroke. INTERVENTION: The active (n = 47) and sham-placebo (n = 48) radial extracorporeal shockwave therapy groups received three treatment sessions (every third day). MAIN MEASURES: The Modified Ashworth Scale, Hmax/Mmax ratio, root mean square, co-contraction ratio, mechanical parameters of the muscle and temperature were measured at baseline and days 2, 5 and 8. RESULTS: Among the 135 potential participants screened, 100 were enrolled and allocated randomly, with 95 participants ultimately being included in the intent-to-treat analysis dataset. The active group showed significantly better improvements in upper limb spasticity and muscle function than did the sham-placebo group. Greater improvements in the Modified Ashworth Scale were observed in the active group than in the sham-placebo group (difference, -0.45; 95% CI, -0.69 to -0.22; P < 0.001). Moreover, significant differences in root mean square, co-contraction ratio and Hmax/Mmax ratio were observed between the two groups (all P < 0.001). The mechanical parameters of the biceps muscle were significantly better in the active group than in the sham-placebo group (P < 0.001). The active group had a higher temperature than the sham-placebo group, although the difference was not significant (P = 0.070). CONCLUSIONS: This study revealed that the treatment with extracorporeal shockwave therapy can relieve upper limb spasticity in people with stroke.

The impact of ankle-foot orthoses on mobility of dual-task walking in stroke patients? A cross-sectional two-factor factorial design clinical trial.

ABSTRACTTo assess the impact of ankle-foot orthoses (AFOs) on mobility and gait during dual-task walking in post-stroke survivors. In this cross-sectional, factorial design trial, stroke survivors performed four randomized tasks: (1) dual-task walking with AFOs, (2) single-task walking with AFOs, (3) dual-task walking without AFOs, and (4) single-task walking without AFOs. Primary outcome was the Timed Up and Go (TUG) test, with secondary outcomes including gait metrics, Tinetti scores, and auditory N-back tests. In the results, 48 subjects (38 males and 10 females; 19-65 years) completed the trial. Patients had a greater TUG score with AFOs compared with non-AFOs conditions (95% CI: 7.22-14.41, P < 0.001) in single-task and dual-task conditions. Secondary outcomes showed marked enhancement with AFOs during dual-task walking, with significant interaction effects in gait metrics, balance, and cognitive function (P < 0.05). Although not statistically significant, dual-task effects of TUG and walking speed were more pronounced during dual-task walking. In conclusion, AFOs enhance mobility and gait during both single and dual-task walking in post-stroke survivors.

Multimodal analysis of gene expression from postmortem brains and blood identifies synaptic vesicle trafficking genes to be associated with Parkinson's disease.

OBJECTIVE: We aimed to identify key susceptibility gene targets in multiple datasets generated from postmortem brains and blood of Parkinson's disease (PD) patients and healthy controls (HC). METHODS: We performed a multitiered analysis to integrate the gene expression data using multiple-gene chips from 244 human postmortem tissues. We identified hub node genes in the highly PD-related consensus module by constructing protein-protein interaction (PPI) networks. Next, we validated the top four interacting genes in 238 subjects (90 sporadic PD, 125 HC and 23 Parkinson's Plus Syndrome (PPS)). Utilizing multinomial logistic regression analysis (MLRA) and receiver operating characteristic (ROC), we analyzed the risk factors and diagnostic power for discriminating PD from HC and PPS. RESULTS: We identified 1333 genes that were significantly different between PD and HCs based on seven microarray datasets. The identified MEturquoise module is related to synaptic vesicle trafficking (SVT) dysfunction in PD (P < 0.05), and PPI analysis revealed that SVT genes PPP2CA, SYNJ1, NSF and PPP3CB were the top four hub node genes in MEturquoise (P < 0.001). The levels of these four genes in PD postmortem brains were lower than those in HC brains. We found lower blood levels of PPP2CA, SYNJ1 and NSF in PD compared with HC, and lower SYNJ1 in PD compared with PPS (P < 0.05). SYNJ1, negatively correlated to PD severity, displayed an excellent power to discriminating PD from HC and PPS. CONCLUSIONS: This study highlights that SVT genes, especially SYNJ1, may be promising markers in discriminating PD from HCs and PPS.

Evaluating the causal effect of circulating proteome on the risk of osteoarthritis-related traits.

OBJECTIVES: This study aims to identify circulating proteins that are causally associated with osteoarthritis (OA)-related traits through Mendelian randomisation (MR)-based analytical framework. METHODS: Large-scale two-sample MR was employed to estimate the effects of thousands of plasma proteins on 12 OA-related traits. Additional analyses including Bayesian colocalisation, Steiger filtering analysis, assessment of protein-altering variants and mapping expression quantitative trait loci to protein quantitative trait loci were performed to investigate the reliability of the MR findings; protein-protein interaction, pathway enrichment analysis and evaluation of drug targets were conducted to deepen the understanding and identify potential therapeutic targets of OA. RESULTS: Dozens of circulating proteins were identified to have putatively causal effects on OA-related traits, and a majority of these proteins were either drug targets or considered druggable. CONCLUSIONS: Through MR analysis, we have identified numerous plasma proteins associated with OA-related traits, shedding light on protein-mediated mechanisms and offering promising therapeutic targets for OA.

Patient pIgR-enriched extracellular vesicles drive cancer stemness, tumorigenesis and metastasis in hepatocellular carcinoma.

BACKGROUND & AIMS: Extracellular vesicles (EVs) play a pivotal role in connecting tumor cells with their local and distant microenvironments. Herein, we aimed to understand the role (on a molecular basis) patient-derived EVs play in modulating cancer stemness and tumorigenesis in the context of hepatocellular carcinoma (HCC). METHODS: EVs from patient sera were isolated, quantified and characterized. The EVs were vigorously tested, both in vitro and in vivo, through various functional assays. Proteomic analysis was performed to identify the functional components of EVs. The presence and level of polymeric immunoglobulin receptor (pIgR) in circulating EVs and tumor and non-tumorous tissues of patients with HCC were determined by ELISA, immunoblotting, immunohistochemistry and quantitative PCR. The functional role and underlying mechanism of EVs with enhanced pIgR expression were elucidated. Blockade of EV-pIgR with neutralizing antibody was performed in nude mice implanted with patient-derived tumor xenografts (PDTXs). RESULTS: Circulating EVs from patients with late-stage HCC (L-HCC) had significantly elevated pIgR expression compared to the EVs released by control individuals. The augmenting effect of L-HCC-EVs on cancer stemness and tumorigenesis was hindered by an anti-pIgR antibody. EVs enriched with pIgR consistently promoted cancer stemness and cancerous phenotypes in recipient cells. Mechanistically, EV-pIgR-induced cancer aggressiveness was abrogated by Akt and ß-catenin inhibitors, confirming that the role of EV-pIgR depends on the activation of the PDK1/Akt/GSK3ß/ß-catenin signaling axis. Furthermore, an anti-pIgR neutralizing antibody attenuated tumor growth in mice implanted with PDTXs. CONCLUSIONS: This study illustrates a previously unknown role of EV-pIgR in regulating cancer stemness and aggressiveness: EV-pIgR activates PDK1/Akt/GSK3ß/ß-catenin signaling cascades. The blockade of the intercellular communication mediated by EV-pIgR in the tumor microenvironment may provide a new therapeutic strategy for patients with cancer. LAY SUMMARY: The World Health Organization estimates that more than 1 million patients will die from liver cancer, mostly hepatocellular carcinoma (HCC), in 2030. Understanding the underlying mechanism by which HCC acquires aggressive attributes is crucial to improving the diagnosis and treatment of patients. Herein, we demonstrated that nanometer-sized extracellular vesicles released by tumors promote cancer stemness and tumorigenesis. Within these oncogenic vesicles, we identified a key component that functions as a potent modulator of cancer aggressiveness. By inhibiting this functional component of EVs using a neutralizing antibody, tumor growth was profoundly attenuated in mice. This hints at a potentially effective therapeutic alternative for patients with cancer.

MRI-based Texture Analysis of Infrapatellar Fat Pad to Predict Knee Osteoarthritis Incidence.

Background Infrapatellar fat pad (IPFP) quality has been implicated as a marker for predicting knee osteoarthritis (KOA); however, no valid quantification for subtle IPFP abnormalities has been established. Purpose To investigate whether MRI-based three-dimensional texture analysis of IPFP abnormalities could help predict incident radiographic KOA. Materials and Methods In this prospective nested case-control study, 690 participants whose knees were at risk for KOA were included from the Pivotal Osteoarthritis Initiative MRI Analyses incident osteoarthritis cohort. All knees had a Kellgren-Lawrence grade of 1 or less at baseline. During the 4-year follow-up, case participants were matched 1:1 to control participants, with incident radiographic KOA as the outcome. MRI scans were segmented at the incident time point of KOA (hereafter, P0), 1 year before P0 (hereafter, P-1), and baseline. MRI-based three-dimensional texture analysis was performed to extract IPFP texture features. Least absolute shrinkage and selection operator and multivariable logistic regressions were applied in the development cohort and evaluated in the test cohort. The area under the receiver operating characteristic curve (AUC) was used to evaluate the discriminative value of the clinical score, IPFP texture score, and MRI Osteoarthritis Knee Score. Results Participants were allocated to development (n = 500, 340 women; mean age, 60 years) and test (n = 190, 120 women; mean age, 61 years) cohorts. In both cohorts, IPFP texture scores (AUC ≥0.75 for all) showed greater discrimination than clinical scores (AUC ≤0.69 for all) at baseline, P-1, and P0, with significant differences in pairwise comparisons (P ≤ .002 for all). Greater predictive and concurrent validities of IPFP texture scores (AUC ≥0.75 for all) compared with MRI Osteoarthritis Knee Scores (AUC ≤0.66 for all) were also demonstrated (P < .001 for all). Conclusion MRI-based three-dimensional texture of the infrapatellar fat pad was associated with future development of knee osteoarthritis. ClinicalTrials.gov registration no.: NCT00080171 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Fischer in this issue.

Signal intensity alteration and maximal area of pericruciate fat pad are associated with incident radiographic osteoarthritis: data from the Osteoarthritis Initiative.

OBJECTIVE: To determine whether pericruciate fat pad (PCFP) signal intensity alteration and maximal area are associated with incident radiographic osteoarthritis (ROA) over 4 years in the Osteoarthritis Initiative (OAI) study. METHODS: Participants were from the Osteoarthritis Initiative (OAI) study. Case knees (n = 355) were defined by incident ROA between 12 and 48 months visits and were matched by sex, age, and radiographic status with control knees (n = 355). Magnetic resonance images (MRIs) were used to assess PCFP signal intensity alteration and PCFP maximal area at P0 (time of onset of ROA), P-1 (1 year prior to P0), and baseline. Conditional logistic regression analyses were applied to assess associations between PCFP measures and the risk of incident ROA. RESULTS: The mean age of participants was 60.1 years and 66.9% were women. In multivariable analyses, PCFP signal intensity alteration measured at three time points (OR [95%CI]: 1.28 [1.10-1.50], 1.52 [1.30-1.78], 1.50 [1.27-1.76], respectively) and PCFP maximal area (OR [95%CI]: 1.21 [1.03-1.42], 1.27 [1.07-1.52], 1.37 [1.15-1.62], respectively) were significantly associated with incident ROA. CONCLUSIONS: PCFP signal intensity alteration and maximal area were associated with incident ROA over 4 years, implying that they may have roles to play in ROA. KEY POINTS: • Pericruciate fat pad signal intensity alteration and maximal area were associated with incident ROA, implying that they may have roles to play in ROA.

Metformin use and associated risk of total joint replacement in patients with type 2 diabetes: a population-based matched cohort study.

BACKGROUND: It is uncertain whether metformin use is associated with reduced risk of joint replacement in patients with type 2 diabetes mellitus. We aimed to establish whether metformin use was associated with a reduced risk of total knee replacement (TKR) or total hip replacement (THR) among these patients. METHODS: We selected patients with type 2 diabetes mellitus that was diagnosed between 2000 and 2012 from the Taiwan National Health Insurance Research Database. We used prescription time-distribution matching and propensity-score matching to balance potential confounders between metformin users and nonusers. We assessed the risks of TKR or THR using Cox proportional hazards regression. RESULTS: We included 20 347 participants who were not treated with metformin and 20 347 who were treated with metformin, for a total of 40 694 participants (mean age 63 yr, standard deviation 11 yr; 49.8% were women) after prescription time-distribution matching. Compared with participants who did not use metformin, those who used metformin had lower risks of TKR or THR (adjusted hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.60-0.81 for TKR or THR; adjusted HR 0.71, 95% CI 0.61-0.84 for TKR; adjusted HR 0.61, 95% CI 0.41-0.92 for THR) after adjustment for covariates. Propensity-score matching analyses (10 163 participants not treated with metformin v. 10 163 treated with metformin) and sensitivity analyses using inverse probability of treatment weighting and competing risk regression showed similar results. INTERPRETATION: Metformin use in patients with type 2 diabetes mellitus was associated with a significantly reduced risk of total joint replacement. Randomized controlled clinical trials in patients with osteoarthritis are warranted to determine whether metformin is effective in decreasing the need for joint replacement.

Quadriceps strength is negatively associated with knee joint structural abnormalities-data from osteoarthritis initiative.

OBJECTIVE: The aim of this study was to explore the longitudinal associations between baseline quadriceps strength and knee joint structural abnormalities in knee osteoarthritis (KOA). METHODS: This study is a longitudinally observational study based on Osteoarthritis Initiative (OAI) cohort, including men and women aged 45-79. Quadriceps strength was measured by isometric knee extension testing at baseline. Knee joint structural abnormalities, including cartilage damage, bone marrow lesions (BMLs), effusion-synovitis and Hoffa-synovitis, were evaluated by Magnetic Resonance Imaging Osteoarthritis Knee Score (MOAKS) at baseline and 1-year follow-up. Generalized estimating equations were employed to examine the associations between quadriceps strength and knee structural abnormalities. All analyses were stratified by sex. RESULTS: One thousand three hundred thirty-eight participants (523 men and 815 women) with a mean age of 61.8 years and a mean BMI of 29.4 kg/m2 were included in this study. For men, no significantly longitudinal association of quadriceps strength with structural abnormalities was detected. In contrast, quadriceps strength was significantly and negatively associated with changes in cartilage damage and BMLs in lateral patellofemoral joint (PFJ) (cartilage damage: OR: 0.91, 95% CI 0.84 to 0.99, P = 0.023; BMLs: OR: 0.85, 95% CI 0.74 to 0.96, P = 0.011) and effusion-synovitis (OR = 0.88, 95% CI 0.78 to 0.99, P = 0.045) among females longitudinally. Higher quadriceps strength was significantly associated with less progression of lateral PFJ cartilage damage, BMLs and effusion-synovitis in females. CONCLUSIONS: Higher quadriceps strength was associated with changes in cartilage damage and BMLs within the lateral PFJ and effusion-synovitis among females, suggesting the potential protective role of quadriceps strength on joint structures in women.

[Meta-analysis for clinical efficacy of traditional Chinese medicine in treating resistant hypertension].

To systematically evaluate the efficacy and safety of traditional Chinese medicine in treating patients with resistant hypertension. CNKI, Wanfang, VIP, CBM, PubMed, Web of Science, Cochrane Library, EMbase and other databases were retrieved by computers to screen out the randomized controlled trial of traditional Chinese medicine in treating resistant hypertension. Cochrane Handbook was used to evaluate the quality of the included literature, RevMan 5.3 and Stata 12.0 was used for Meta-analysis. Finally, 11 literatures meeting the criteria were included, involving 1 023 patients. The results of Meta-analysis showed that the combined therapy of standard triple antihypertensive regimen with traditional Chinese medicine could further reduce systolic blood pressure of patients with resistant hypertension(MD=-16.69, 95%CI[-22.21,-11.16], P<0.000 01), reduce diastolic blood pressure(MD=-7.51, 95%CI[-8.26,-6.76], P<0.000 01), improve the effective rate of anti-hypertension(OR=5.16, 95%CI[3.01, 8.84], P<0.000 01), improve the up-to-standard rate of blood pressure(OR=3.01, 95%CI[1.49, 6.09], P=0.002), and improve the effectiveness of clinical symptoms(OR=4.48, 95%CI[2.31, 8.68], P<0.000 01), with no significant effect on creatinine level(MD=-2.51, 95%CI[-6.91, 1.89], P=0.26). The results of this study indicated that the combined therapy of standard triple antihypertensive regimen with traditional Chinese medicine could further improve the clinical efficacy in patients with resistant hypertension with a good safety, but more high-quality clinical studies are still needed to verify this conclusion.

Chrm3 protects against acinar cell necrosis by stabilizing caspase-8 expression in severe acute pancreatitis mice model.

Acinar cells in acute pancreatitis (AP) die through apoptosis and necrosis, the impacts of which are quite different. Early clinical interference strategies on preventing the progress of AP to severe acute pancreatitis (SAP) are the elimination of inflammation response and inhibition of necrosis. Muscarinic acetylcholine receptor M3 was encoded by Chrm3 gene. It is one of the best-characterized receptors of pancreatic ß cells and regulates insulin secretion, but its function in AP remains unclear. In this study, we explored the function of Chrm3 gene in the regulation of cell death in l-arginine-induced SAP animal models. We found that Chrm3 was upregulated in pancreatitis, and we further confirmed the localization of Chrm3 resided in both pancreatic islets and acinar cell membranes. The reduction of Chrm3 decreased the pathological lesion of SAP and reduced amylase activities in serum. Consistently, Chrm3 can suppress acinar cells necrosis markedly, but has no effect on regulating apoptosis after l-arginine treatment. It was shown that Chrm3 attenuated acinar cells necrosis at least in part by stabilizing caspase-8. Thus, this study indicates that Chrm3 is critical participants in SAP, and regulation of Chrm3 expression might be a useful therapeutic strategy for preventing pathologic necrosis.

Low dispersion in the infectiousness of COVID-19 cases implies difficulty in control.

The individual infectiousness of coronavirus disease 2019 (COVID-19), quantified by the number of secondary cases of a typical index case, is conventionally modelled by a negative-binomial (NB) distribution. Based on patient data of 9120 confirmed cases in China, we calculated the variation of the individual infectiousness, i.e., the dispersion parameter k of the NB distribution, at 0.70 (95% confidence interval: 0.59, 0.98). This suggests that the dispersion in the individual infectiousness is probably low, thus COVID-19 infection is relatively easy to sustain in the population and more challenging to control. Instead of focusing on the much fewer super spreading events, we also need to focus on almost every case to effectively reduce transmission.

Identification of pathogenic genes and transcription factors in vitiligo.

Our study aimed to identify the key genes and upstream regulators in vitiligo. To screen the pathogenic genes of vitiligo, an integrated analysis was performed by using the microarray datasets in vitiligo derived from the Gene Expression Omnibus (GEO) database. The functional annotation and potential pathways of differentially expressed genes (DEGs) were further explored by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. We constructed a vitiligo-specific transcriptional regulatory network to identify crucial transcriptional factors that target the DEGs in vitiligo. From two GEO datasets, we identified 1863 DEGs (744 downregulated DEGs and 1,119 upregulated DEGs [false discovery rate < 0.05, |Combined.ES| > 1]) between lesional tissues and nonlesional tissues. GO and KEGG analyses revealed that ubiquitin-mediated proteolysis and the endoplasmic reticulum were significantly enriched pathways for DEGs. The expressions of premelanosome (PMEL), melan-A (MLANA), dopachrome tautomerase (DCT), SRY-boxtranscription factor 10 (SOX10), tyrosinase-related protein 1 (TYRP1), and melanocortin 1 receptor (MC1R) were shown to be involved in the pathogenesis of vitiligo. We concluded that PMEL, MLANA), DCT, SOX10, TYRP1, and MC1R may play a role in vitiligo, among which TYRP1 and MC1R are regulated by forkhead box J2 (FOXJ2). Our finding may contribute to the development of new potential biomarkers, reveal the underlying pathogenesis of vitiligo, and identify novel therapeutic targets for vitiligo.

Age and Sex Differences in Rates of Influenza-Associated Hospitalizations in Hong Kong.

Few studies have explored age and sex differences in the disease burden of influenza, although men and women probably differ in their susceptibility to influenza infections. In this study, quasi-Poisson regression models were applied to weekly age- and sex-specific hospitalization numbers of pneumonia and influenza cases in the Hong Kong SAR, People's Republic of China, from 2004 to 2010. Age and sex differences were assessed by age- and sex-specific rates of excess hospitalization for influenza A subtypes A(H1N1), A(H3N2), and A(H1N1)pdm09 and influenza B, respectively. We found that, in children younger than 18 years, boys had a higher excess hospitalization rate than girls, with the male-to-female ratio of excess rate (MFR) ranging from 1.1 to 2.4. MFRs of hospitalization associated with different types/subtypes were less than 1.0 for adults younger than 40 years except for A(H3N2) (MFR = 1.6), while all the MFRs were equal to or higher than 1.0 in adults aged 40 years or more except for A(H1N1)pdm09 in elderly persons aged 65 years or more (MFR = 0.9). No MFR was found to be statistically significant (P < 0.05) for hospitalizations associated with influenza type/subtype. There is some limited evidence on age and sex differences in hospitalization associated with influenza in the subtropical city of Hong Kong.

Hospitalization risk of the 2009 H1N1 pandemic cases in Hong Kong.

BACKGROUND: Reliable assessment for the severity of the 2009 H1N1 pandemic influenza is critical for evaluation of vaccination strategies for future pandemics. This study aims to estimate the age-specific hospitalization risks of the 2009 pandemic cases during the first wave in Hong Kong, by combining the findings from the serology and disease burden studies. METHODS: Excess hospitalization rates associated with the pandemic H1N1 were estimated from Poisson regression models fitted to weekly total numbers of non-accidental hospitalization from 2005 to 2010. Age-specific infection-hospitalization risks were calculated as excess hospitalization rates divided by the attack rates in the corresponding age group, which were estimated from serology studies previously conducted in Hong Kong. RESULTS: Excess hospitalization rate associated with pandemic H1N1 was highest in the 0-4 age group (881.3 per 100,000 population), followed by the 5-14, 60+, 15-29, 50-59, 30-39 and 40-49 age groups. The hospitalization risk of the infected cases (i.e. infection-hospitalization risk) was found highest in the 60+ age group and lowest in the 15-29 age group, with the estimates of 17.5% and 0.7%, respectively. CONCLUSIONS: People aged 60 or over had a relatively high infection-hospitalization risk during the first wave of the 2009 H1N1 pandemic, despite of a low attack rate in this age group. The findings support the policy of listing older people as the priority group for pandemic vaccination.

Immune response analysis of solid organ transplantation recipients inoculated with inactivated COVID-19 vaccine: A retrospective analysis.

Objective: This study aimed to evaluate the efficacy and safety of solid organ transplantation recipients inoculated with an inactivated COVID-19 vaccine. Methods: We retrospectively analyzed the antibody levels and related adverse events of non-transplantation subjects and solid organ transplant recipients, both pre-transplantation (individuals awaiting organ transplantation) and post-transplantation (individuals who have undergone organ transplantation), who received inactivated COVID-19 vaccines from February 2021 to July 2022. Results: The study included 38 pre-transplantation vaccination group, 129 post-transplantation vaccination group, and 246 non-transplantation group. The antibody titer was assessed monthly within the period of 1-12 months after the last injection. The antibody-positive rate among the three groups were 36.84, 20.30, 61.17% (P < 0.05). The antibody-positive rates among three groups with one, two doses vaccine were not significantly different (P > 0.05), but were significantly different after three doses (P < 0.05). The antibody titers among three groups were significantly different after two doses (P < 0.05). Adverse reactions occurred in six transplant recipients, which were relieved after treatment, and not in the non-transplantation subjects. Conclusion: Inactivated COVID-19 vaccine is safe and effective for solid organ transplantation recipients, at least two doses of which should be completed before organ transplant surgery.