Clinical efficacy of Osteoking in knee osteoarthritis therapy: a prospective, multicenter, non-randomized controlled study in China

BackgroundOsteoking has been extensively used for the treatment of knee osteoarthritis (KOA). However, it is lack of high-quality evidence on the clinical efficacy of Osteoking against KOA and the comparison with that of nonsteroidal anti-inflammatory drugs (NSAIDs).AimsTo evaluate the efficacy and safety of Osteoking in treating KOA.MethodsIn the current study, a total of 501 subjects were recruited from 20 medical centers, and were divided into the Osteoking treatment group (n = 428) and the NSAIDs treatment group (n = 73). The Propensity Score Matching method was used to balance baseline data of different groups. Then, the therapeutic effects of Osteoking and NSAIDs against KOA were evaluated using VAS score, WOMAC score, EQ-5D-3L and EQ-VAS, while the safety of the two treatment were both assessed based on dry mouth, dizziness, diarrhea, etc.ResultsAfter 8 weeks of treatment, the Osteoking group was compared with the NSAIDs group, the VAS score [2.00 (1.00, 3.00) vs. 3.00 (2.00, 4.00)], WOMAC pain score [10.00 (8.00, 13.00) vs. 11.00 (8.00, 16.00) ], WOMAC physical function score [32.00 (23.00, 39.00) vs. 39.07 ± 16.45], WOMAC total score [44.00 (31.00, 55.00) vs. 53.31 ± 22.47) ], EQ-5D-3L score [0.91 (0.73, 0.91) vs. 0.73 (0.63, 0.83) ] and EQ-VAS score [80.00 (79.00, 90.00) vs. 80.00 (70.00, 84.00) ] were improved by the treatment of Osteoking for 8 weeks more effectively than that by the treatment of NSAIDs. After 8 weeks of treatment with Osteoking, the VAS scores of KOA patients with the treatment of Osteoking for 8 weeks were reduced from 6.00 (5.00, 7.00) to 2.00 (1.00, 3.00) (p < 0.05), which was better than those with the treatment of NSAIDs starting from 2 weeks during this clinical observation. Importantly, further subgroup analysis revealed that the treatment of Osteoking was more suitable for alleviating various clinical symptoms of KOA patients over 65 years old, with female, KL II-III grade and VAS 4-7 scores, while the clinical efficacy of NSAIDs was better in KOA patients under 65 years old and with VAS 8–10 scores. Of note, there were no differences in adverse events and adverse reactions between the treatment groups of the two drugs.ConclusionOsteoking may exert a satisfying efficacy in relieving joint pain and improving life quality of KOA patients without any adverse reactions, especially for patients with KL II-III grades and VAS 4–7 scores.Clinical Trial Registration:https://www.chictr.org.cn/showproj.html?proj=55387, Identifier ChiCTR200003447

Acetylome analyses provide novel insights into the effects of chronic intermittent hypoxia on hippocampus-dependent cognitive impairment

IntroductionChronic intermittent hypoxia (CIH) can negatively affect hippocampal function through various molecular mechanisms. Protein acetylation, a frequently occurring modification, plays crucial roles in synaptic plasticity and cognitive processes. However, the global protein acetylation induced by CIH in the hippocampus and its specific effects on hippocampal function and behavior remain poorly understood.MethodsTo address this gap, we conducted a study using liquid chromatography-tandem mass spectrometry to analyze the lysine acetylome and proteome of the hippocampus in healthy adult mice exposed to intermittent hypoxia for 4 weeks (as a CIH model) compared to normoxic mice (as a control).ResultsWe identified and quantified a total of 2,184 lysine acetylation sites in 1,007 proteins. Analysis of these acetylated proteins revealed disturbances primarily in oxidative phosphorylation, the tricarboxylic acid (TCA) cycle, and glycolysis, all of which are localized exclusively to mitochondria. Additionally, we observed significant changes in the abundance of 21 proteins, some of which are known to be associated with cognitive impairments.DiscussionThis study helps to elucidate the molecular mechanisms underlying CIH-induced changes in protein acetylation in the hippocampus. By providing valuable insights into the pathophysiological processes associated with CIH and their impacts on hippocampal function, our findings contribute to a better understanding of the consequences of CIH-induced changes in protein acetylation in the hippocampus and the potential role of CIH in cognitive impairment

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Phosphodiesterase and psychiatric disorders: a two-sample Mendelian randomization study

Abstract Background Phosphodiesterases (PDEs) have been associated with psychiatric disorders in observational studies; however, the causality of associations remains unestablished. Methods Specifically, cyclic nucleotide PDEs were collected from genome-wide association studies (GWASs), including PDEs obtained by hydrolyzing both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (PDE1A, PDE2A, and PDE3A), specific to cGMP (PDE5A, PDE6D, and PDE9A) and cAMP (PDE4D and PDE7A). We performed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the relationship between PDEs and nine psychiatric disorders. The inverse-variance-weighted (IVW) method, MR-Egger, and weighted median were used to estimate causal effects. The Cochran’s Q test, MR-Egger intercept test, MR Steiger test, leave-one-out analyses, funnel plot, and MR pleiotropy residual sum and outlier (MR-PRESSO) were used for sensitivity analyses. Results The PDEs specific to cAMP were associated with higher-odds psychiatric disorders. For example, PDE4D and schizophrenia (SCZ) (odds ratios (OR) = 1.0531, P IVW = 0.0414), as well as major depressive disorder (MDD) (OR = 1.0329, P IVW = 0.0011). Similarly, PDE7A was associated with higher odds of attention-deficit/hyperactivity disorder (ADHD) (OR = 1.0861, P IVW = 0.0038). Exploring specific PDE subtypes and increase intracellular cAMP levels can inform the development of targeted interventions. We also observed PDEs (which hydrolyzes both cAMP and cGMP) was associated with psychiatric disorders [OR of PDE1A was 1.0836 for autism spectrum disorder; OR of PDE2A was 0.8968 for Tourette syndrome (TS) and 0.9449 for SCZ; and OR of PDE3A was 0.9796 for MDD; P < 0.05]. Furthermore, psychiatric disorders also had some causal effects on PDEs [obsessive–compulsive disorder on increased PDE6D and decreased PDE2A and PDE4D; anorexia nervosa on decreased PDE9A]. The results of MR were found to be robust using multiple sensitivity analysis. Conclusions In this study, potential causal relationships between plasma PDE proteins and psychiatric disorders were established. Exploring other PDE subtypes not included in this study could provide a more comprehensive understanding of the role of PDEs in psychiatric disorders. The development of specific medications targeting PDE subtypes may be a promising therapeutic approach for treating psychiatric disorders

Calcium Homeostasis and Psychiatric Disorders: A Mendelian Randomization Study

Observational studies have investigated the impact of calcium homeostasis on psychiatric disorders; however, the causality of associations is yet to be established. Bidirectional Mendelian randomization (MR) analysis of calcium homeostasis hormones was conducted on nine psychiatric disorders. Calcium, serum 25-hydroxyvitamin D levels (25OHD), parathyroid hormone, and fibroblast growth factor 23 are the major calcium homeostasis hormones. The causality was evaluated by the inverse variance weighted method (IVW) and the MR Steiger test, while Cochran’s Q test, the MR-Egger intercept test, funnel plot, and the leave-one-out method were used for sensitivity analyses. Bonferroni correction was used to determine the causative association features (p −4). Schizophrenia (SCZ) was significantly associated with decreased 25OHD concentrations with an estimated effect of −0.0164 (Prandom-effect IVW = 2.39 × 10−7). In the Multivariable MR (MVMR) analysis adjusting for potentially confounding traits including body mass index, obesity, mineral supplements (calcium, fish oil, and vitamin D) and outdoor time (winter and summer), the relationship between SCZ and 25OHD remained. The genetically predicted autism spectrum disorder and bipolar disorder were also nominally associated with decreased 25OHD. This study provided evidence for a causal effect of psychiatric disorders on calcium homeostasis. The clinical monitoring of 25OHD levels in patients with psychiatric disorders is beneficial

Acupotomy Therapy for Knee Osteoarthritis Pain: Systematic Review and Meta-Analysis

Background and Purpose. Knee osteoarthritis (OA) is a major public health problem, and currently, few effective medical treatments exist. Chinese acupotomy therapy has been widely used for the treatment of knee OA in China. We conducted this systematic review and meta-analysis to evaluate the efficacy of Chinese acupotomy in treating knee OA to inform clinical practice. Methods. We performed a comprehensive search on PubMed, the Cochrane Library, EMBASE, and four Chinese databases for articles published prior to June 2020. We included only randomized controlled trials (RCTs) that used acupotomy therapy as the major intervention in adults with knee OA, were published in either Chinese and English, included more than 20 subjects in each group, and included pain and function in the outcome measures. Knee OA was defined by the American College of Rheumatology or Chinese Orthopedic Association criteria in all studies. We extracted the visual analogue scale (VAS) pain score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score, the total effectiveness rate, the modified Japanese Orthopedic Association (JOA) activities of daily living score, and Lysholm’s score. We calculated the mean difference (MD) or risk ratio (RR) for all relevant outcomes. Meta-analyses were conducted using random-effects models when appropriate. Results. We identified 1317 potentially relevant studies, thirty-two of which met the eligibility criteria and were conducted in China between 2007 and 2020. A total of 3021 knee OA patients (62.96% female, median age: 57 years, and median disease duration: 33 months) were included. The treatment duration ranged from 1 week to 5 weeks (median: 3 weeks). The typical acupotomy treatment involved releasing soft tissue adhesions and was performed once a week for 1–5 weeks until the pain was relieved. The control group treatments included acupuncture (8 studies), electroacupuncture (10 studies), sodium hyaluronate (8 studies), radiofrequency electrotherapy (1 study), and nonsteroidal anti-inflammatory drugs (NSAIDs, 5 studies). The results from the meta-analysis showed that acupotomy led to superior improvements in the VAS pain score (MD = −1.11; 95% confidence interval (CI), −1.51 to −0.71; p < 0.00001) and WOMAC pain score (MD = −2.32; 95% CI, −2.94 to −1.69; p < 0.00001), a higher total effectiveness rate (RR = 1.15; 95% CI, 1.09–1.21; p < 0.00001), and superior improvements in the JOA score (MD = 6.39; 95% CI, 4.11–9.76; p < 0.00001) and Lysholm’s score (MD = 12.75; 95% CI, 2.61–22.89; p = 0.01) for overall pain and function. No serious adverse events were reported. Conclusion. Chinese acupotomy therapy may relieve pain and improve function in patients with knee OA. Furthermore, rigorously designed and well-controlled RCTs are warranted

Interferon Inhibition Enhances the Pilot-Scale Production of Rabies Virus in Human Diploid MRC-5 Cells

Inactivated vaccines based on cell culture are very useful in the prevention and control of many diseases. The most popular strategy for the production of inactivated vaccines is based on monkey-derived Vero cells, which results in high productivity of the virus but has a certain carcinogenic risk due to non-human DNA contamination. Since human diploid cells, such as MRC-5 cells, can produce a safer vaccine, efforts to develop a strategy for inactivated vaccine production using these cells have been investigated using MRC-5 cells. However, most viruses do not replicate efficiently in MRC-5 cells. In this study, we found that rabies virus (RABV) infection activated a robust interferon (IFN)-&beta; response in MRC-5 cells but almost none in Vero cells, suggesting that the IFN response could be a key limiting factor for virus production. Treatment of the MRC-5 cells with IFN inhibitors increased RABV titers by 10-fold. Additionally, the RABV titer yield was improved five-fold when using IFN receptor 1 (IFNAR1) antibodies. As such, we established a stable IFNAR1-deficient MRC-5 cell line (MRC-5IFNAR1&minus;), which increased RABV production by 6.5-fold compared to normal MRC-5 cells. Furthermore, in a pilot-scale production in 1500 square centimeter spinner flasks, utilization of the MRC-5IFNAR1&minus; cell line or the addition of IFN inhibitors to MRC cells increased RABV production by 10-fold or four-fold, respectively. Thus, we successfully established a human diploid cell-based pilot scale virus production platform via inhibition of IFN response for rabies vaccines, which could also be used for other inactivated virus vaccine production