Treatment algorithms of relapsing multiple sclerosis: an exploration based on the available disease-modifying therapies in China.

Multiple sclerosis (MS) was defined as a rare disease in China due to its low prevalence. For a long time, interferon ß was the only approved disease-modifying therapy (DMT). Since the first oral DMT was approved in 2018, DMT approval accelerated, and seven DMTs were approved within 5 years. With an increasing number of DMTs being prescribed in clinical practice, it is necessary to discuss the standardized MS treatment algorithms depending on the disease activity and DMT availability. In this review paper, more than 20 Chinese experts in MS have reviewed the therapeutic progress of MS in China and worldwide and discussed algorithms for treating relapsing MS (RMS) based on the available DMTs in China, providing insights for establishing the standardized RMS treatment algorithms in this country.

Treatment algorithms of relapsing multiple sclerosis in China In this review paper, more than 20 Chinese experts in MS have reviewed the therapeutic progress of MS in China and worldwide and discussed algorithms for treating relapsing MS (RMS) based on the available DMTs in China, providing insights for establishing the standardized RMS treatment algorithms in this country: 1) CIS and RRMS account for more than 90% of the MS patients and most of them are mild to moderate; 2) MS patients should initiate DMT treatments as soon as the disease has been diagnosed in order to reduce the risk of disease progression; 3) Patients who have been diagnosed with MS should start treatment with fundamental DMTs unless the disease course has been highly active; 4) MAGNIMS score may be a suitable and simplified assessment tool for measuring treatment response to DMTs; 5) Patients treated with corticosteroids and NSIS should be switched to the standardized DMT treatment during remission in accordance with disease activity.

Multiple approaches to reduce reconstitution time of lyophilized drug products with high protein concentration.

Background: Lyophilized drug products with high protein concentration often perform long reconstitution time, which is inconvenient for clinical use. The objective of this work is to achieve short reconstitution time with multiple and combined strategies. Methods: Here, we describe the following approaches that lead to reduction of reconstitution time, including adding annealing step, decreasing headspace pressure, decreasing protein concentration with reducing diluent volume, increasing high surface-area-to-height ratio of the cakes, increasing frequency of swirling and diluent temperature. Results: Among these strategies, reducing diluent volume to achieve high protein concentration and reducing headspace pressure show markedly reduction of reconstitution time. Moreover, we propose combined strategies to mitigate the reconstitution time, at the same time, to achieve same target dose in clinics. Conclusions: Therefore, this paper provides insights on the application of multiple strategies to accelerate the reconstitution of lyophilized drug products with high concentration, and facilitates their widespread clinical application.

Efficacy and safety of low- and ultralow-dose rituximab in neuromyelitis optica spectrum disorder.

BACKGROUND: Rituximab effectively targets B cells and reduces relapses in neuromyelitis optica spectrum disorder (NMOSD). But the ideal dosage and treatment intervals remain unanswered. We aimed to assess the efficacy and safety of low and ultralow-dose rituximab in NMOSD. METHODS: We conducted a retrospective analysis of NMOSD patients treated with rituximab at two Chinese tertiary hospitals. Patients received either a low-dose regimen (500 mg reinfusion every 6 months) or an ultralow-dose regimen: 100 to 300 mg rituximab based on CD19+B cells (100 mg for 1-1.5% of peripheral blood mononuclear cells, 200 mg for 1.5-5%, and 300 mg for over 5%). RESULTS: We analyzed data from 136 patients (41 in the low-dose group, 95 in the ultralow-dose group) with median follow-up durations of 43 and 34.2 months, respectively. Both groups exhibited similar sex distribution, age at disease onset, annual relapse rate, and baseline disease duration. Survival analysis showed that ultralow-dose rituximab was noninferior to low-dose rituximab in preventing relapses. Infusion reactions occurred in 20 of 173 (11.6%) low-dose treatments and 9 of 533 (1.7%) ultralow-dose treatments. B-cell re-emergence was observed in 137 of 236 (58.1%) monitors in the low-dose group and 367 of 1136 (32.3%) monitors in the ultralow-dose group. CONCLUSION: Ultralow dose rituximab was noninferior to low-dose rituximab in preventing NMOSD relapses. A randomized controlled trial is essential to validate these findings.

Role of the cGAS-STING pathway in radiotherapy for non-small cell lung cancer.

One of the most important therapeutic interventions for non-small cell lung cancer is radiotherapy. Ionizing radiation (IR) is classified by traditional radiobiology principles as a direct cytocidal therapeutic agent against cancer, although there is growing recognition of other antitumor immunological responses induced by this modality. The most effective therapeutic combinations to harness radiation-generated antitumor immunity and enhance treatment results for malignancies resistant to existing radiotherapy regimens could be determined by a more sophisticated understanding of the immunological pathways created by radiation. Innate immune signaling is triggered by the activation of cGAS-STING, and this promotes adaptive immune responses to help fight cancer. This identifies a molecular mechanism radiation can use to trigger antitumor immune responses by bridging the DNA-damaging ability of IR with the activation of CD8 + cytotoxic T cell-mediated killing of tumors. We also discuss radiotherapy-related parameters that affect cGAS-STING signaling, negative consequences of cGAS-STING activation, and intriguing treatment options being tested in conjunction with IR to support immune activation by activating STING-signaling. Improved therapeutic outcomes will result from a better understanding of how IR promotes cGAS-STING signaling in immune-based treatment regimens that maximize radiotherapy's anticancer effectiveness.

A multicentre, prospective, double-blind study comparing the accuracy of autoantibody diagnostic assays in myasthenia gravis: the SCREAM study.

Background: Laboratory determination of autoantibodies against acetylcholine receptor (AChR), muscle-specific kinase (MuSK) and other autoantigens have been integrated into the diagnosis of myasthenia gravis (MG). However, evidence supporting the selection of methodologies is lacking. Methods: In this prospective, multicentre cohort study, we recruited patients with suspected MG to evaluate the diagnostic accuracy of cell-based assay (CBA), radioimmunoprecipitation assay (RIPA) and enzyme-linked immunosorbent assay (ELISA) in detecting AChR and MuSK autoantibodies. This study is registered with www.clinicaltrials.gov, number NCT05219097. Findings: 2272 eligible participants were recruited, including 2043 MG, 229 non-MG subjects. AChR antibodies were detected in 1478, 1310, and 1280 out of a total of 2043 MG patients by CBA, RIPA, and ELISA, respectively; sensitivity, 72.3% (95% CI, 70.3-74.3), 64.1% (95% CI, 62.0-66.2), 62.7% (95% CI, 60.5-64.8); specificity, 97.8% (95% CI, 95.0-99.3), 97.8% (95% CI, 95.0-99.3), 94.8% (95% CI, 91.9-97.7). MuSK antibodies were found in 59, 50, and 54 from 2043 MG patients by CBA, RIPA and ELISA, respectively; sensitivity, 2.9% (95% CI, 2.2-3.7), 2.4% (95% CI, 1.8-3.2), 2.6% (95% CI, 2.0-3.4); specificity, 100% (95% CI, 98.4-100), 100% (95% CI, 98.4-100), and 99.1% (95% CI, 96.9-99.9). The area under the curve of AChR antibodies tested by CBA was 0.858, and there were statistical differences with RIPA (0.843; p = 0.03) and ELISA (0.809; p < 0.0001). Interpretation: CBA has a higher diagnostic accuracy compared to RIPA or ELISA in detecting AChR and MuSK autoantibodies for MG diagnosis. Funding: New Terrain Biotechnology, Inc., Tianjin, China.

Multi-objective optimization of hydrogen production system based on the combined supercritical cycle and gas turbine plant.

In this paper, considering the hydrogen production cycle coupled with the supercritical CO2 cycle, hydrogen is produced as a clean fuel along with power and heat production. Also, the world's need for clean energy doubles the solutions to achieve clean hydrogen energy. The investigated cycle has a supercritical CO2 cycle with a combustion chamber where enriched fuel is introduced. Combustion products produce work in the gas turbine, and further hydrogen separation is formed with the help of water gas shift reaction and hydrogen separation membrane. In the thermodynamic analysis, combustion chamber known as the most irreversible member of set, where the most exergy is lost. The energy and exergy efficiency for whole set are 64.82%, 52.46% respectively. Produced hydrogen mass flow rate calculated 46.8 kg/h. Also, multi-objective optimization based on genetic algorithm were done and the results were reported. All calculation and optimization method has been done in MATLAB software.

Clinical use of dimethyl fumarate in multiple sclerosis treatment: an update to include China, using a modified Delphi method.

Dimethyl fumarate (DMF) is a widely used oral disease-modifying therapy for multiple sclerosis (MS). Its efficacy and safety profiles are supported by over a decade of experience. Differences exist between Asia and Europe/United States in the prevalence and characteristics of MS; most data for DMF are derived from populations outside Asia. DMF was recently (2021) approved for use in China. The objectives of this review were to evaluate the evidence for DMF's profile, to provide an update to healthcare providers on current knowledge surrounding its use and to assess the relevance of existing data to use in China. This study used a modified Delphi method based on the insights of a scientific Steering Committee (SC), with a structured literature review conducted to assess the data of DMF. The literature review covered all papers in English (from 01 January 2011 to 21 February 2022) that include 'dimethyl fumarate' and 'multiple sclerosis', and their MeSH terms, on PubMed, supplemented by EMBASE and Citeline searches. Papers were categorized by topic and assessed for relevance and quality, before being used to formulate statements summarizing the literature on each subject. SC members voted on/revised statements, requiring ⩾80% agreement and ⩽10% disagreement for inclusion. Statements not reaching this level were discussed further until agreement was reached or until there was agreement to remove the statement. A total of 1030 papers were retrieved and used to formulate the statements and evidence summaries considered by the SC members. A total of 45 statements were agreed by the SC members. The findings support the positive efficacy and safety profile of DMF in treating patients with MS. Limited Chinese patient data are an ongoing consideration; however, based on current evidence, the statements are considered applicable to both the global and Chinese populations. DMF is a valuable addition to address unmet MS treatment needs in China. Registration: Not applicable.

Smart nanostructures for targeted oxygen-producing photodynamic therapy of skin photoaging and potential mechanism.

Background: Photodynamic therapy increases collagen and decreases solar fibrosis in photoaged skin; however, the efficacy of photodynamic therapy is limited in tissues with a hypoxic microenvironment. Methods: A novel autogenous oxygen-targeted nanoparticle, named MCZT, was synthesized based on the zeolitic imidazole framework material ZIF-8, methyl aminolevulinate, catalase and an anti-TRPV1 monoclonal antibody, and its effects on skin photoaging were investigated. Results: MCZT was successfully synthesized and showed uniform particle size, good dispersion, and excellent biocompatibility and safety. Moreover, MCZT effectively alleviated UV-induced inflammation, cellular senescence and apoptosis in HFF-1 cells. In in vivo models, MCZT ameliorated UV-evoked erythema and wrinkling, inflammation and oxidative stress, as well as the loss of collagen fibers and water, in the skin of mice. Conclusion: These findings suggest that MCZT holds promising potential for the treatment of skin photoaging.

Flexible and printable integrated biosensors for monitoring sweat and skin condition.

Wearable and flexible sensors are playing increasing roles in health monitoring (like physiological electrical signals and components of biofluids). Therein, sweat as a carrier of informative biomarkers would attract great attention for health status identification. However, most wearable biosensors have a short lifetime with complex fabrication processes and expensive costs, which would largely limit the application scene to some extent. Here, we developed a state-of-the-art flexible and integrated sensor patch with screen-printing technology for in-situ and real-time monitoring of electrolyte balance and skin state. The screen-printed sensor patch was easily fabricated, highly reproducible, disposable and relatively stable, which was extremely for sweat sensors with low cost. The state of art sensors on the patch of Na+, pH, skin impedance and temperature all showed excellent performance with high linearity (coefficient of determinations (R2) are 0.998, 0.994, 0.998 and 0.997, respectively). Besides, the detection ranges of Na+ and pH sensors are wide enough for sweat analysis of 10-100 mM and 2-8, respectively. The proposed device provides a new strategy for real-time sweat analysis, preventing dehydration and skin state monitoring during exercise.

MiR-101: An Important Regulator of Gene Expression and Tumor Ecosystem.

MiRNAs are small single-stranded non-coding RNAs. MiRNA contributes to the transcriptional and post-transcriptional regulation of mRNA in different cell types, including mRNA transcription inhibition and mRNA decay and phenotypes via the effect of several essential oncogenic processes and tumor microenvironment. MiR-101 is a highly conserved miRNA that was found to alter the expression in various human cancers. MiR-101 has been reported to have tumor oncogenic and suppressive effects to regulate tumorigenesis and tumor progression. In this review, we summarize the new findings about the roles of miR-101 in cancers and the underlying mechanisms of targeting genes degradation and microenvironment regulation, which will improve biological understanding and design of novel therapeutics.

Investigation of Parasitic Infection in Crocodile Lizards (Shinisaurus crocodilurus) Using High-Throughput Sequencing.

The highly endangered crocodile lizard (Shinisaurus crocodilurus) continues to be impacted by disease, especially in captive breeding populations. In this paper, based on high-throughput sequencing, we investigated parasitic infections in captive and wild crocodile lizard populations in the Daguishan National Nature Reserve and Guangdong Luokeng Shinisaurus crocodilurus National Nature Reserve. The results show that the overall parasitic infection rate in crocodile lizards was 33.33% (23/69). Four parasite genera were detected, including Eimeria, Cryptosporidium, Nematopsis, and Acanthamoeba, with infection rates of 15.94% (11/69), 17.39% (12/69), 7.25% (5/69), and 4.35% (3/69), respectively. Significant differences in the infection rate were found between the different parasite species (χ2 = 8.54, p < 0.05, chi-squared test). The parasitic infection rates in the captive and wild populations were 39.29% (22/56) and 7.69% (1/13), respectively, which were significantly different (p < 0.05, Fisher's exact test). However, no significant differences in the infection rates of the four parasite genera were found between the captive and wild populations (p > 0.05, Fisher's exact test). The parasitic infection rates in Daguishan and Luokeng were 34.09% (15/44) and 32.00% (8/25), respectively, which were not significantly different (p > 0.05, Fisher's exact test). However, significant differences in terms of species were found in the two reserves (p < 0.01, Fisher's exact test). Only Cryptosporidium infection showed a significant difference between the two regions (p < 0.01, Fisher's exact test). Our results suggest that captive crocodile lizards are more susceptible to parasitic diseases than wild crocodile lizards and that Cryptosporidium infection varies by geographical region. This study provides basic information about the parasites of endangered crocodile lizards, as well as a reference for disease control and conservation.

Determining levels of linguistic deficit by applying cluster analysis to the aphasia quotient of Western Aphasia Battery in post-stroke aphasia.

The aphasia quotient of Western Aphasia Battery (WAB-AQ) has been used as an inclusion criterion and as an outcome measure in clinical, research, or community settings. The WAB-AQ is also commonly used to measure recovery. This study aimed to quantitatively determine levels of the linguistic deficit by using a cluster analysis of the WAB-AQ in post-stroke aphasia (PSA). 308 patients were extracted from the database. Cutoff scores are defined by mean overlap WAB-AQ scores of clusters by systematic cluster analysis, the method of which is the farthest neighbor element, and the metrics are square Euclidean distance and Pearson correlation, performed on the full sample of WAB-AQ individual subitem scores. A 1-way analysis of variance, with post hoc comparisons conducted, was used to determine whether clusters had significant differences. Three clusters were identified. The scores for severe, moderate, and mild linguistic deficit levels ranged from 0 to 30, 30.1 to 50.3, and 50.4 to 93.7, respectively. For PSA, the cluster analysis of WAB-AQ supports a 3-impairment level classification scheme.

Expression of TRAF6 in peripheral blood B cells of patients with myasthenia gravis.

BACKGROUND: Tumor necrosis factor receptor-associated factor 6 (TRAF6) can regulate the activation of inflammatory signaling pathways by acting as an E3 ubiquitin ligase, which enhances B cell activation. This study aimed to evaluate the expression of TRAF6 in the peripheral blood B cells of myasthenia gravis (MG) patients and analyze the relationships between TRAF6 expression and clinical characteristics. METHOD: In our study, the expression level of TRAF6 in peripheral blood B cells of 89 patients was measured by flow cytometry compared with that of healthy subjects. The effects of disease severity, MG classification and immunotherapy on TRAF6 expression level were also analyzed. RESULTS: In our study, TRAF6 expression was elevated in CD19+ B cells and CD19+CD27+ memory B cells in generalized MG (GMG) patients compared with ocular MG (OMG) patients (p = 0.03 and p = 0.03, respectively). There was a significant positive correlation between the TRAF6 expression level and disease severity in both OMG patients and GMG patients (CD19+ B cells: OMG: p < 0.001, r = 0.89; GMG: p = 0.001, r = 0.59; CD29+CD27+ B cells: OMG: p = 0.001, r = 0.80; GMG: p = 0.048, r = 0.38). TRAF6 expression was significantly elevated in CD19+ B cells and CD19+CD27+ memory B cells in GMG with acute aggravation compared with GMG in MMS (p = 0.009 and p = 0.028, respectively). In the eleven MG patients who were followed, TRAF6 expression in B cells and memory B cells was significantly decreased after treatment (p = 0.03 and p < 0.01, respectively). CONCLUSION: TRAF6 is potentially a useful biomarker of inflammation in patients with MG, and might be used to evaluate the effectiveness of treatment.

Relative Entropy of Distance Distribution Based Similarity Measure of Nodes in Weighted Graph Data.

Many similarity measure algorithms of nodes in weighted graph data have been proposed by employing the degree of nodes in recent years. Despite these algorithms obtaining great results, there may be still some limitations. For instance, the strength of nodes is ignored. Aiming at this issue, the relative entropy of the distance distribution based similarity measure of nodes is proposed in this paper. At first, the structural weights of nodes are given by integrating their degree and strength. Next, the distance between any two nodes is calculated with the help of their structural weights and the Euclidean distance formula to further obtain the distance distribution of each node. After that, the probability distribution of nodes is constructed by normalizing their distance distributions. Thus, the relative entropy can be applied to measure the difference between the probability distributions of the top d important nodes and all nodes in graph data. Finally, the similarity of two nodes can be measured in terms of this above-mentioned difference calculated by relative entropy. Experimental results demonstrate that the algorithm proposed by considering the strength of node in the relative entropy has great advantages in the most similar node mining and link prediction.

Nuclear factor-kappa B and effector molecules in photoaging.

Nuclear factor-kappa B (NF-κB) has important but complex functions in the photoaging of the human skin. This protein complex is activated upon UV irradiation and plays a key role in the signalling pathway of the inflammatory cascade. NF-κB induces the expression of various proinflammatory cytokines, such as tumour necrosis factor (TNF) and interleukin-1 (IL-1). These proinflammatory cytokines can in turn stimulate the activation of NF-κB, forming a vicious cycle. These processes cause chronic inflammation and contribute to skin ageing. In addition, the activation of NF-κB upregulates the expression of matrix metalloproteinases (MMPs) and leads to the degradation of structural proteins in the dermis. NF-κB disrupts the barrier function of the skin under prolonged and repeated UV stimulations in these ways. Such activity causes chronic skin damage, followed by the formation of wrinkles, dryness, roughness, laxity, and other photoaging manifestations. This study on the NF-κB signalling pathway and effector molecules provides a new perspective to understand and prevent photoaging.

Design of Sports Rehabilitation Training System Based on EEMD Algorithm.

Motor function rehabilitation training is to restore the motor function of hand injury to the maximum extent and meet the needs of patients' daily behavior. At present, motor function evaluation and rehabilitation training work have disadvantages such as relying on the subjective experience of physicians, unable to quantitatively assess the loss of motor function, and single rehabilitation training method. Most of these methods only focus on the independent motion range of a single organ, lack of consideration of the constraint relationship between adjacent fingers, and do not build a visual model for it. To end this issue, for the purpose of sports rehabilitation, combined with the status and application of rehabilitation machines, this paper proposed a cycling rehabilitation training system based on physiological signal extraction of ensemble empirical mode decomposition (EEMD) algorithm. Results compared with the previous rehabilitation training, the muscle tension level of patients' upper limbs decreased, and the strength of some muscles also increased. With the progress of rehabilitation training, the contralateral dominance coefficient showed an upward trend, which further confirmed the role of the proposed method in sports rehabilitation, and also provided a new idea for the evaluation of rehabilitation training effect of patients in the future.

Clinical analysis of alcoholic pellagra: A single-center retrospective study.

BACKGROUND: Pellagra caused by niacin deficiency in alcoholics can be easily misdiagnosed because of similar symptoms to other alcohol-related diseases and the lack of the classical triad of signs. AIM: This study aimed to define the clinical presentation of alcoholic pellagra for early diagnosis and timely treatment. METHODS: The clinical data of 16 alcohol-dependent patients who had pellagra and treated in our hospital from January 2002 to December 2019 were retrospectively analyzed. The local medical ethics committee approval (Medical Ethics Committee of Affiliated Hospital of XuZhou Medical University, XYFY2020-KL247-02) for this study has been obtained. RESULTS: The main complaints of the 16 patients were skin lesions (six cases), diarrhea (six cases), and mental disorders (four cases). Then, 13 cases had typical skin lesions, and 3 patients had a full spectrum of diarrhea, dementia, and dermatitis (3D). In terms of the main diagnosis, 2 patients had pellagra and Wernicke's encephalopathy, 3 patients had pellagra and alcohol-withdrawal syndrome, and the other patients had pellagra. After sufficient amounts of niacin and multivitamin B were given, clinical symptoms improved rapidly, and no sequelae were observed during follow-up. CONCLUSIONS: Pellagra is rarely manifested as a full 3D spectrum, with only one or two characteristics, which lack diagnostic specificity, especially in individuals with alcoholism. Physicians should maintain a high degree of suspicion of niacin deficiency in alcoholics. Alcohol-dependent patients with pellagra may be accompanied by complications of Wernicke's encephalopathy and alcohol-withdrawal syndrome. Prompt identification and timely treatment with a sufficient amount of niacin in combination with other vitamins and a certain amount of Zn can achieve a good prognosis of pellagra.

The incidence and prevalence, diagnosis, and treatment of multiple sclerosis in China: a narrative review.

In 2018, the first list of rare diseases was published by the National Health Council of China, and multiple sclerosis (MS) was included in this list. Since then, the Chinese government and neurologists have made efforts to improve the clinical outcomes of patients with MS. During last few years, the incidence of MS in China was also investigated. The early and accurate diagnosis of MS was improved due to the application and promotion of magnetic resonance imaging and new diagnosis criteria. The market for and medical insurance access to disease-modifying therapies (DMTs) has been greatly accelerated, which has provided more treatment options and improved clinical outcomes for patients with MS, as well as reduced treatment cost. The pattern of MS in China is gradually changing, from delayed to early diagnosis, and from no treatment to treatment with DMTs during remission. This narrative review aimed to summarize an update to the status of MS in China, including incidence and prevalence, diagnosis, and available treatments. This would help to better understand the diagnosis and treatment gap between mainland China and other Asian regions, demonstrating the necessity of accurate diagnosis and optimized treatment of MS in China.

Suppression of CCT3 inhibits melanoma cell proliferation by downregulating CDK1 expression.

The eukaryotic chaperonin family is vital for cell survival. The dysregulation of chaperonin-containing TCP-1 subunit 3 (CCT3) is implicated in several types of malignant tumors' development. However, its functional role in melanoma remains unknown. Here we elucidate the functional contribution to CCT3 to melanoma progression. The results indicated that CCT3 highly expressed in melanoma tissues, and CCT3 overexpression is correlated with clinical stage in melanoma patients. Knockdown of CCT3 by shRNA in melanoma cells inhibited cell proliferation and cell cycle progression and induced cell apoptosis in vitro. In vivo, tumor growth in the nude mice was significantly inhibited after CCT3 silencing. Importantly, the gene array analysis showed that CCT3 depletions inhibited cyclins and cell cycle regulation signaling and further evaluation demonstrated that CDK1 expression was significantly decreased after CCT3 knockdown. Additionally, Functional rescues experiments also indicated that decreased cell proliferation due to CCT3 silencing was rescued by CDK1 overexpression. Overall, our findings suggest that CCT3 depletions prohibited melanoma progression by downregulating CDK1 expression and is a potential therapeutic target for melanoma.