Advances in virus-like particle-based SARS-CoV-2 vaccines.

The Coronavirus Disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has incurred devastating human and economic losses. Vaccination remains the most effective approach for controlling the COVID-19 pandemic. Nonetheless, the sustained evolution of SARS-CoV-2 variants has provoked concerns among the scientific community regarding the development of next-generation COVID-19 vaccines. Among these, given their safety, immunogenicity, and flexibility to display varied and native epitopes, virus-like particle (VLP)-based vaccines represent one of the most promising next-generation vaccines. In this review, we summarize the advantages and characteristics of VLP platforms, strategies for antigen display, and current clinical trial progress of SARS-CoV-2 vaccines based on VLP platforms. Importantly, the experience and lessons learned from the development of SARS-CoV-2 VLP vaccines provide insights into the development of strategies based on VLP vaccines to prevent future coronavirus pandemics and other epidemics.

SP1­mediated ADAMTS5 transcription promotes IL­1ß­induced chondrocyte injury via Wnt/ß­catenin pathway in osteoarthritis.

Osteoarthritis (OA) is a chronic disease that involves chondrocyte injury. ADAMTS5 has been confirmed to mediate chondrocyte injury and thus regulate OA progression, but its underlying molecular mechanisms remain unclear. In the present study, interleukin­1ß (IL­1ß)­induced chondrocytes were used to mimic OA in vitro. Cell proliferation and apoptosis were assessed by MTT assay, EdU assay and flow cytometry, and protein levels of ADAMTS5, specificity protein 1 (SP1), matrix­related markers and Wnt/ß­catenin pathway­related markers were examined using western blotting. In addition, ELISA was performed to measure the concentrations of inflammation factors, and oxidative stress was evaluated by detecting SOD activity and MDA levels. The mRNA expression levels of ADAMTS5 and SP1 were determined by reverse transcription­quantitative PCR, and the interaction between SP1 and ADAMTS5 was analyzed using a dual­luciferase reporter assay and chromatin immunoprecipitation assay. IL­1ß suppressed proliferation, but promoted apoptosis, extracellular matrix degradation, inflammation and oxidative stress in chondrocytes. ADAMTS5 was upregulated in IL­1ß­induced chondrocytes, and its knockdown alleviated IL­1ß­induced chondrocyte injury. SP1 could bind to the ADAMTS5 promoter region to promote its transcription, and SP1 knockdown relieved IL­1ß­induced chondrocyte injury by reducing ADAMTS5 expression. The SP1/ADAMTS5 axis activated the Wnt/ß­catenin pathway, and the Wnt/ß­catenin pathway agonist, SKL2001, reversed the protective effect of ADAMTS5 knockdown on chondrocyte injury induced by IL­1ß. To the best of our knowledge, the present study was the first to reveal the interaction between SP1 and ADAMTS5 in OA progression and indicated that the SP1/ADAMTS5 axis mediates OA progression by regulating the Wnt/ß­catenin pathway.

Malignant atrophic papulosis (Degos disease) with central nervous system involvement.

A 49-year-old man presented with a 2-year history of weakness and sensory disturbances in the bilateral lower extremities, vesicorectal dysfunction, and progressive gait disturbances. Brain MRI revealed multiple ischemic and hemorrhagic cortical/subcortical lesions with patchy enhancement involving the frontal and parietal lobes, suggesting the possibility of distal perforating arteries injury. Spine MRI revealed lesions of the cervical and thoracic spinal cord with associated enhancement. The diagnosis of malignant atrophic papulosis (Degos disease) with central nervous system involvement was prompted by the characteristic skin lesions.

Problematic internet gaming and non-suicidal self-injury in Chinese adolescents: Moderating and mediating roles of anxiety.

INTRODUCTION: Despite consistent reports of the association between problematic internet gaming (PIG) and non-suicidal self-injury (NSSI), an increase in PIG does not necessarily lead to increased NSSI. This apparent paradox indicates the presence of other mediators and moderators in the PIG-NSSI association. This study aimed to investigate the role of anxiety as a potential moderating and mediating factor of the PIG-NSSI association in Chinese adolescents. METHODS: A cross-sectional study was conducted among 10,479 Chinese adolescents (50.5% male; age range, 9-18 years). Standardized self-report questionnaires were used to assess the severity of PIG, anxiety, and NSSI. Spearman correlation and multiple linear regression were applied to examine the relationships among PIG, anxiety, and NSSI. Both moderating and mediating effects of anxiety were assessed using Hayes' methods. RESULTS: PIG, anxiety symptoms, and NSSI significantly correlated with one another. Anxiety significantly moderated the relationship between PIG and NSSI [B = 0.002, standard error (SE) = 0.000, p < 0.001], and it partially mediated the PIG-NSSI association [B = 0.017, SE = 0.001, 95% confidence interval (CI) 0.014-0.021]. Social concern and concentration were the two dimensions of anxiety that exerted the strongest mediation effect (B = 0.017, SE = 0.002, 95% CI 0.014-0.020). CONCLUSIONS: Adolescents with PIG and high anxiety are likely to suffer more severe NSSI and may benefit from interventions to reduce anxiety symptoms.

Therapeutic effect of tempo in Mozart's "Sonata for two pianos" (K. 448) in patients with epilepsy: An electroencephalographic study.

BACKGROUND: Mozart's "Sonata for two pianos" (Köchel listing 448) has proven effective as music therapy for patients with epilepsy, but little is understood about the mechanism of which feature in it impacted therapeutic effect. This study explored whether tempo in that piece is important for its therapeutic effect. METHODS: We measured the effects of tempo in Mozart's sonata on clinical and electroencephalographic parameters of 147 patients with epilepsy who listened to the music at slow, original, or accelerated speed. As a control, patients listened to Haydn's Symphony no. 94 at original speed. RESULTS: Listening to Mozart's piece at original speed significantly reduced the number of interictal epileptic discharges. It decreased beta power in the frontal, parietal, and occipital regions, suggesting increased auditory attention and reduced visual attention. It also decreased functional connectivity among frontal, parietal, temporal, and occipital brain regions, also suggesting increased auditory attention and reduced visual attention. No such effects were observed after patients listened to the slow or fast version of Mozart's piece, or to Haydn's symphony at normal speed. CONCLUSIONS: These results suggest that Mozart's "Sonata for two pianos" may exert therapeutic effects by regulating attention when played at its original tempo, but not slower or faster. These findings may help guide the design and optimization of music therapy against epilepsy.

Case report: Orthostatic leg tremor as the initial manifestation in a patient with metabotropic glutamate receptor-5 encephalitis without cortical dysfunction: complexities in identification and treatment.

Objective: Metabotropic glutamate receptor 5 (mGluR5) encephalitis is such a rare type of autoimmune encephalitis that its diagnosis remains a challenge. Case report: A 19-year-old female patient initially presented with anxiety and orthostatic leg tremors without cortical dysfunction. We found that this patient was positive for mGluR5 antibodies in both serum (1:1,000) and cerebrospinal fluid (1:32). After comprehensive intervention, the patient showed complete recovery at the 18-month follow-up. Discussion: This report expands our knowledge of the possible presentations of mGluR5 encephalitis for early diagnosis, which makes it possible to prevent serious consequences and improve the prognosis.

Tri-templating Synthesis of Multilevel Mesoporous Silica Microspheres with a Complex Interior Structure for Efficient CO2 Capture and Catalysis.

Multilevel porous architectures with microscopic shape control and tailor-made complex structures offer great potential for various innovative applications, but their elaborate design and synthesis have remained a scientific and technological challenge. Herein, we report a simple and effective tri-templating method, in which microscale Pickering droplets, nanoscale polystyrene colloids (PS), and molecular cetyltrimethylammonium chloride micelles are synchronously employed, for the fabrication of such micro-nanohierarchical mesoporous silica microspheres. In this protocol, Pickering droplet-directed interfacial sol-gel growth and its spatially confined surfactant assembly-directed sol-gel coating on PS suspensions are coupled together, enabling the successful formation of structured mesoporous silica that consists of numerous nanocompartments enclosed by a permeable shell. By varying the quantity of PS colloidal templates, rational regulation of the complex interior structure is achieved. Also, ascribed to the multilevel arrangement, this peculiar architecture not only shows desirable fast mass transport of external molecules but also possesses easy handling ability. After loading with tetraethylenepentamine or enzyme species, the yielded microspherical CO2 sorbents or immobilized biocatalysts, respectively, exhibit enhanced CO2 capture capacity and enzymatic catalysis efficiency. Notably, taking advantage of their microscopic characteristics, the immobilized biocatalysts could be ideally packed in a fixed-bed reactor for long-term continuous-flow enzymatic reactions. This tri-templating strategy provides a new synthetic route to access other multilevel microscopic materials with fascinating complex structures and paves a way to promote their practical applications.

Effect of Repeated Home Quarantine on Anxiety, Depression, and PTSD Symptoms in a Chinese Population During the COVID-19 Pandemic: A Cross-sectional Study.

Background: Strict quarantines can prevent the spread of the COVID-19 pandemic, but also increase the risk of mental illness. This study examined whether the people who have experienced repeated home quarantine performance more negative emotions such as anxiety, depression, and post-traumatic stress disorder (PTSD) in a Chinese population. Methods: We collected data from 2,514 participants in Pi County, Chengdu City, and stratified them into two groups. Group 1 comprised 1,214 individuals who were quarantined only once in early 2020, while Group 2 comprised 1,300 individuals who were quarantined in early 2020 and again in late 2020. Both groups were from the same community. The GAD-7, PHQ-9, and PCL-C scales were used to assess symptoms of anxiety, depression, and PTSD between the two groups. Results: Analyses showed that total PHQ-9 scores were significantly higher in Group 2 than in Group 1 (p < 0.001) and the quarantine times and age are independent predictors of symptoms of depression (p < 0.001). The two groups did not differ significantly in total GAD-7 or PCL-C scores. Conclusion: Increasing quarantine times was associated with moderate to severe depression symptoms, but not with an increase in symptoms of anxiety or PTSD.

Relapsing and Immune-Responsive Paroxysmal Jaw Clonus With Blepharospasm and Sialorrhea Associated With D2R Autoantibodies.

OBJECTIVES: To extend the symptomatic spectrum of acute neurologic syndrome associated with dopamine-2 receptor (D2R) antibodies. METHODS: A 13-year-old adolescent boy was admitted to the Neurology Department with abnormal jaw movements. The initial evaluation included laboratory examinations of blood, chest radiography, brain MRI, EEG, and neuropsychologic tests. Serum and CSF samples were collected for immunologic studies. The clinical outcome of the patient was followed up for 18 months after the first hospitalization. RESULTS: Paroxysmal jaw clonus, blepharospasm, and sialorrhea were observed in the patient with a history of Tourette syndrome and obsessive-compulsive disease and with an acute neurologic syndrome associated with D2R antibodies. The symptoms responded to IV methylprednisolone (IVMP), relapsed twice during prednisone reduction, and, finally, improved after the combined treatment of IVMP and IV immunoglobulin. DISCUSSION: Recognizing paroxysmal jaw clonus (possibly with blepharospasm and sialorrhea) and considering the relationship between these episodes and D2R antibodies will be helpful in the early diagnosis and treatment of immune neurologic syndromes.

The Benefits of Music Listening for Induced State Anxiety: Behavioral and Physiological Evidence.

BACKGROUND: Some clinical studies have indicated that neutral and happy music may relieve state anxiety. However, the brain mechanisms by which these effective interventions in music impact state anxiety remain unknown. METHODS: In this study, we selected music with clinical effects for therapy, and 62 subjects were included using the evoked anxiety paradigm. After evoking anxiety with a visual stimulus, all subjects were randomly divided into three groups (listening to happy music, neutral music and a blank stimulus), and EEG signals were acquired. RESULTS: We found that different emotional types of music might have different mechanisms in state anxiety interventions. Neutral music had the effect of alleviating state anxiety. The brain mechanisms supported that neutral music ameliorating state anxiety was associated with decreased power spectral density of the occipital lobe and increased brain functional connectivity between the occipital lobe and frontal lobe. Happy music also had the effect of alleviating state anxiety, and the brain mechanism was associated with enhanced brain functional connectivity between the occipital lobe and right temporal lobe. CONCLUSIONS: This study may be important for a deep understanding of the mechanisms associated with state anxiety music interventions and may further contribute to future clinical treatment using nonpharmaceutical interventions.

Psychiatric symptoms as initial manifestation in neuromyelitis optica spectrum disorder without cortical lesions: A report of two cases.

Diagnosing neuromyelitis optica spectrum disorder (NMOSD) remains a challenge, especially in patients with atypical presentations. Here, we describe two NMOSD patients who initially presented psychiatric symptoms without cortical lesions. This report expands our understanding of the possible presentations of NMOSD. Knowledge of rare initial symptoms may allow timely diagnosis and early therapeutic intervention, preventing more severe attacks affecting the spinal cord or eyes.

Abnormal brain activity in nonsuicidal self-injury: a coordinate-based activation likelihood meta-analysis of functional neuroimaging studies.

Background: The high prevalence of nonsuicidal self-injury (NSSI) in youths demonstrates a substantial population-level burden on society. NSSI is often associated with emotional and social skill deficits. To date, several studies have aimed to identify the underlying neural mechanism of those deficits in NSSI by using functional magnetic resonance imaging (fMRI). However, their conclusions display poor consistency. Objective: We aimed to conduct a meta-analysis using activation likelihood estimation (ALE) for fMRI data based on emotional and cognitive tasks to clarify the underlying neural processing deficits of NSSI. Methods: We searched for MRI studies of NSSI in the PubMed, Cochrane, and Embase databases. We identified significant foci for the included studies and conducted two ALE meta-analyses as follows: (i) activation for the NSSI contrast healthy control group and (ii) deactivation for the NSSI contrast healthy controls. Considering the diverse sex composition of study participants and possible bias from one large sample study, we conducted sensitivity analyses for the meta-analysis. Results: Nine studies comprising 359 participants were included, and the results demonstrated substantial activation in NSSI patients compared with healthy controls in two clusters located in the right medial frontal gyrus extending to the rostral anterior cingulate and the left inferior frontal gyrus extending to the insula. Conclusions: The results suggest that individuals with NSSI show brain activity alterations that underpin their core symptoms, including poor emotional regulation and reward processing deficits. Our findings provide new insights into the neural mechanism of NSSI, which may serve as functional biomarkers for developing effective diagnosis and therapeutic interventions for these patients.

Severe psychological distress among patients with epilepsy during the COVID-19 outbreak in southwest China.

OBJECTIVE: To compare the severity of psychological distress between patients with epilepsy and healthy controls during the COVID-19 outbreak in southwest China, as well as identify potential risk factors of severe psychological distress among patients with epilepsy. METHODS: This cross-sectional case-control study examined a consecutive sample of patients older than 15 years treated at the epilepsy center of West China Hospital between February 1 and February 29, 2020. As controls, sex- and age-matched healthy visitors of inpatients (unrelated to the patients) were also enrolled during the same period. Data on demographics and attention paid to COVID-19 were collected by online questionnaire, data on epilepsy features were collected from electronic medical records, and psychological distress was evaluated using the 6-item Kessler Psychological Distress Scale (K-6). Potential risk factors of severe psychological distress were identified using multivariate logistic regression. RESULTS: The 252 patients and 252 controls in this study were similar along all demographic variables except family income. Patients with epilepsy showed significantly higher K-6 scores than healthy controls and spent significantly more time following the COVID-19 outbreak (both P < .001). Univariate analyses associated both diagnosis of drug-resistant epilepsy and time spent paying attention to COVID-19 with severe psychological distress (defined as K-6 score >12; both P ≤ .001). Multivariate logistic regression identified two independent predictors of severe psychological distress: time spent paying attention to COVID-19 (odds ratio [OR] = 1.172, 95% confidence interval [CI] = 1.073-1.280) and diagnosis of drug-resistant epilepsy (OR = 0.283, 95% CI = 0.128-0.623). SIGNIFICANCE: During public health outbreaks, clinicians and caregivers should focus not only on seizure control but also on mental health of patients with epilepsy, especially those with drug-resistant epilepsy. K-6 scores > 12 indicate severe psychological distress. This may mean, for example, encouraging patients to engage in other activities instead of excessively following media coverage of the outbreak.

Proprotein convertase subtilisin/kexin 9 inhibitors in reducing cardiovascular outcomes: a systematic review and meta-analysis.

BACKGROUND: To evaluate the effects of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors on major adverse cardiovascular events (MACE). METHODS: Our systematic review included randomised controlled trials if they studied PCSK9 inhibitors in patients for primary and/or secondary prevention of cardiovascular diseases or with hypercholesterolaemia/hyperlipidaemia. Dichotomous variables from individual studies were pooled by relative risks (RR) and their 95% CIs using the random-effect model. Risk difference (RD) in the 10-year frame was also estimated using the pooled RR and the estimated baseline risk using the control group. Grading of Recommendation Assessment, Development and Evaluation was used to assess the quality of evidence. RESULTS: We included 54 trials with 97 910 patients in the analysis. Compared with controls, PCSK9 inhibitors significantly reduced the risk of MACE by 16% (RR, 0.84; 95% CI 0.79 to 0.89; RD: 47 fewer per 1000 vs 286 as the baseline risk; 95% CI 32 to 59 fewer), non-fatal myocardial infarction (MI) by 17% (RR, 0.83; 95% CI 0.74 to 0.93; RD, 35 fewer per 1000 vs 207 as the baseline; 95% CI 13 to 53 fewer) and any stroke by 25% (RR, 0.75; 95% CI 0.65 to 0.85; RD, 16 fewer per 1000 vs 61 as the baseline; 95% CI 9 to 21 fewer) with moderate quality evidence. No significant differences were found between PCSK9 inhibitors and control groups in all-cause mortality, cardiovascular death, heart failure or unstable angina with low-quality evidence. CONCLUSIONS: This study demonstrated that PCSK9 inhibitors could significantly reduce the risk of MACE, non-fatal MI and stroke. TRIAL REGISTRATION: PROSPERO; CRD42017073904.

Response to treatment schedules after the first antiepileptic drug failed.

OBJECTIVE: After the failure of the first antiepileptic drug (AED) at doses > 50% defined daily dose (DDD), there are three options for patients with epilepsy: combination therapy, alternative therapy, and increased dosage of the first AED. However, present studies have not provided evidence for which option is best. Therefore, we conducted this retrospective observational cohort study to compare the effects of three treatment schedules. METHODS: Patients diagnosed with newly diagnosed epilepsy at the epilepsy clinic of West China Hospital between August 2006 and February 2016 were evaluated for eligibility for this study. Patients who failed to respond to the first AED at doses > 50% DDD were included, and divided into three cohorts: increased dosage, combination therapy, and alternative therapy. Cumulative incidence curves for time to seizure freedom were compared for different cohorts by Gray test. Competing risk regression was conducted to evaluate the association of clinical predictors with seizure freedom. RESULTS: Altogether, 502 patients (277 male, 55.2%) were included for further analysis, and the median duration of follow-up was 32 months (range = 8-127). The probability of seizure freedom was significantly higher in patients receiving combination therapy (n = 323) compared to the alternative therapy cohort (n = 76, P < 0.001) and increased dosage cohort (n = 103, P = 0.025). Competing risk regression analysis showed that combination therapy significantly increased the probability of seizure freedom (hazard ratio [HR] = 2.423, 95% confidence interval [CI] = 1.529-3.841, P < 0.001). In addition, male sex and generalized seizure were significantly associated with increased probability of seizure freedom (male sex: HR = 1.440, 95% CI = 1.106-1.880, P = 0.007; generalized seizure: HR = 1.543, 95% CI = 1.176-2.020, P = 0.002). SIGNIFICANCE: Combination therapy may increase the probability of seizure freedom for patients with first AED failure due to lack of efficacy.

Nonhuman primate models of focal cerebral ischemia.

Rodents have been widely used in the production of cerebral ischemia models. However, successful therapies have been proven on experimental rodent stroke model, and they have often failed to be effective when tested clinically. Therefore, nonhuman primates were recommended as the ideal alternatives, owing to their similarities with the human cerebrovascular system, brain metabolism, grey to white matter ratio and even their rich behavioral repertoire. The present review is a thorough summary of ten methods that establish nonhuman primate models of focal cerebral ischemia; electrocoagulation, endothelin-1-induced occlusion, microvascular clip occlusion, autologous blood clot embolization, balloon inflation, microcatheter embolization, coil embolization, surgical suture embolization, suture, and photochemical induction methods. This review addresses the advantages and disadvantages of each method, as well as precautions for each model, compared nonhuman primates with rodents, different species of nonhuman primates and different modeling methods. Finally it discusses various factors that need to be considered when modelling and the method of evaluation after modelling. These are critical for understanding their respective strengths and weaknesses and underlie the selection of the optimum model.

Impact of Drug Manipulation on Seizure Freedom in Adults with Uncontrolled Epilepsy: A Prospective Controlled Study in Rural China.

INTRODUCTION: It has been suggested that uncontrolled epilepsy might not necessarily equate to drug resistance when antiepileptic drugs (AEDs) are used at relatively low doses, a practice frequently observed in rural areas of China. OBJECTIVE: To assess the clinical benefits of further drug manipulation in this situation, we prospectively followed up the outcomes of patients with uncontrolled epilepsy while taking relatively low doses of AEDs. METHODS: The study included patients aged 16 years and older with uncontrolled epilepsy and who were receiving at least one AED at a dosage below 50% of the World Health Organization (WHO) defined daily dose (DDD) (50% DDD) (Group 1). Patients with drug-resistant epilepsy were included for comparison (Group 2). Both groups were followed-up for at least 2 years. Seizure outcomes after further drug manipulations were recorded at the last follow-up. RESULTS: A total of 197 patients (55.3% male) were included in Group 1 and 32 (46.9% male) in Group 2; their mean duration of follow-up was 28.85 ± 1.90 and 30.91 ± 2.04 months, respectively. At the last follow-up, 16.8% (33/197) of patients in Group 1 had become seizure-free compared with none in Group 2 (p < 0.001). Seventeen of 93 (18.3%) patients in Group 1 became seizure free after increasing the dosage of baseline AED(s) alone. Only 5.5% (3/55) of patients who had failed to respond to an AED at ≥50% DDD at baseline became seizure free compared with 21.1% (30/142) who did not have such a history (p = 0.001). The number of AEDs taken at a dosage below 50% DDD at baseline was not associated with seizure outcome. CONCLUSIONS: Uncontrolled epilepsy could become controlled in a substantial proportion of patients by dose increase alone, particularly if there is no history of drug failure at ≥50% DDD.