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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in countless infections and caused millions of deaths since its emergence in 2019. Coronavirus disease 2019 (COVID-19)-associated mortality is caused by uncontrolled inflammation, aberrant immune response, cytokine storm, and an imbalanced hyperactive immune system. The cytokine storm further results in multiple organ failure and lung immunopathology. Therefore, any potential treatments should focus on the direct elimination of viral particles, prevention strategies, and mitigation of the imbalanced (hyperactive) immune system. This review focuses on cytokine secretions of innate and adaptive immune responses against COVID-19, including interleukins, interferons, tumor necrosis factor-alpha, and other chemokines. In addition to the review focus, we discuss potential immunotherapeutic approaches based on relevant pathophysiological features, the systemic immune response against SARS-CoV-2, and data from recent clinical trials and experiments on the COVID-19-associated cytokine storm. Prompt use of these cytokines as diagnostic markers and aggressive prevention and management of the cytokine storm can help determine COVID-19-associated morbidity and mortality. The prophylaxis and rapid management of the cytokine storm appear to significantly improve disease outcomes. For these reasons, this study aims to provide advanced information to facilitate innovative strategies to survive in the COVID-19 pandemic.

Forefoot strike becomes popular among runners because it facilitates better impact attenuation. However, forefoot strike may overload the plantar fascia and impose risk of plantar fasciitis. This study aimed to examine and compare the foot arch deformation and plantar fascia tension between different foot strike techniques in running using a computational modelling approach. A three-dimensional finite element foot model was reconstructed from the MRI of a healthy runner. The foot model included twenty bones, bulk soft tissue, ligaments, tendons, and plantar fascia. The time-series data of segmental kinematics, foot muscle force, and ankle joint reaction force were derived from a musculoskeletal model of the same participant based on the motion capture analysis and input as the boundary conditions for the finite element analysis. Rearfoot strike and forefoot strike running were simulated using a dynamic explicit solver. The results showed that, compared to rearfoot strike, forefoot strike reduced the foot arch height by 9.12% and increased the medial longitudinal arch angle by 2.06%. Forefoot strike also increased the plantar connective tissues stress by 18.28–200.11% and increased the plantar fascia tensile force by 18.71–109.10%. Although it is currently difficult to estimate the threshold value of stress or force that results in injury, forefoot strike runners appeared to be more vulnerable to plantar fasciitis.

With the introduction of direct-acting antiviral (DAA) agents, hepatitis C virus (HCV) treatment has dramatically improved. However, there are insufficient data on the benefits of DAA therapy in hepatocellular carcinoma (HCC). The purpose of this study was to investigate the outcome of patients who received DAA therapy after HCC treatment. We retrospectively reviewed patients with HCV-related HCC in a single medical center, and the outcome of patients with or without DAA therapy was analyzed. In total, 107 HCC patients were enrolled, of whom 60 had received DAA therapy after treatment for HCC. There were no significant intergroup differences in age, sex, laboratory results, or tumor burden. A more advanced stage was noted in the no DAA group (P = 0.003). In the treatment modality, sorafenib was commonly prescribed in the no DAA group (P = 0.007). The DAA group had a longer overall survival (OS) time than the no DAA group (P<0.001). When stratified by Barcelona Clinic Liver Cancer staging, the DAA group had better OS in the HCC stages 0-A and B-C (P = 0.034 and P = 0.006). There were 35 patients who received DAA therapy after curative HCC therapy. At a median follow-up of 20 months, 37.1% patients had HCC recurrence after DAA therapy. There was no statistical difference in recurrence-free survival between patients receiving and those not receiving DAA (P = 0.278). DAA therapy improved the survival outcome of HCC patients and did not increase recurrent HCC after curative therapy. .

Bipolar disorder is a highly heritable mental illness that transmits intergeneratively. Previous studies supported that first-degree relatives (FDRs), such as parents, offspring, and siblings, of patients with bipolar disorder, had a higher risk of bipolar disorder. However, whether FDRs of bipolar patients have an increased risk of schizophrenia, major depressive disorder (MDD), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) remains unclear. Among the entire population in Taiwan, 87 639 patients with bipolar disorder and 188 290 FDRs of patients with bipolar disorder were identified in our study. The relative risks (RRs) of major psychiatric disorders were assessed among FDRs of patients with bipolar disorder. FDRs of patients with bipolar disorder were more likely to have a higher risk of major psychiatric disorders, including bipolar disorder (RR 6.12, 95% confidence interval (CI) 5.95-6.30), MDD (RR 2.89, 95% CI 2.82-2.96), schizophrenia (RR 2.64, 95% CI 2.55-2.73), ADHD (RR 2.21, 95% CI 2.13-2.30), and ASD (RR 2.10, 95% CI 1.92-2.29), than the total population did. These increased risks for major psychiatric disorders were consistent across different familial kinships, such as parents, offspring, siblings, and twins. A dose-dependent relationship was also found between risk of each major psychiatric disorder and numbers of bipolar patients. Our study was the first study to support the familial coaggregation of bipolar disorder with other major psychiatric disorders, including schizophrenia, MDD, ADHD, and ASD, in a Taiwanese (non-Caucasian) population. Given the elevated risks of major psychiatric disorders, the public health government should pay more attention to the mental health of FDRs of patients with bipolar disorder.

In this article, we explicitly construct the coordinates associated with the Penrose diagram in spacetimes connected via a spacelike thin shell in the following two examples: the generalized black-to-white hole bounce with mass difference and the Schwarzschild-to-de Sitter transition. We point out the issue of the first junction condition in the Penrose diagram constructed by cutting and pasting analytically known metrics with spherical symmetry by a static spacelike thin shell. With the goal of a global conformal coordinate chart associated with the corresponding Penrose diagram without discontinuity at the thin shell, we give a procedure consisting of three conformal transformations that serve different purposes. The first two of them are used to generate a continuous coordinate patch covering the entire thin shell, and therefore, the Penrose diagram can be constructed properly by patches with overlapping. The third transformation removes any coordinate singularity reintroduced by the first two transformations at the event horizons.

Resveratrol is a natural polyphenolic compound that shows great potential in neuroprotection, anti-inflammation,and antioxidation. Previous studies have demonstrated that resveratrol can effectively treat various animal models of retinal diseases. The aim of the research was to use an animal experimental model to assess the effectiveness of resveratrol in treating retinal-related diseases in various animal models of retinal diseases such as ischemia-reperfusion injury, diabetic retinopathy, glaucoma, chronic ocular hypertension, optic neuritis, age-related macular degeneration, and retinopathy of prematurity. Furthermore, this study aims to reveal the underlying mechanisms of resveratrol related to the treatment of retina-related diseases. A search was conducted across several databases, including PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, and OVID. The search time was from the establishment of the database to October 2024 to collect studies on resveratrol intervention in animal models of retinal diseases. The studies included in this paper adopted the SYRCLE's risk of bias tool. Stata 16.0 and RevMan 5.4 software were used to analyze and visualize the results. Our meta-analysis comprises 26 studies and 365 animals demonstrates the following effects of resveratrol compared to the control group: a significant increase in the number of retinal ganglion cells (SMD = 3.91, 95% Cl = [2.97, 4.86], 0.00001) and superoxide dismutase activity (SMD = 3.14, 95% Cl = [0.96, 5.33], 0.005). Moreover, a decrease in malondialdehyde (SMD = -9.29,95% Cl = [-12.84, -5.74], 0.00001), reactive oxygen species level (SMD = -4.29,95% Cl = [-6.25, -2.32], 0.0001), cyclooxygenase-2 (SMD = -2.66, 95% Cl = [-4.01, -1.30], 0.0001), tumour necrosis factor-α(SMD = -3.96,95% Cl = [-6.27, -1.65], = 0.0008) and interleukin-6 (SMD = -3.32,95% Cl = [-4.20, -2.44], 0.00001) was observed. The A-wave amplitude and B-wave amplitude showed an increase respectively (MD = 105.92,95% Cl = [58.99, 152.84], 0.00001); (MD = 158.00,95% Cl = [86.35, 229.65], 0.0001), along with an increase in inner retinal thickness (SMD = 6.33, 95% CI = [5.10, 7.56], 0.00001) and total retinal thickness (SMD = 2.70, 95%Cl = [0.77, 4.83], 0.01). Subgroup analysis showed that different doses of resveratrol were associated with an increase in the number of RGCs ( 0.05). Resveratrol improves retinal diseases through multiple mechanisms: i) Neuroprotection: it activates the SIRT1/NF-κB and Nrf2 pathways, inhibits Caspase-3 expression, and promotes the survival of RGCs and ii) Antioxidation: it upregulates SOD activity, reduces the levels of MDA and ROS, and alleviates oxidative damage and iii) Anti-inflammation: it inhibits the COX-2, TNF-α, IL-6, and NF-κB pathways, alleviating the inflammatory response. These mechanisms resulted in enhanced amplitude of A/B waves, improved retinal thickness and visual function. Resveratrol has neuroprotective, anti-inflammatory and antioxidant effects through multiple mechanisms, thereby reducing retinal damage and maintaining the structure and function of the retina. This provides preclinical support for its possible therapeutic uses in the management of retinal diseases. https://www.crd.york.ac.uk/PROSPERO/myprospero.

Background Numerous studies have documented factors that are associated with substance use behaviors among college-aged individuals. However, relatively few studies have considered the heterogeneity of the college experience by field of study (i.e., college major) and how that educational context might affect students’ health behaviors differently. Drawing from theories and prior research, this study investigates whether college majors are associated with different substance use behaviors, both during college and upon graduation. Methods The study analyzed longitudinal data from the National Longitudinal Survey of Youth 97 ( N  = 1031), specifically data on individuals who obtained a bachelor’s degree, to examine the associations between college fields of study and trajectories of three substance use behaviors: smoking, heavy alcohol use, and marijuana use. Results The results indicate that social science and business majors were associated with more substance use behaviors than arts and humanities and STEM majors. However, social science majors were associated with a faster decrease in substance use behaviors over time. Importantly, the differences we found in mean levels of substance use behaviors and trajectories were not explained by demographic characteristics, family SES background, childhood health conditions, and employment experience. Further analysis that examined college major and each substance use behavior individually suggests that the associations were stronger for heavy alcohol use and marijuana use. Moreover, we found the associations were more pronounced in men than women. Conclusions The study finds that not all college majors show the same level of engagement in substance use behaviors over time, and that the associations also vary by (1) the specific substance use behavior examined and (2) by gender. These findings suggest it is important to consider that the different learning and educational contexts that college majors provide may also be more or less supportive of certain health behaviors, such as substance use. Practical implications are discussed.

Machine translation has received significant attention in the field of natural language processing not only because of its challenges but also due to the translation needs that arise in the daily life of modern people. In this study, we design a new machine translation model named X-Transformer, which refines the original Transformer model regarding three aspects. First, the model parameter of the encoder is compressed. Second, the encoder structure is modified by adopting two layers of the self-attention mechanism consecutively and reducing the point-wise feed forward layer to help the model understand the semantic structure of sentences precisely. Third, we streamline the decoder model size, while maintaining the accuracy. Through experiments, we demonstrate that having a large number of decoder layers not only affects the performance of the translation model but also increases the inference time. The X-Transformer reaches the state-of-the-art result of 46.63 and 55.63 points in the BiLingual Evaluation Understudy (BLEU) metric of the World Machine Translation (WMT), from 2014, using the English–German and English–French translation corpora, thus outperforming the Transformer model with 19 and 18 BLEU points, respectively. The X-Transformer significantly reduces the training time to only 1/3 times that of the Transformer. In addition, the heat maps of the X-Transformer reach token-level precision (i.e., token-to-token attention), while the Transformer model remains at the sentence level (i.e., token-to-sentence attention).

Glioblastoma multiforme (GBM) is one of the most aggressive cancers. Despite recent advances in multimodal therapies, high-grade glioma remains fatal. Temozolomide (TMZ) is an alkylating agent used worldwide for the clinical treatment of GBM; however, the innate and acquired resistance of GBM limits its application. Here, we found that TMZ inhibited the proliferation and induced the G2/M arrest of GBM cells. Therefore, we performed microarrays to identify the cell cycle- and apoptosis-related genes affected by TMZ. Notably, GADD45A was found to be up-regulated by TMZ in both cell cycle and apoptosis arrays. Furthermore, GADD45A knockdown (GADD45A kd ) enhanced the cell growth arrest and cell death induced by TMZ, even in natural (T98) and adapted (TR-U373) TMZ-resistant cells. Interestingly, GADD45A kd decreased the expression of O 6 -methylguanine-DNA methyltransferase (MGMT) in TMZ-resistant cells (T98 and TR-U373). In MGMT-deficient/TMZ-sensitive cells (U87 and U373), GADD45A kd decreased TMZ-induced TP53 expression. Thus, in this study, we investigated the genes influenced by TMZ that were important in GBM therapy, and revealed that GADD45A plays a protective role against TMZ treatment which may through TP53-dependent and MGMT-dependent pathway in TMZ-sensitive and TMZ-resistant GBM, respectively. This protective role of GADD45A against TMZ treatment may provide a new therapeutic strategy for GBM treatment.

Tumor necrosis factor (TNF)-α and matrix metalloproteinases (MMPs) are elevated in pleural fluids of tuberculous pleuritis (TBP) where pleural mesothelial cells (PMCs) conduct the first-line defense against Mycobacterium tuberculosis (MTB). However, the clinical implication of TNF-α and MMPs in TBP and the response of PMCs to MTB infection remain unclear. We measured pleural fluid levels of TNF-α and MMPs in patients with TBP (n = 18) or heart failure (n = 18) as controls. Radiological scores for initial effusion amount and residual pleural fibrosis at 6-month follow-up were assessed. In vitro human PMC experiments were performed to assess the effect of heat-killed M. tuberculosis H37Ra (MTBRa) on the expression of TNF-α and MMPs. As compared with controls, the effusion levels of TNF-α, MMP-1 and MMP-9 were significantly higher and correlated positively with initial effusion amount in patients with TBP, while TNF-α and MMP-1, but not MMP-9, were positively associated with residual pleural fibrosis of TBP. Moreover, effusion levels of TNF-α had positive correlation with those of MMP-1 and MMP-9 in TBP. In cultured PMCs, MTBRa enhanced TLR2 and TLR4 expression, activated ERK signaling, and upregulated TNF-α mRNA and protein expression. Furthermore, knockdown of TLR2, but not TLR4, significantly inhibited ERK phosphorylation and TNF-α expression. Additionally, both MTBRa and TNF-α markedly induced MMP-1 and MMP-9 synthesis in human PMCs, and TNF-α neutralization substantially reduced the production of MMP-1, but not MMP-9, in response to MTBRa stimulation. MTBRa activates TLR2/ERK signalings to induce TNF-α and elicit MMP-1 and MMP-9 in human PMCs, which are associated with effusion volume and pleural fibrosis and may contribute to pathogenesis of TBP. Further investigation of manipulation of TNF-α and MMP expression in pleural mesothelium may provide new insights into the mechanisms and rational treatment strategies for TBP.