Pathogenesis, diagnosis, and treatment of epilepsy: electromagnetic stimulation-mediated neuromodulation therapy and new technologies.

Epilepsy is a severe, relapsing, and multifactorial neurological disorder. Studies regarding the accurate diagnosis, prognosis, and in-depth pathogenesis are crucial for the precise and effective treatment of epilepsy. The pathogenesis of epilepsy is complex and involves alterations in variables such as gene expression, protein expression, ion channel activity, energy metabolites, and gut microbiota composition. Satisfactory results are lacking for conventional treatments for epilepsy. Surgical resection of lesions, drug therapy, and non-drug interventions are mainly used in clinical practice to treat pain associated with epilepsy. Non-pharmacological treatments, such as a ketogenic diet, gene therapy for nerve regeneration, and neural regulation, are currently areas of research focus. This review provides a comprehensive overview of the pathogenesis, diagnostic methods, and treatments of epilepsy. It also elaborates on the theoretical basis, treatment modes, and effects of invasive nerve stimulation in neurotherapy, including percutaneous vagus nerve stimulation, deep brain electrical stimulation, repetitive nerve electrical stimulation, in addition to non-invasive transcranial magnetic stimulation and transcranial direct current stimulation. Numerous studies have shown that electromagnetic stimulation-mediated neuromodulation therapy can markedly improve neurological function and reduce the frequency of epileptic seizures. Additionally, many new technologies for the diagnosis and treatment of epilepsy are being explored. However, current research is mainly focused on analyzing patients' clinical manifestations and exploring relevant diagnostic and treatment methods to study the pathogenesis at a molecular level, which has led to a lack of consensus regarding the mechanisms related to the disease.

Cell-drug conjugates.

By combining living cells with therapeutics, cell-drug conjugates can potentiate the functions of both components, particularly for applications in drug delivery and therapy. The conjugates can be designed to persist in the bloodstream, undergo chemotaxis, evade surveillance by the immune system, proliferate, or maintain or transform their cellular phenotypes. In this Review, we discuss strategies for the design of cell-drug conjugates with specific functions, the techniques for their preparation, and their applications in the treatment of cancers, autoimmune diseases and other pathologies. We also discuss the translational challenges and opportunities of this class of drug-delivery systems and therapeutics.

Managing intraoperative rupture of internal carotid pseudoaneurysms during endoscopic transnasal optic canal decompression: a case report.

Background: Endoscopic transnasal optic canal decompression is widely used in the treatment of traumatic optic neuropathy (TON) following head and craniofacial trauma. Intraoperative hemorrhage is a catastrophic surgical complication during optic canal decompression. Case description: We present two cases of patients with TON who suffered unexpected intra-operative massive bleeding during endoscopic transnasal optic canal decompression. After intraoperative hemostasis was achieved, emergent cerebral angiograms demonstrated the formation of internal carotid pseudoaneurysms, which were immediately embolized with coils combined with or without Onyx with balloon assistance. One of these cases was also complicated by a postoperative cerebrospinal fluid leak, which failed to be treated with lumbar drainage but was successfully repaired with endoscopic transnasal surgery. Conclusion: The intra-operative rupture of ICA pseudoaneurysm is a rare but catastrophic complication in TON patients. Intraoperative massive bleeding indicates rupture of ICA pseudoaneurysm. Postoperative emergency angiography and endovascular therapy should be arranged to evaluate and repair the cerebral vascular injury. Endoscopic trans-nasal surgery repairing CSF leaks resistant to lumbar drainage could be efficient and safe following pseudoaneurysm embolization.

Reformulating lipid nanoparticles for organ-targeted mRNA accumulation and translation.

Fully targeted mRNA therapeutics necessitate simultaneous organ-specific accumulation and effective translation. Despite some progress, delivery systems are still unable to fully achieve this. Here, we reformulate lipid nanoparticles (LNPs) through adjustments in lipid material structures and compositions to systematically achieve the pulmonary and hepatic (respectively) targeted mRNA distribution and expression. A combinatorial library of degradable-core based ionizable cationic lipids is designed, following by optimisation of LNP compositions. Contrary to current LNP paradigms, our findings demonstrate that cholesterol and phospholipid are dispensable for LNP functionality. Specifically, cholesterol-removal addresses the persistent challenge of preventing nanoparticle accumulation in hepatic tissues. By modulating and simplifying intrinsic LNP components, concurrent mRNA accumulation and translation is achieved in the lung and liver, respectively. This targeting strategy is applicable to existing LNP systems with potential to expand the progress of precise mRNA therapy for diverse diseases.

Recent Progress in Glucose-Responsive Insulin.

Insulin replacement therapy is indispensable in the treatment of type 1 and advanced type 2 diabetes. However, insulin's clinical application is challenging due to its narrow therapeutic index. To mitigate acute and chronic risks of glucose excursions, glucose-responsive insulin (GRI) has long been pursued for clinical application. By integrating with glucose-sensitive elements, GRI is capable of releasing or activating insulin in response to plasma or interstitial glucose levels without external monitoring, therefore improving glycemic control and reducing hypoglycemic risk. In this perspective, first we introduce the history of GRI development, followed by a review of major glucose-responsive components which can be leveraged to control insulin delivery. Subsequently, we highlight the recent advances in glucose-responsive insulin delivery carriers and insulin analogs. Finally, we provide a look to the future and the challenges of clinical application of GRI.

Light-Boosting Highly Sensitive and Ultrafast Piezoelectric Sensor Based on Composite Membrane of Copper Phthalocyanine and Graphene Oxide.

Self-powered wearable pressure sensors based on flexible electronics have emerged as a new trend due to the increasing demand for intelligent and portable devices. Improvements in pressure-sensing performance, including in the output voltage, sensitivity and response time, can greatly expand their related applications; however, this remains challenging. Here, we report on a highly sensitive piezoelectric sensor with novel light-boosting pressure-sensing performance, based on a composite membrane of copper phthalocyanine (CuPC) and graphene oxide (GO) (CuPC@GO). Under light illumination, the CuPC@GO piezoelectric sensor demonstrates a remarkable increase in output voltage (381.17 mV, 50 kPa) and sensitivity (116.80 mV/kPa, <5 kPa), which are approximately twice and three times of that the sensor without light illumination, respectively. Furthermore, light exposure significantly improves the response speed of the sensor with a response time of 38.04 µs and recovery time of 58.48 µs, while maintaining excellent mechanical stability even after 2000 cycles. Density functional theory calculations reveal that increased electron transfer from graphene to CuPC can occur when the CuPC is in the excited state, which indicates that the light illumination promotes the electron excitation of CuPC, and thus brings about the high polarization of the sensor. Importantly, these sensors exhibit universal spatial non-contact adjustability, highlighting their versatility and applicability in various settings.

[Effect of CD8+ CD28- T Cells on Acute Graft-Versus-Host Disease after Haploidentical Hematopoietic Stem Cell Transplantation].

OBJECTIVE: To investigate the effect of CD8+ CD28- T cells on acute graft-versus-host disease(aGVHD) after haploidentical hematopoietic stem cell transplantation(haplo-HSCT). METHODS: The relationship between absolute count of CD8+ CD28- T cells and aGVHD in 60 patients with malignant hematological diseases was retrospectively analyzed after haplo-HSCT, and the differences in the incidence rate of chronic graft-versus host disease(cGVHD), infection and prognosis between different CD8+ CD28- T absolute cells count groups were compared. RESULTS: aGVHD occurred in 40 of 60 patients after haplo-HSCT, with an incidence rate of 66.67%. The median occurrence time of aGVHD was 32.5(20-100) days. At 30 days after the transplantation, the absolute count of CD8+ CD28- T cells of aGVHD group was significantly lower than that of non-aGVHD group (P =0.03). Thus the absolute count of CD8+ CD28- T cells at 30 days after transplantation can be used to predict the occurrence of aGVHD to some extent. At 30 days after transplantation, the incidence rate of aGVHD in the low cell count group (CD8+ CD28- T cells absolute count < 0.06/µl) was significantly higher than that in the high cell count group (CD8+ CD28- T cells absolute count ≥0.06/µl,P =0.011). Multivariate Cox regression analysis further confirmed that the absolute count of CD8+ CD28-T cells at 30 days after transplantation was an independent risk factor for aGVHD, and the risk of aGVHD in the low cell count group was 2.222 times higher than that in the high cell count group (P =0.015). The incidence of cGVHD, fungal infection, EBV infection and CMV infection were not significantly different between the two groups with different CD8+ CD28- T cells absolute count. The overall survival, non-recurrent mortality and relapse rates were not significantly different between different CD8+ CD28- T cells absolute count groups. CONCLUSION: Patients with delayed CD8+ CD28- T cells reconstitution after haplo-HSCT are more likely to develop aGVHD, and the absolute count of CD8+ CD28- T cells can be used to predict the incidence of aGVHD to some extent. The absolute count of CD8+ CD28- T cells after haplo-HSCT was not associated with cGVHD, fungal infection, EBV infection, and CMV infection, and was also not significantly associated with the prognosis after transplantation.

Platelet-Drug Conjugates Engineered via One-step Fusion Approach for Metastatic and Postoperative Cancer Treatment.

The exploration of cell-based drug delivery systems for cancer therapy has gained growing attention. Approaches to engineering therapeutic cells with multidrug loading in an effective, safe, and precise manner while preserving their inherent biological properties remain of great interest. Here, we report a strategy to simultaneously load multiple drugs in platelets in a one-step fusion process. We demonstrate doxorubicin (DOX)-encapsulated liposomes conjugated with interleukin-15 (IL-15) could fuse with platelets to achieve both cytoplasmic drug loading and surface cytokine modification with a loading efficiency of over 70 % within minutes. Due to their inherent targeting ability to metastatic cancers and postoperative bleeding sites, the engineered platelets demonstrated a synergistic therapeutic effect to suppress lung metastasis and postoperative recurrence in mouse B16F10 melanoma tumor models.

Transdermal gene delivery.

Gene delivery has revolutionized conventional medical approaches to vaccination, cancer, and autoimmune diseases. However, current gene delivery methods are limited to either intravenous administration or direct local injections, failing to achieve well biosafety, tissue targeting, drug retention, and transfection efficiency for desired therapeutic outcomes. Transdermal drug delivery based on various delivery strategies can offer improved therapeutic potential and superior patient experiences. Recently, there has been increased foundational and clinical research focusing on the role of the transdermal route in gene delivery and exploring its impact on the efficiency of gene delivery. This review introduces the recent advances in transdermal gene delivery approaches facilitated by drug formulations and medical devices, as well as discusses their prospects.

Grooved Microneedle Patch Augments Adoptive T Cell Therapy Against Solid Tumors via Diverting Regulatory T Cells.

The efficacy of adoptive T cell therapy (ACT) for the treatment of solid tumors remains challenging. In addition to the poor infiltration of effector T (Teff) cells limited by the physical barrier surrounding the solid tumor, another major obstacle is the extensive infiltration of regulatory T (Treg) cells, a major immunosuppressive immune cell subset, in the tumor microenvironment. Here, this work develops a grooved microneedle patch for augmenting ACT, aiming to simultaneously overcome physical and immunosuppressive barriers. The microneedles are engineered through an ice-templated method to generate the grooved structure for sufficient T-cell loading. In addition, with the surface modification of chemokine CCL22, the MNs could not only directly deliver tumor-specific T cells into solid tumors through physical penetration, but also specifically divert Treg cells from the tumor microenvironment to the surface of the microneedles via a cytokine concentration gradient, leading to an increase in the ratio of Teff cells/Treg cells in a mouse melanoma model. Consequently, this local delivery strategy of both T cell receptor T cells and chimeric antigen receptor T cells via the CCL22-modified grooved microneedles as a local niche could significantly enhance the antitumor efficacy and reduce the on-target off-tumor toxicity of ACT.

Injectable and Sprayable Fluorescent Nanoprobe for Rapid Real-Time Detection of Human Colorectal Tumors.

The development of minimally invasive surgery has greatly advanced precision tumor surgery, but sometime suffers from restricted visualization of the surgical field, especially during the removal of abdominal tumors. A 3-D inspection of tumors could be achieved by intravenously injecting tumor-selective fluorescent probes, whereas most of which are unable to instantly distinguish tumors via in situ spraying, which is urgently needed in the process of surgery in a convenient manner. In this study, this work has designed an injectable and sprayable fluorescent nanoprobe, termed Poly-g-BAT, to realize rapid tumor imaging in freshly dissected human colorectal tumors and animal models. Mechanistically, the incorporation of γ-glutamyl group facilitates the rapid internalization of Poly-g-BAT, and these internalized nanoprobes can be subsequently activated by intracellular NAD(P)H: quinone oxidoreductase-1 to release near-infrared fluorophores. As a result, Poly-g-BAT can achieve a superior tumor-to-normal ratio (TNR) up to 12.3 and enable a fast visualization (3 min after in situ spraying) of tumor boundaries in the xenograft tumor models, Apcmin/+ mice models and fresh human tumor tissues. In addition, Poly-g-BAT is capable of identifying minimal premalignant lesions via intravenous injection.

2D Exfoliation Chemistry Towards Covalent Pseudo-Layered Phosphate Framework Derived by Radical/Strain-Synergistical Process.

2D compounds exfoliated from weakly bonded bulk materials with van der Waals (vdW) interaction are easily accessible. However, the strong internal ionic/covalent bonding of most inorganic crystal frameworks greatly hinders 2D material exfoliation. Herein, we first proposed a radical/strain-synergistic strategy to exfoliate non-vdW interacting pseudo-layered phosphate framework. Specifically, hydroxyl radicals (⋅OH) distort the covalent bond irreversibly, meanwhile, H2O molecules as solvents, further accelerating interlayered ionic bond breakage but mechanical expansion. The innovative 2D laminar NASICON-type Na3V2(PO4)2O2F crystal, exfoliated by ⋅OH/H2O synergistic strategy, exhibits enhanced sodium-ion storage capacity, high-rate performance (85.7 mAh g-1 at 20 C), cyclic life (2300 cycles), and ion migration rates, compared with the bulk framework. Importantly, this chemical/physical dual driving technique realized the effective exfoliation for strongly coupled pseudo-layered frameworks, which accelerates 2D functional material development.

Ability of Helicobacter pylori to internalize into Candida.

The following are our views regarding the "letter to the editor" (Helicobacter is preserved in yeast vacuoles! Does Koch's postulates confirm it?) by Alipour and Gaeini, and the response "letter to the editor" (Candida accommodates non-culturable Helicobacter pylori in its vacuole-Koch's postulates aren't applicable) by Siavoshi and Saniee. Alipour and Gaeini rejected the methods, results, discussion, and conclusions summarized in a review article by Siavoshi and Saniee. The present article reviews and discusses evidence on the evolutionary adaptation of Helicobacter pylori (H. pylori) to thrive in Candida cell vacuoles and concludes that Candida could act as a Trojan horse, transporting potentially infectious H. pylori into the stomach of humans.

Association between reversal agents (sugammadex vs. neostigmine) for neuromuscular block and postoperative pulmonary complications: A retrospective analysis.

AIMS: Residual neuromuscular blockade has been linked to pulmonary complications in the postoperative period. This study aimed to determine whether sugammadex was associated with a lower risk of postoperative pulmonary complications (PPCs) compared with neostigmine. METHODS: This retrospective cohort study was conducted in a tertiary academic medical center. Patients ≥18 year of age undergoing noncardiac surgical procedures with general anesthesia and mechanical ventilation were enrolled between January 2019 and September 2021. We identified all patients receiving rocuronium and reversal with neostigmine or sugammadex via electronic medical record review. The primary endpoint was a composite of PPCs (including pneumonia, atelectasis, respiratory failure, pulmonary embolism, pleural effusion, or pneumothorax). The incidence of PPCs was compared using propensity score analysis. RESULTS: A total of 1786 patients were included in this study. Among these patients, 976 (54.6%) received neostigmine, and 810 (45.4%) received sugammadex. In the whole sample, PPCs occurred in 81 (4.54%) subjects (7.04% sugammadex vs. 2.46% neostigmine). Baseline covariates were well balanced between groups after overlap weighting. Patients in the sugammadex group had similar risk (overlap weighting OR: 0.75; 95% CI: 0.40 to 1.41) compared to neostigmine. The sensitivity analysis showed consistent results. In subgroup analysis, the interaction P-value for the reversal agents stratified by surgery duration was 0.011. CONCLUSION: There was no significant difference in the rate of PPCs when the neuromuscular blockade was reversed with sugammadex compared to neostigmine. Patients undergoing prolonged surgery may benefit from sugammadex, which needs to be further investigated.

Inflammation-Responsive Hydrogel Accelerates Diabetic Wound Healing through Immunoregulation and Enhanced Angiogenesis.

Angiogenesis is a prominent component during the highly regulated process of wound healing. The application of exogenous vascular endothelial growth factor (VEGF) has shown considerable potential in facilitating angiogenesis. However, its effectiveness is often curtailed due to chronic inflammation and severe oxidative stress in diabetic wounds. Herein, an inflammation-responsive hydrogel incorporating Prussian blue nanoparticles (PBNPs) is designed to augment the angiogenic efficacy of VEGF. Specifically, the rapid release of PBNPs from the hydrogel under inflammatory conditions effectively alleviates the oxidative stress of the wound, therefore reprogramming the immune microenvironment to preserve the bioactivity of VEGF for enhanced angiogenesis. In vitro and in vivo studies reveal that the PBNPs and VEGF co-loaded hydrogel is biocompatible and possesses effective anti-inflammatory properties, thereby facilitating angiogenesis to accelerate the wound healing process in a type 2 diabetic mouse model.

Short-term association of particulate matter and cardiovascular disease mortality in Shanghai, China between 2003 and 2020.

Objective: Evidence regarding the effects of particulate matter (PM) pollutants on cardiovascular disease (CVD) mortality remains limited in Shanghai, China. Our objective was to thoroughly evaluate associations between PM pollutants and CVD mortality. Methods: Daily data on CVD mortality, PM (PM10 and PM2.5) pollutants, and meteorological variables in Shanghai, China were gathered from 2003 to 2020. We utilized a time-series design with the generalized additive model to assess associations between PM pollutants and CVD mortality. Additionally, we conducted stratified analyses based on sex, age, education, and seasons using the same model. Results: We found that PM pollutants had a significant association with CVD mortality during the study period. Specifically, there was a 0.29% (95%CI: 0.14, 0.44) increase in CVD mortality for every 10 µg/m3 rise in a 2-day average (lag01) concentration of PM10. A 0.28% (95% CI: 0.07, 0.49) increase in CVD mortality was associated with every 10 µg/m3 rise in PM2.5 concentration at lag01. Overall, the estimated effects of PM10 and PM2.5 were larger in the warm period compared with the cold period. Furthermore, males and the older adult exhibited greater susceptibility to PM10 and PM2.5 exposure, and individuals with lower education levels experienced more significant effects from PM10 and PM2.5 than those with higher education levels. Conclusion: Our findings suggested that PM pollutants have a substantial impact on increasing CVD mortality in Shanghai, China. Moreover, the impacts of air pollution on health may be altered by factors such as season, sex, age, and educational levels.

Direct and rapid thermal shock for recycling spent graphite in lithium-ion batteries.

Due to the rapid increase in the number of spent lithium-ion batteries, there has been a growing interest in the recovery of degraded graphite. In this work, a rapid thermal shock (RTS) strategy is proposed to regenerate spent graphite for use in lithium-ion batteries. The results of structural and morphological characterization demonstrate that the graphite is well regenerated by the RTS process. Additionally, an amorphous carbon layer forms and coats onto the surface of the graphite, contributing to excellent rate performance. The regenerated graphite (RG-1000) displays excellent rate performance, with capacities of 413 mAh g-1 at 50 mA g-1 and 102.1 mAh g-1 at 1000 mA g-1, respectively. Furthermore, it demonstrates long-term cycle stability, maintaining a capacity of 80 mAh g-1 at 1000 mA g-1 with a capacity retention of 78.4 % after 600 cycles. This RTS method enables rapid and efficient regeneration of spent graphite anodes for lithium-ion batteries, providing a facile and environmentally friendly strategy for their direct regeneration.

[Clinical Characteristics and Prognosis of Acute Myeloid Leukemia Patients with GATA2 Gene Mutation].

OBJECTIVE: To investigate the clinical characteristics, coexisting gene mutations and prognosis of acute myeloid leukemia (AML) patients with GATA2 gene mutation. METHODS: The clinical data of 370 newly diagnosed AML patients treated in our hospital from January 2008 to January 2021 was analyzed retrospectively, the next-generation sequencing technology was used to detect the mutated genes in those patients. The clinical characteristics of AML patients with GATA2 mutations, the co-mutated genes of GATA2 mutations, and the effect of GATA2 mutation on prognosis were analyzed. RESULTS: A total of 23 patients (6.2%) with GATA2 mutation was detected in 370 AML patients. Compared with GATA2 non-mutation group, patients in GATA2 mutation group were mostly normal karyotypes (P =0.037) and in low-risk cytogenetic stratification (P =0.028). The incidence of CEBPAdm and NRAS in GATA2 mutation group was significantly higher than that in GATA2 non-mutation group (P =0.010, P =0.009). There were no statistically significant differences between the two groups in terms of sex, age, white blood cell count (WBC), platelet count, hemoglobin, bone marrow (BM) blast, induction chemotherapy regimen and CR rate (P >0.05). Among the 23 patients with GATA2 mutation, the most common co-mutated genes were CEBPAdm, NRAS (both 39.1%), NPM1, FLT3, TET2, WT1 (all 17.4%), ASXL1 and IDH1 (both 13.0%). Survival analysis showed that there was no statistical difference in 5-year overall survival (OS) and leukemia-free survival (LFS) rates between patients with and without GATA2 mutations in whole cohort (n=370) (P =0.306, P =0.308). Among 306 patients without CEBPAdm, the 5-year OS and LFS rates in GATA2 mutation group showed an increasing trend compared with GATA2 non-mutation group, but the difference was not statistically significant (P =0.092, P =0.056). Among 64 patients with CEBPAdm, there was no statistically significant difference in 5-year OS rate between the GATA2 mutation group and the GATA2 non-mutation group (P =0.104), but the 5-year LFS rate of the GATA2 mutation group was significantly decreased (P =0.047). Among the 23 patients with GATA2 mutation, 16 cases received the "3+7" induction regimen, of which 12 cases received allogeneic hematopoietic stem cell transplantation (allo-HSCT); 7 cases received the "DCAG" induction regimen, of which 3 cases received allo-HSCT. The CR rate was not statistically different between the "3+7" regimen group and the "DCAG" regimen group (P =1.000). The 5-year OS rate and LFS rate in the transplantation group were significantly higher than the chemotherapy group (P =0.021, P =0.020). CONCLUSION: GATA2 mutation is more common in AML patients with normal karyotype and low-risk cytogenetic stratification, and it is significantly associated with CEBPAdm and NRAS co-mutations. The prognostic significance of GATA2 is influenced by CEBPAdm. The choice of "3+7" or "DCAG" induction regimen in patients with GATA2 mutation does not affect their CR rate, while the choice of allo-HSCT can significantly improved the prognosis compared with chemotherapy only.

Viscoelastic Extracellular Matrix Enhances Epigenetic Remodeling and Cellular Plasticity.

Living tissue and extracellular matrices possess viscoelastic properties, but understanding how viscoelastic matrix regulates chromatin and the epigenome is limited. Here, we find that the regulation of the epigenetic state by the viscoelastic matrix is more pronounced on softer matrices. Cells on viscoelastic matrices exhibit larger nuclei, increased nuclear lamina ruffling, loosely organized chromatin, and faster chromatin dynamics, compared to those on elastic matrices. These changes are accompanied by a global increase in euchromatic marks and a local increase in chromatin accessibility at the cis -regulatory elements associated with neuronal and pluripotent genes. Consequently, viscoelastic matrices enhanced the efficiency of reprogramming fibroblasts into neurons and induced pluripotent stem cells, respectively. Together, our findings demonstrate the key roles of matrix viscoelasticity in the regulation of epigenetic state, and uncover a new mechanism of biophysical regulation of chromatin and cell reprogramming, with implications for the design of smart materials to engineer cell fate.