Functional effects of drugs and toxins interacting with NaV1.4.

NaV1.4 is a voltage-gated sodium channel subtype that is predominantly expressed in skeletal muscle cells. It is essential for producing action potentials and stimulating muscle contraction, and mutations in NaV1.4 can cause various muscle disorders. The discovery of the cryo-EM structure of NaV1.4 in complex with ß1 has opened new possibilities for designing drugs and toxins that target NaV1.4. In this review, we summarize the current understanding of channelopathies, the binding sites and functions of chemicals including medicine and toxins that interact with NaV1.4. These substances could be considered novel candidate compounds or tools to develop more potent and selective drugs targeting NaV1.4. Therefore, studying NaV1.4 pharmacology is both theoretically and practically meaningful.

Identification of a novel oligopeptide from defatted walnut meal hydrolysate as a potential neuroprotective agent.

Free radical damage and oxidative stress are thought to play a crucial role in the development of neurodegenerative diseases. Walnut peptides, especially walnut oligopeptides, have been shown to protect nerve cells from oxidative stress and inflammatory damage, as well as improve memory function. In this study, walnut peptides were obtained from walnut meal through enzymatic hydrolysis, ultrafiltration, and gel filtration chromatography. A novel oligopeptide called AQ was successfully isolated and its chemical structure was identified as AASCDQ using ESI-MS/MS. AQ demonstrated remarkable scavenging activity against O2- free radicals (81.00%), DPPH free radicals (79.40%), and ABTS free radicals (67.09%) at a concentration of 1 mg mL-1. Furthermore, AQ exhibited strong neuroprotective effects against hydrogen peroxide-induced damage in SH-SY5Y cells, reducing cell injury and apoptosis. AQ also effectively inhibited the secretion of pro-inflammatory factors NO (IC50 = 46.03 ± 0.32 µM) and suppressed the expression of IL-6 and TNF-α in RAW264.7 cells stimulated by LPS. In vivo experiments demonstrated that AQ promoted angiogenesis in the quail chick chorioallantoic membrane assay and reduced ROS accumulation in Caenorhabditis elegans, thereby extending its lifespan. The anti-inflammatory mechanism of AQ was further confirmed by western blotting. In summary, the novel oligopeptide AQ possesses potential neuroprotective effects, including antioxidant, anti-inflammatory, angiogenic, and anti-aging properties, making it a promising candidate for the development of functional foods and pharmaceutical products.

Interaction of physical activity and low-level air pollution on cardiovascular disease: a prospective cohort study in UK Biobank.

To investigate the associations of physical activity (PA), low-level air pollution, and interaction on cardiovascular diseases (CVD) incidence based on the UK Biobank. PA was measured by the International Physical Activity Questionnaire and five air pollutants were estimated using Land Use Regression. All association estimates were based on Cox regression. Dose-response relationship was explored by restricted cubic spline, while multiplicative and additive interaction were examined by Pinteraction and relative excess risk due to interaction (RERI). As deviating proportional hazards assumption, we analyzed data as follow-up < 4 years and ≥ 4 years, separately. PA with 1000-4000 Metabolic Equivalent Task (MET) min/week showed the strongest protective impact on CVD incidence, while only low-level nitrogen dioxides (NO2) showed negative impact among five air pollutants and was considered for further analysis. Multiplicative interaction between PA and NO2 was observed during ≥ 4 years follow-up (Pinteraction = 0.049) while not during < 4 years (Pinteraction = 0.290). Positive additive interactions were found for high PA and low NO2 (< 20 µg/m3) group (RERI: 0.07, 95% confidence intervals: 0.02-0.11) during < 4 years, and for moderate PA with NO2 at 40- µg/m3 (0.07, 0.02-0.13) and < 20 µg/m3 (0.07, 0.02-0.12), while high PA showed similar results with NO2 at 40-, 20- and < 20 µg/m3 during ≥ 4 years. PA about 1000-4000 METs min/week showed the lowest CVD risk. Possibility of interaction with PA and NO2 is more likely to present with the increase in follow-up duration. We call for the optimal thresholds of PA, and exploring interaction thoroughly by considering types of PA.

Nonlinear responses of biofilm bacteria to alkyl-chain length of parabens by DFT calculation.

Parabens can particularly raise significant concerns regarding the disruption of microbial ecology due to their antimicrobial properties. However, the responses of biofilm bacteria to diverse parabens with different alkyl-chain length remains unclear. Here, theoretical calculations and bioinformatic analysis were performed to decipher the influence of parabens varying alkyl-chain lengths on the biofilm bacteria. Our results showed that the disturbances in bacterial community did not linearly response to the alkyl-chain length of parabens, and propylparaben (PrP), with median chain length, had more severe impact on bacterial community. Despite the fact that paraben lethality linearly increased with chain length, the PrP had a higher chemical reactions potential than parabens with shorter or longer alkyl-chain. The chemical reactions potential was critical in the nonlinear responses of bacterial community to alkyl-chain length of parabens. PrP could impose selective pressure to disturb the bacterial community, because it had a more profound contribution to deterministic assembly process. Furthermore, N-acyl-homoserine lactones was also significantly promoted under PrP exposure, confirming that PrP could affect the bacterial community by influencing the quorum-sensing system. Overall, our study reveals the nonlinear responses of bacterial communities to the alkyl-chain lengths of parabens and provides insightful perspectives for the better regulation of parabens. ENVIRONMENTAL IMPLICATION: Parabens are recognized as emerging organic pollutants, which specially raise great concerns due to their antimicrobial properties disturbing microbial ecology. However, few study have addressed the relationship between bacterial community responses and the molecular structural features of parabens with different alkyl-chain length. This investigation revealed nonlinear responses of the bacterial community to the alkyl-chain length of parabens through DFT calculation and bioinformatic analysis and identified the critical roles of chemical reactions potential in nonlinear responses of bacterial community. Our results benefit the precise evaluation of ecological hazards posed by parabens and provide useful insights for better regulation of parabens.

Artificial Intelligence-Enhanced Waveguide "Photonic Nose"- Augmented Sensing Platform for VOC Gases in Mid-Infrared.

On-chip nanophotonic waveguide sensor is a promising solution for miniaturization and label-free detection of gas mixtures utilizing the absorption fingerprints in the mid-infrared (MIR) region. However, the quantitative detection and analysis of organic gas mixtures is still challenging and less reported due to the overlapping of the absorption spectrum. Here,an Artificial-Intelligence (AI) assisted waveguide "Photonic nose" is presented as an augmented sensing platform for gas mixture analysis in MIR. With the subwavelength grating cladding supported waveguide design and the help of machine learning algorithms, the MIR absorption spectrum of the binary organic gas mixture is distinguished from arbitrary mixing ratio and decomposed to the single-component spectra for concentration prediction. As a result, the classification of 93.57% for 19 mixing ratios is realized. In addition, the gas mixture spectrum decomposition and concentration prediction show an average root-mean-square error of 2.44 vol%. The work proves the potential for broader sensing and analytical capabilities of the MIR waveguide platform for multiple organic gas components toward MIR on-chip spectroscopy.

CdgB Regulates Morphological Differentiation and Toyocamycin Production in Streptomyces diastatochromogenes 1628.

Bis (3',5')-cyclic diguanylic acid (c-di-GMP) is a ubiquitous second messenger that controls several metabolic pathways in bacteria. In Streptomyces, c-di-GMP is associated with morphological differentiation, which is related to secondary metabolite production. In this study, we identified and characterized a diguanylate cyclase (DGC), CdgB, from Streptomyces diastatochromogenes 1628, which may be involved in c-di-GMP synthesis, through genetic and biochemical analyses. To further investigate the role of CdgB, the cdgB-deleted mutant strain Δ-cdgB and the cdgB-overexpressing mutant strain O-cdgB were constructed by genetic engineering. A phenotypic analysis revealed that the O-cdgB colonies exhibited reduced mycelium formation, whereas the Δ-cdgB colonies displayed wrinkled surfaces and shriveled mycelia. Notably, O-cdgB demonstrated a significant increase in the toyocamycin (TM) yield by 47.3%, from 253 to 374 mg/L, within 10 days. This increase was accompanied by a 6.7% elevation in the intracellular concentration of c-di-GMP and a higher transcriptional level of the toy cluster within four days. Conversely, Δ-cdgB showed a lower c-di-GMP concentration (reduced by 6.2%) in vivo and a reduced toyocamycin production (decreased by 28.9%, from 253 to 180 mg/L) after 10 days. In addition, S. diastatochromogenes 1628 exhibited a slightly higher inhibitory effect against Fusarium oxysporum f. sp. cucumerinum and Rhizoctonia solani compared to Δ-cdgB, but a lower inhibition rate than that of O-cdgB. The results imply that CdgB provides a foundational function for metabolism and the activation of secondary metabolism in S. diastatochromogenes 1628.

Design, synthesis and evaluation of a pyrazolo[3,4-d]pyrimidine derivative as a novel and potent TGFß1R1 inhibitor.

The transforming growth factor ß1 (TGFß1)/SMAD signaling pathway regulates many vital physiological processes. The development of potent inhibitors targeting activin receptor-like kinase 5 (ALK5) would provide potential treatment reagents for various diseases. A significant number of ALK5 inhibitors have been discovered, and they are currently undergoing clinical evaluation at various stages. However, the clinical demands were far from being met. In this study, we utilized an alternative conformation-similarity-based virtual screening (CSVS) combined with a fragment-based drug designing (FBDD) strategy to efficiently discover a potent and active hit with a novel chemical scaffold. After structural optimization in the principle of group replacement, compound 57 was identified as the most promising ALK5 inhibitor. Compound 57 demonstrated significant inhibitory effects against the TGF-ß1/SMAD signaling pathway. It could markedly attenuate the production of extracellular matrix (ECM) and deposition of collagen. Also, the lead compound showed adequate pharmacokinetic (PK) properties and good in vivo tolerance. Moreover, treatment with compound 57 in two different xerograph models showed significant inhibitory effects on the growth of pancreatic cancer cells. These results suggested that lead compound 57 refers as a promising ALK5 inhibitor both in vitro and in vivo, which merits further validation.

Observation of spatiotemporal optical vortices enabled by symmetry-breaking slanted nanograting.

Providing additional degrees of freedom to manipulate light, spatiotemporal optical vortex (STOV) beams carrying transverse orbital angular momentum are of fundamental importance for spatiotemporal control of light-matter interactions. Unfortunately, existing methods to generate STOV are plagued by various limitations such as inefficiency, bulkiness, and complexity. Here, we theoretically propose and experimentally demonstrate a microscale singlet platform composed of a slanted nanograting to generate STOV. Leveraging the intrinsic topological singularity induced by C2 symmetry and z-mirror symmetry breaking of the slanted nanograting, STOV is generated through the Fourier transform of the spiral phase in the momentum-frequency space to the spatiotemporal domain. In experiments, we observe the space-time evolution of STOV carried by femtosecond pulses using a time-resolved interferometry technique and achieve a generation efficiency exceeding 40%. Our work sheds light on a compact and versatile platform for light pulse shaping, and paves the way towards a fully integrated system for spatiotemporal light manipulation.

Highly stable Ag-doped Cu2O immobilized cellulose-derived carbon beads with enhanced visible-light photocatalytic degradation of levofloxacin.

Ag-doped Cu2O immobilized carbon beads (Ag/Cu2O@CB) based composite photocatalysts have been prepared for the removal of levofloxacin, an antibiotic, from water. The photocatalysts were prepared by the processes of chemical reduction and in-situ solid-phase precipitation. The composite photocatalyst was characterized by a porous and interconnected network structure. Ag nanoparticles were deposited on Cu2O particles to develop a metal-based semiconductor to increase the catalytic efficiency of the system and the separation efficiency of the photogenerated carriers. Cellulose-derived carbon beads (CBs) can also be used as electron storage libraries which can capture electrons released from the conduction band of Cu2O. The results revealed that the maximum catalytic degradation efficiency of the composite photocatalyst for the antibiotic levofloxacin was 99.02 %. The Langmuir-Hinshelwood model was used to study the reaction kinetics, and the process of photodegradation followed first-order kinetics. The maximum apparent rate was recorded to be 0.0906 min-1. The mass spectrometry technique showed that levofloxacin degraded into carbon dioxide and water in the presence of the photocatalyst. The results revealed that the easy-to-produce photocatalyst was stable and efficient in levofloxacin removing.

Identification of Pancreatic Metastasis Cells and Cell Spheroids by the Organelle-Targeting Sensor Array.

Pancreatic cancer is a highly malignant and metastatic cancer. Pancreatic cancer can lead to liver metastases, gallbladder metastases, and duodenum metastases. The identification of pancreatic cancer cells is essential for the diagnosis of metastatic cancer and exploration of carcinoma in situ. Organelles play an important role in maintaining the function of cells, the various cells show significant differences in organelle microenvironment. Herein, six probes are synthesized for targeting mitochondria, lysosomes, cell membranes, endoplasmic reticulum, Golgi apparatus, and lipid droplets. The six fluorescent probes form an organelles-targeted sensor array (OT-SA) to image pancreatic metastatic cancer cells and cell spheroids. The homology of metastatic cancer cells brings the challenge for identification of these cells. The residual network (ResNet) model has been proven to automatically extract and select image features, which can figure out a subtle difference among similar samples. Hence, OT-SA is developed to identify pancreatic metastasis cells and cell spheroids in combination with ResNet analysis. The identification accuracy for the pancreatic metastasis cells (> 99%) and pancreatic metastasis cell spheroids (> 99%) in the test set is successfully achieved respectively. The organelles-targeting sensor array provides a method for the identification of pancreatic cancer metastasis in cells and cell spheroids.

Particle sizes crucially affected the release of additives from tire wear particles during UV irradiation and mechanical abrasion.

In the environment, tire wear particles (TWPs) could release various additives to induce potential risk, while the effects of particle size on the additive release behavior and ecological risk from TWPs remain unknown. This study investigated the effects and mechanisms of particle sizes (>2 mm, 0.71-1 mm, and <0.1 mm) on the release behavior of TWPs additives under mechanical abrasion and UV irradiation in water. Compared to mechanical abrasion, UV irradiation significantly increased the level of additives released from TWPs. Especially, the additive releasing characteristics were critically affected by the particle sizes of TWPs, manifested as the higher release in the smaller-size ones. After 60 d of UV irradiation, the concentration of antioxidant N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) reached 10.79 mg/L in the leachate of small-sized TWPs, 2.78 and 5.36 times higher than that of medium-sized and large-sized TWPs. The leachate of the small-sized TWPs also showed higher cytotoxicity. •OH and O2•- were identified as the main reactive oxygen species (ROS), which exhibited higher concentrations and dramatic attack on small-sized TWPs to cause pronounced fragmentation and oxidation, finally inducing the higher release of additives. This paper sheds light on the crucial effects and mechanism of particle sizes in the release behavior of TWPs additives, provides useful information to assess the ecological risk of TWPs.

Discovery of potential components characteristic by conjugated enone from the branches and leaves of Croton lauioides with anti-neuroinflammatory activity via regulating the NF-κB pathway.

In this study, the chemical composition and pharmacological activity of Croton lauioides were investigated for the first time. The bioactive and HPLC-UV guided isolation led to the discovery of twenty-three conjugated enone-type components (1-23), including nine previously unknown sesquiterpenoid derivatives (1-4, 9-10, 12-14). Notably, compounds 1 and 12 are epoxides containing an endoperoxide bridge (1) or a unique dioxaspiro core (12), respectively. Compounds 2-7 are non-benzenoid aromatics featuring a tropone function, while 9-11 possess a rare rearranged scaffold with tropone shift into benzene. Extensive characterization was performed using NMR spectra, HRESIMS data, and electronic circular dichroism (ECD) calculations. Furthermore, we evaluated the bioactivities of all isolated compounds against neuroinflammation in LPS-stimulated BV-2 microglial cells. Remarkably, most sesquiterpenoid derivatives exhibited significant NO inhibit activities, and compound 5 showed the most potent effect with an IC50 value of 0.14 ± 0.04 µM. Structure-activity relationship (SAR) analysis revealed that sesquiterpenoids modified with endocyclic enone conjugation may serve as a key pharmacophore for NO inhibition, particularly involving aromatic tropone moiety. The qPCR and Western blot results demonstrated that 5 exerted an inhibitory effect on the mRNA levels of iNOS, TNF-α and COX-2 in a time-dependent manner, as well as suppressed the protein expression of iNOS, TNF-α, COX-2. In mechanism, 5 could prevented activation of NF-κB pathway by suppressing phosphorylation of p65 and IκB-α. These findings revealed C. lauioides might be a promising resource for drug candidate development targeting neuroinflammation.

Development and Validation of Knowledge Assessment Scales for Dementia and Urinary Incontinence in Community Older People.

To develop and validate scales for reliably assessing dementia and urinary incontinence knowledge of older adults in the community. Items were generated through a literature review, refined through a Delphi study (n = 19), and then revised through a pilot study (n = 29). Item analysis and exploratory factor analysis were applied to finalize the scales (n = 244). Construct validity, reliability, and acceptability were evaluated (n = 243). The two knowledge assessment scales for dementia and urinary incontinence, respectively, comprised 12 items and 8 items. Model fit indicators of both met the criteria of confirmatory factor analysis. Cronbach's α were .82 and .70, respectively. Completion ratio and completion time of the two scales was 83.51% and 4.22 ± 1.90 minutes. The knowledge assessment scales for dementia and urinary incontinence with satisfactory validity, reliability, and acceptability, could be served as valid tools for disease prevention and management among older adults in the community.

Vasorin exocytosed from glioma cells facilitates angiogenesis via VEGFR2/AKT signaling pathway.

Glioma is a highly vascularized tumor of the central nervous system. Angiogenesis plays a predominant role in glioma progression and is considered an important therapeutic target. Our previous study showed that vasorin (VASN), a transmembrane protein, is overexpressed in glioma and promotes angiogenesis; however, the potential mechanism remains unclear. In this study, we found that human vascular endothelial cells (hECs) co-cultured with VASN-overexpressing glioma cells exhibited accelerated migration ability and increased expression of VASN originated from glioma cells. VASN was found in exosomes secreted by glioma cells and could be taken up by hECs. hECs showed more edge filopodia and significantly upregulated expression of endothelial tip cell marker gene and protein levels after co-culture with VASN-overexpressing glioma cells. In clinical glioma tissue and orthotopic transplantation glioma tissue, the vascular density and the number of vascular endothelial cells with a tip cell phenotype in VASN-overexpressed tissues were significantly higher than in tissues with low expression. At the molecular level, VASN interacted with VEGFR2 and caused internalization and autophosphorylation of VEGFR2 protein, and then activated the AKT signaling pathway. Our study collectively reveals the function and mechanism of VASN in facilitating angiogenesis in glioma, providing a new therapeutic target for glioma. Implications: These findings demonstrate that VASN exocytosed from glioma cells enhanced the migration of vascular endothelial cells by VEGFR2/AKT signaling pathway.

Effects of haemodiafiltration or haemofiltration compared with haemodialysis on prognosis in patients with end-stage renal disease: protocol an updated systematic review and meta-analysis of randomised trials with trial sequential analysis.

INTRODUCTION: Haemodialysis is the most common treatment option for patients with life-sustaining end-stage kidney disease (ESKD). In recent years, haemodiafiltration or haemofiltration has been widely used in patients with ESKD, and there are still conflicting findings as to whether both are superior to traditional haemodialysis. This systematic review and meta-analysis were designed to determine whether haemodiafiltration or haemofiltration is more effective than haemodialysis in reducing all-cause mortality risk in patients with ESKD. METHODS AND ANALYSIS: We will perform a systematic PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library and Scopus search, including studies published before September 2023. Randomised controlled trials will be included exploring the effects of haemodiafiltration or haemofiltration compared with haemodialysis on prognosis in patients with ESKD. Outcomes of interest include all-cause mortality, cardiovascular events, dialysis adequacy and adverse effects. The Cochrane Collaboration tools (ROB-2) will assess the bias risk. Available data will be used to calculate effect sizes. Heterogeneity between studies will be evaluated with I2. The trial sequential analysis will be used to eliminate false-positive results. The certainty of the evidence will be assessed using Grading of Recommendations, Assessment, Development and Evaluation criteria. ETHICS AND DISSEMINATION: This systematic review and meta-analysis was deemed exempt from ethics review. Results will be disseminated through publication in peer-reviewed journals and research conferences. PROSPERO REGISTRATION NUMBER: CRD42023464509.

Ultralow-loss optical interconnect enabled by topological unidirectional guided resonance.

Grating couplers that interconnect photonic chips to off-chip components are crucial for various optoelectronics applications. Despite numerous efforts in past decades, the existing grating couplers are still far from optimal in energy efficiency and thus hinder photonic integration toward a larger scale. Here, we propose a strategy to achieve ultralow-loss grating couplers by using unidirectional guided resonances (UGRs), suppressing the useless downward radiation with no mirror on the bottom. By engineering the dispersion and apodizing the geometry of grating, we experimentally realize a grating coupler with a record-low loss of -0.34 dB and 1-dB bandwidth exceeding 30 nm at the telecom wavelength of 1550 nm and further demonstrate an optic via with a loss of only -0.94 dB. Given that UGRs ubiquitously exist in a variety of grating geometries, our work sheds light on a systematic method to achieve energy-efficient optical interconnect and paves the way to large-scale photonic integration.

Millimeter-scale magnetic implants paired with a fully integrated wearable device for wireless biophysical and biochemical sensing.

Implantable sensors can directly interface with various organs for precise evaluation of health status. However, extracting signals from such sensors mainly requires transcutaneous wires, integrated circuit chips, or cumbersome readout equipment, which increases the risks of infection, reduces biocompatibility, or limits portability. Here, we develop a set of millimeter-scale, chip-less, and battery-less magnetic implants paired with a fully integrated wearable device for measuring biophysical and biochemical signals. The wearable device can induce a large amplitude damped vibration of the magnetic implants and capture their subsequent motions wirelessly. These motions reflect the biophysical conditions surrounding the implants and the concentration of a specific biochemical depending on the surface modification. Experiments in rat models demonstrate the capabilities of measuring cerebrospinal fluid (CSF) viscosity, intracranial pressure, and CSF glucose levels. This miniaturized system opens the possibility for continuous, wireless monitoring of a wide range of biophysical and biochemical conditions within the living organism.

Rational Design of Potent α-Conotoxin PeIA Analogues with Non-Natural Amino Acids for the Inhibition of Human α9α10 Nicotinic Acetylcholine Receptors.

α-Conotoxins (α-CTxs) are structurally related peptides that antagonize nicotinic acetylcholine receptors (nAChRs), which may serve as new alternatives to opioid-based treatment for pain-related conditions. The non-natural amino acid analogues of α-CTxs have been demonstrated with improved potency compared to the native peptide. In this study, we chemically synthesized Dab/Dap-substituted analogues of α-CTx PeIA and evaluated their activity at heterologously expressed human α9α10 nAChRs. PeIA[S4Dap, S9Dap] had the most potent half-maximal inhibitory concentration (IC50) of 0.93 nM. Molecular dynamic simulations suggested that the side chain amino group of Dap4 formed additional hydrogen bonds with S168 and D169 of the receptor and Dap9 formed an extra hydrogen bond interaction with Q34, which is distinctive to PeIA. Overall, our findings provide new insights into further development of more potent analogues of α-CTxs, and PeIA[S4Dap, S9Dap] has potential as a drug candidate for the treatment of chronic neuropathic pain.

Hypertension, microvascular obstruction and infarct size in patients with STEMI undergoing PCI: Pooled analysis from 7 cardiac magnetic resonance imaging studies.

BACKGROUND: Mortality after ST-segment elevation myocardial infarction (STEMI) is increased in patients with hypertension. The mechanisms underlying this association are uncertain. We sought to investigate whether patients with STEMI and prior hypertension have greater microvascular obstruction (MVO) and infarct size (IS) compared with those without hypertension. METHODS: We pooled individual patient data from 7 randomized trials of patients with STEMI undergoing primary percutaneous coronary intervention (PCI) in whom cardiac magnetic resonance imaging was performed within 1 month after reperfusion. The associations between hypertension and MVO, IS, and mortality were assessed in multivariable adjusted models. RESULTS: Among 2174 patients (61.3 ± 12.6 years, 76% male), 1196 (55.0%) had hypertension. Patients with hypertension were older, more frequently diabetic and had more extensive coronary artery disease than those without hypertension. MVO and IS measured as percent LV mass were not significantly different in patients with and without hypertension (adjusted differences 0.1, 95% CI -0.3 to 0.6, P = .61 and -0.2, 95% CI -1.5 to 1.2, P = .80, respectively). Hypertension was associated with a higher unadjusted risk of 1-year death (hazard ratio [HR] 2.28, 95% CI 1.44-3.60, P < .001), but was not independently associated with higher mortality after multivariable adjustment (adjusted HR 1.04, 95% CI 0.60-1.79, P = .90). CONCLUSION: In this large-scale individual patient data pooled analysis, hypertension was not associated with larger IS or MVO after primary PCI for STEMI.

High-frequency rTMS over bilateral primary motor cortex improves freezing of gait and emotion regulation in patients with Parkinson's disease: a randomized controlled trial.

Background: Freezing of gait (FOG) is a common and disabling phenomenon in patients with Parkinson's disease (PD), but effective treatment approach remains inconclusive. Dysfunctional emotional factors play a key role in FOG. Since primary motor cortex (M1) connects with prefrontal areas via the frontal longitudinal system, where are responsible for emotional regulation, we hypothesized M1 may be a potential neuromodulation target for FOG therapy. The purpose of this study is to explore whether high-frequency rTMS over bilateral M1 could relieve FOG and emotional dysregulation in patients with PD. Methods: This study is a single-center, randomized double-blind clinical trial. Forty-eight patients with PD and FOG from the Affiliated Hospital of Xuzhou Medical University were randomly assigned to receive 10 sessions of either active (N = 24) or sham (N = 24) 10 Hz rTMS over the bilateral M1. Patients were evaluated at baseline (T0), after the last session of treatment (T1) and 30 days after the last session (T2). The primary outcomes were Freezing of Gait Questionnaire (FOGQ) scores, with Timed Up and Go Test (TUG) time, Standing-Start 180° Turn (SS-180) time, SS-180 steps, United Parkinson Disease Rating Scales (UPDRS) III, Hamilton Depression scale (HAMD)-24 and Hamilton Anxiety scale (HAMA)-14 as secondary outcomes. Results: Two patients in each group dropped out at T2 and no serious adverse events were reported by any subject. Two-way repeated ANOVAs revealed significant group × time interactions in FOGQ, TUG, SS-180 turn time, SS-180 turning steps, UPDRS III, HAMD-24 and HAMA-14. Post-hoc analyses showed that compared to T0, the active group exhibited remarkable improvements in FOGQ, TUG, SS-180 turn time, SS-180 turning steps, UPDRS III, HAMD-24 and HAMA-14 at T1 and T2. No significant improvement was found in the sham group. The Spearman correlation analysis revealed a significantly positive association between the changes in HAMD-24 and HAMA-14 scores and FOGQ scores at T1. Conclusion: High-frequency rTMS over bilateral M1 can improve FOG and reduce depression and anxiety in patients with PD.