Therapy Research Articles

Over-the-counter antibiotics compromising aminoglycoside activity

Abstract Introduction Antimicrobial resistance (AMR) is a global issue that needs addressing. While antibiotic stewardship has improved often by restricting antibiotic use, some antibiotics that are still sold legally over the counter (OTC), notably in sore throat medications. Recent findings suggest OTC antibiotics could trigger cross-resistance to antibiotics used in clinical treatments, whether systemic or topical. Here we investigated the impact of three antibiotics contained in OTC sore throat medicines on emerging AMR in vitro. Methods Bacterial pathogens were exposed to a bactericidal concentration of an aminoglycoside in the presence or absence of a during-use concentration of bacitracin, gramicidin or tyrothricin in a time–kill assay. Damage to the bacterial membrane was also investigated by measuring potassium leakage and membrane potential alteration post-OTC antibiotic exposure. Results Gramicidin (15 µg/mL) significantly decreased the bactericidal activity of amikacin, tobramycin or gentamicin in Acinetobacter baumannii. It also decreased gentamicin bactericidal activity in Enterobacter cloacae, Escherichia coli and Klebsiella pneumoniae, while tyrothricin decreased the aminoglycoside efficacy in E. cloacae and E. coli. Gramicidin significantly decreased bacterial membrane potential and caused significant potassium leakage. Conclusion Gramicidin and to some extent tyrothricin impacted aminoglycoside efficacy by affecting membrane potential, which is essential for aminoglycosides uptake. Thus, some OTC antibiotics can interfere with aminoglycoside activity, which could in turn affect treatment efficacy. Although the likelihood of OTC antibiotics and aminoglycosides being used at the same time might not be common, this research highlights one potential reason for OTC antibiotics’ usage to result in treatment failure and their contribution to AMR development.

Multigeographic clinical assessment of a molecular diagnostic assay for detection of key codons to predict decreased susceptibility or resistance to cephalosporins in Neisseria gonorrhoeae.

Cephalosporin resistance in Neisseria gonorrhoeae has severely compromised the efficacy of World Health Organization (WHO)-recommended therapies. This study aimed to methodologically evaluate the optimized Six-CodonPlus assay, and additionally conducted a multicenter evaluation to assess its clinical application, especially for predicting antimicrobial resistance (AMR). For methodological evaluation, 397 sequence-known N. gonorrhoeae isolates were evaluated for specificity, 17 nongonococcal isolates were assessed for cross-reactivity, 159 uncultured urogenital swabs and urine samples were evaluated for sensitivity at the clinical level. For multicenter evaluation, 773 isolates with confirmed phenotypic data and 718 clinical urogenital swabs collected from four geographical cities were, respectively, utilized for the evaluation of AMR-prediction strategies and the clinical application of the assay. The assay accurately identified specific single-nucleotide polymorphisms in resistance-associated genes, the detection limits dropped to 10 copies/reaction for individual targets. The specificity reached 100% and no cross-reactivity occurred with double-target confirmation. The assay could be directly applied to clinical samples containing over 20 copies/reaction. Multicenter evaluation formulated two optimal strategies for decreased susceptibility prediction in specific scenarios, and one tactic for prediction of resistance and identification of FC428-like strains. High sensitivity of 86.84% (95% CI, 71.11-95.05) and specificity of 99.59% (95% CI, 98.71-99.89) for resistance prediction were demonstrated for ceftriaxone (CRO). Regarding N. gonorrhoeae identification among multicenter swabs, specificity reached 97.53% (95% CI, 95.49-98.69), and sensitivity reached 93.77% (95% CI, 90.04-96.22). The Six-CodonPlus assay exhibited excellent detection performance and formulated optimal AMR-related prediction strategy with regional adaptability, providing critical information for population screening and clinical treatment.

Ginsenoside Rg1 Promotes Wound Healing in Mice with Superficial Second-Degree Burns Through Energy Metabolism, Cell Migration, and Cell Adhesion Pathways.

Natural products are known to have distinct roles in the treatment of various diseases. However, the potential role of ginsenoside Rg1 (GRg1) in the context of scald injuries remains unclear. This study aimed to elucidate the effects of GRg1 on scald wound healing by utilizing a mouse scald wound model and administering varying concentrations of GRg1 orally. RNA sequencing (RNA-seq) was employed to identify the signaling pathways and key genes influenced by GRg1 in the wound healing process. Our findings indicate that mice treated with a low concentration of GRg1 exhibited a significantly higher wound healing rate compared with the model group and other treatment groups. Through RNA-seq, we observed that the gene expression profile in the wound tissues of the low-concentration-treated group was consistent with that of the normal control group. Furthermore, a low concentration of GRg1 was found to maintain cellular energy metabolism homeostasis by enhancing mitochondrial aerobic respiration and the tricarboxylic acid cycle. In addition, GRg1 facilitated wound healing by restoring the expression of genes associated with cell migration and adhesion. Confirming the appropriate concentration of GRg1 that accelerates tissue healing at scald sites and enhances our understanding of the efficacy and molecular mechanisms underlying the therapeutic effects of natural products in disease treatment.

A small-molecule carrier for the intracellular delivery of a membrane-impermeable protein with retained bioactivity.

Intracellular protein delivery has the potential to revolutionize cell-biological research and medicinal therapy, with broad applications in bioimaging, disease treatment, and genome editing. Herein, we demonstrate successful delivery of a functional protein, cytochrome c (CYC), by using a boron cluster anion as molecular carrier of the superchaotropic anion type (B12Br11OPr2-). CYC was delivered into lipid bilayer vesicles as well as living cells, with a cellular uptake ratio approaching 90%. Mechanistic studies showed that CYC was internalized into cells through a permeation pathway directly into the cytoplasm, bypassing endosomal entrapment. Upon carrier-assisted internalization, CYC retained its bioactivity, as reflected by an induced cell apoptosis rate of 25% at low dose (1 µM). This study furbishes a direct protein delivery method by a molecular carrier with high efficiency, confirming the potential of inorganic cluster ions as protein transport vehicles with an extensive range of future cell-biological or biomedical applications.

Unilateral biportal endoscopic vs. open surgery in the treatment of young obese patients’ lumbar degenerative diseases: a retrospective study

BackgroundObesity accelerates the development of lumbar disease and increase the risk during surgery. Unilateral biportal endoscopic discectomy (UBE) is a newly developed minimally invasive technique, which refers to the spinal surgery under unilateral double-channel endoscopic surgery. Therefore, the purpose of this study is whether UBE decompression alone can bring good clinical results to young obese patients with lumbar degenerative diseases.MethodsThe patients with lumbar diseases who underwent UBE and open surgery (open discectomy) in our hospital from February 2020 to February 2022 were selected as young (age ≤ 44 years old) and obesity (BMI ≥ 30 kg/m2). The patients were evaluated with VAS, ODI, JOA and modified Macnab score before operation, 1 month, 6 months and 12 months after operation. Nerve root function sensation, muscle strength and tendon reflex were evaluated. The operation time, estimated blood loss, postoperative hospital stay, incidence of postoperative complications and reoperation rate were recorded. MRI quantitative lumbar multifidus muscle (LMM) comparison was performed 12 months after operation.Results77 patients were included, and the scores of VAS, ODI and JOA were similar in the two groups during the last follow-up. There were no difference in nerve root function sensation, muscle strength or tendon reflex. However, one month after operation, the VAS back score and ODI improvement in the UBE group were significantly better than those in the open group, which were 2.44 ± 0.97, 33.10 ± 6.78 and 2.93 ± 0.79 and 36.13 ± 5.84, respectively, with a statistically significant difference (p = 0.020 and 0.038). According to the modified Macnab criteria, UBE group, the excellent and good rate was 97.2%. The excellent and good rate of open group was 97.6%. The estimated blood loss and postoperative hospital stay in UBE group (36.81 ± 17.81, 3.92 ± 1.32) were significantly better than those in open group (104.88 ± 31.41, 6.41 ± 1.94), with a statistically significant difference (p = 0.010). There was no significant difference in operation time between the two groups (p = 0.070). The number of complications in UBE group was 2 (5.6%) and open group was 4 (9.8%). The fat infiltration rate of 19.3%+11.0% in UBE group was significantly lower than that of 27.0%±13.9% in open group (p = 0.010).ConclusionUBE has the advantage of early recovery in the treatment of lumbar degenerative diseases in young obese patients, and reduces the damage to LMM, so it has a good clinical effect.

Evaluating Long-Term Outcomes of Children Undergoing Surgical Treatment for Congenital Heart Disease for National Audit in England and Wales.

There is strong interest in the evaluation of longer-term outcome metrics for congenital heart diseases (CHDs); however, registries focus on postoperative metrics. Informed by user online discussion forums and scoping of national data, we selected sentinel CHDs and long-term outcome metrics suitable for routine monitoring. We then developed sentinel CHD phenotypes and algorithms for identifying treatment pathway procedures using clinical codes. Finally, we calculated the metrics within a retrospective national cohort analysis. The 9 selected sentinel CHDs had a higher-than-average prevalence, typically involved surgery in infancy, and were associated with an increased risk of late mortality. The selected metrics of survival and reinterventions at 1, 5, and 10 years were both important and feasible. The cohort included 29 319 (41.3% of all operated CHD births) English and Welsh children born with sentinel CHDs in 2000 to 2022. Example metrics at age 10 years included: survival-hypoplastic left heart syndrome: 57.6% (95% CI, 54.9%-60.4%), functionally univentricular heart: 86.7% (95% CI, 84.6%-88.9%), transposition of the great arteries: 93.1% (95% CI, 92.2%-93.9%), pulmonary atresia: 81.0% (95% CI, 79.1%-82.9%), atrioventricular septal defect: 88.5% (95% CI, 87.5%-89.5%), tetralogy of Fallot: 95.1% (95% CI, 94.4%-95.8%), aortic stenosis: 94.4% (95% CI, 93.3%-95.6%), coarctation: 96.7% (95% CI, 96.2%-97.3%), and ventricular septal defect: 96.9% 95% CI, (96.4%-97.3%); and (2) cumulative incidence of reintervention-hypoplastic left heart syndrome : 54.5% (95% CI, 51.5%-57.3%), functionally univentricular heart: 57.3% (95% CI, 53.9%-60.5%), transposition of the great arteries: 20.9% (95% CI, 19.5%-22.3%), pulmonary atresia: 66.8% (95% CI, 64.2%-69.1%), atrioventricular septal defect: 21.6% (20.3%-23.0%), tetralogy of Fallot: 26.6% (95% CI, 25.2%-28.0%), aortic stenosis: 31.2% (95% CI, 28.8%-33.6%), coarctation: 19.8% (95% CI, 18.6%-21.1%), and ventricular septal defect: 6.1% (95% CI, 5.5%-6.8%). It is feasible to report important long-term outcomes of survival and reintervention for sentinel CHDs using routinely collected procedure records, adding value to national audit.

Fecal microbiota transplantation against moderate-to-severe atopic dermatitis: A randomized, double-blind controlled explorer trial.

Fecal microbiota transplantation (FMT) is a novel treatment for inflammatory diseases. Herein, we assess its safety, efficacy, and immunological impact in patients with moderate-to-severe atopic dermatitis (AD). In this randomized, double-blind, placebo-controlled clinical trial, we performed the efficacy and safety assessment of FMT for moderate-to-severe adult patients with AD. All patients received FMT or placebo once a week for 3 weeks, in addition to their standard background treatments. Patients underwent disease severity assessments at weeks 0, 1, 2, 4, 8, 12, and 16, and blood and fecal samples were collected for immunologic analysis and metagenomic shotgun sequencing, respectively. Safety was monitored throughout the trial. Improvements in eczema area and severity index (EASI) scores and percentage of patients achieving EASI 50 (50% reduction in EASI score) were greater in patients treated with FMT than in placebo-treated patients. No serious adverse reactions occurred during the trial. FMT treatment decreased the Th2 and Th17 cell proportions among the peripheral blood mononuclear cells, and the levels of TNF-α, and total IgE in serum. By contrast, the expression levels of IL-12p70 and perforin on NK cells were increased. Moreover, FMT altered the abundance of species and functional pathways of the gut microbiota in the patients, especially the abundance of Megamonas funiformis and the pathway for 1,4-dihydroxy-6-naphthoate biosynthesis II. FMT was a safe and effective therapy in moderate-to-severe adult patients with AD; the treatment changed the gut microbiota compositions and functions.

Dirichlet latent modelling enables effective learning and sampling of the functional protein design space

Engineering proteins with desired functions and biochemical properties is pivotal for biotechnology and drug discovery. While computational methods based on evolutionary information are reducing the experimental burden by designing targeted libraries of functional variants, they still have a low success rate when the desired protein has few or very remote homologous sequences. Here we propose an autoregressive model, called Temporal Dirichlet Variational Autoencoder (TDVAE), which exploits the mathematical properties of the Dirichlet distribution and temporal convolution to efficiently learn high-order information from a functionally related, possibly remotely similar, set of sequences. TDVAE is highly accurate in predicting the effects of amino acid mutations, while being significantly 90% smaller than the other state-of-the-art models. We then use TDVAE to design variants of the human alpha galactosidase enzymes as potential treatment for Fabry disease. Our model builds a library of diverse variants which retain sequence, biochemical and structural properties of the wildtype protein, suggesting they could be suitable for enzyme replacement therapy. Taken together, our results show the importance of accurate sequence modelling and the potential of autoregressive models as protein engineering and analysis tools.

Wearable Multifunctional Hydrogel for Oral Microenvironment Visualized Sensing Coupled with Sonodynamic Bacterial Elimination and Tooth Whitening.

Bacterial-driven dental caries and tooth discoloration are growing concerns as the most common oral health problems. Current diagnostic methods and treatment strategies hardly allow simultaneous early detection and non-invasive treatment of these oral diseases. Herein, a wearable multifunctional double network hydrogel combined with polyaniline and barium titanate (PANI@BTO) nanoparticles is developed for oral microenvironment visualized sensing and sonodynamic therapy. Due to the colorimetric properties of polyaniline, the hydrogel displays a highly sensitive and selective response for visualized sensing of oral acidic microenvironment. Meanwhile, the barium titanate in the hydrogel efficiently generates reactive oxygen species (ROS) under ultrasound irradiation, realizing non-invasive treatment in the oral cavity. Through bacterial elimination experiments and tooth whitening studies, the hydrogel can achieve the dual effect of effectively inhibiting the growth of cariogenic bacteria and degrading tooth surface pigments. Owing to the visualized sensing of the oral acidic microenvironment and efficient sonodynamic therapy function, the proposed hydrogel system offers a solution for the prevention of caries and tooth whitening, which is promising in developing the biomedical system targeting the simultaneous sensing and therapy for oral diseases.

Understanding the Role of Type I Interferons in Cutaneous Lupus and Dermatomyositis: Toward Better Therapeutics.

A 29-year-old female presented to a rheumatology-dermatology clinic with a pruritic rash that began 6 months prior, after a viral illness. She had previously been diagnosed with eczema and treated with antihistamines and topical steroids without improvement. She also noted fatigue, hair loss, and severe scalp pruritus. Physical examination was notable for violaceous periorbital edema, scaly erythematous papules on the metacarpophalangeal joints of bilateral hands, dilated capillaries of the proximal nail folds, scaly plaques on bilateral elbows, and excoriated erythematous plaques on upper chest, back and hips. The patient reported no muscle weakness, and strength testing and creatinine phosphokinase were normal. Magnetic resonance imaging of the thigh showed no evidence of inflammation or edema. Antibody testing was negative. A diagnosis of clinically amyopathic dermatomyositis was made. Computed tomography scans of the chest, abdomen and pelvis, colonoscopy, and mammogram showed no evidence of cancer. The patient was initiated on methotrexate. Her cutaneous manifestations persisted with debilitating intractable pruritus, and thus, she was transitioned to mycophenolate mofetil, again with minimal improvement. Intravenous immunoglobulin was not approved by insurance given the lack of muscle involvement in her disease. This patient's case highlights a common clinical scenario in rheumatology and dermatology and raises several important issues related to the immunologic underpinnings of cutaneous lupus erythematosus (CLE) and dermatomyositis (DM): What is the role of type I interferon (IFN) in triggering skin disease in CLE and DM? What is the role of IFN in the pathogenesis of skin inflammation in CLE and DM? Can we apply what we know about IFN-targeted therapeutics in CLE and DM to develop better treatments for skin disease?

Melissa officinalis Regulates Lipopolysaccharide-Induced BV2 Microglial Activation via MAPK and Nrf2 Signaling.

Neuroinflammation and microglial activation play critical roles in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Modulating microglial activation may help prevent the progression of these disorders. This study aimed to investigate the effects and mechanisms of Melissa officinalis ethanol extract on lipopolysaccharide (LPS)-induced microglial activation in BV2 cells. Cell viability and nitric oxide (NO) production were assessed using MTT assay and Griess reagent, while inflammatory cytokine levels were measured by qPCR. Key inflammatory pathways, including MAPK, TLR4, and antioxidant biomarkers, were analyzed through western blot and immunofluorescence. Rosmarinic acid content in M. officinalis was determined using high-performance liquid chromatography (HPLC). The results demonstrated that M. officinalis ethanol extract significantly inhibited LPS-induced NO production and reduced inflammatory cytokine expression. Additionally, it downregulated inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TLR4, NF-κB, and MAPK signaling pathways (p38, JNK, ERK), while increasing the expression of antioxidant markers, including Nrf2, HO-1, catalase, and SOD2. In conclusion, M. officinalis ethanol extract exerts neuroprotective effects by modulating inflammation and enhancing antioxidant defenses, suggesting its potential in the prevention and treatment of inflammation-related neurodegenerative diseases.

Novel plasmid-mediated CMY variant (CMY-192) conferring ceftazidime-avibactam resistance in multidrug-resistant Escherichia coli.

The rapid rise of multidrug resistance (MDR) among Gram-negative bacteria has accelerated the development of novel therapies. Ceftazidime-avibactam (CZA) is a novel β-lactam/β-lactamase inhibitor recently approved for the treatment of limited infectious diseases. Here, we describe a novel CMY variant, CMY-192, that confers high-level resistance to CZA. This gene was detected in a clinical MDR Escherichia coli strain (Ec73552) isolated from an outpatient with a community-acquired urinary tract infection who had not received prior CZA treatment. Ec73552 was typed as O101:H9-ST10, a high-risk clone associated with human and animal diseases. Ec73552 was able to colonize the bladder in a mouse model, suggesting that this strain was uropathogenic. CMY-192 shared the highest amino acid identity (98.95%) with CMY-172 and conferred at least a 32-fold increase in CZA MIC (from ≤0.125/4 to 8/4 mg/L) when cloned into a CZA-susceptible E. coli DH5α strain. Knockout of CMY-192 in Ec73552 resulted in a 256-fold reduction in CZA MIC (from 64/4 to 0.25/4 mg/L). CMY-192 was encoded on an IncB/O/K/Z-type plasmid (pCMY192). Conjugation assays confirmed that pCMY192 was self-transmissible, resulting in a 256-fold increase in the CZA MIC of the recipient. Notably, pCMY192 cured in Ec73552 did not confer a growth advantage, while the conjugant exhibited reduced biomass and growth rate, indicating that fitness costs imposed by pCMY192 may have been compensated in Ec73552. Our findings highlight the importance of continuous monitoring of CZA susceptibility to prevent the spread of resistance in clinical settings.

Multi-omics evaluation of clinical-grade human umbilical cord-derived mesenchymal stem cells in synergistic improvement of aging related disorders in a senescence-accelerated mouse model

BackgroundThe prevalence of age-related disorders, particularly in neurological and cardiovascular systems, is an increasing global health concern. Mesenchymal stem cell (MSC) therapy, particularly using human umbilical cord-derived MSCs (HUCMSCs), has shown promise in mitigating these disorders. This study investigates the effects of HUCMSCs on aging-related conditions in a senescence-accelerated mouse model (SAMP8), with a focus on DNA damage, gut microbiota alterations, and metabolic changes.MethodsSAMP8 mice were treated with clinical-grade HUCMSCs via intraperitoneal injections. Behavioral and physical assessments were conducted to evaluate cognitive and motor functions. The Single-Strand Break Mapping at Nucleotide Genome Level (SSiNGLe) method was employed to assess DNA single-strand breaks (SSBs) across the genome, with particular attention to exonic regions and transcription start sites. Gut microbiota composition was analyzed using 16S rRNA sequencing, and carboxyl metabolomic profiling was performed to identify changes in circulating metabolites.ResultsHUCMSC treatment significantly improved motor coordination and reduced anxiety in SAMP8 mice. SSiNGLe analysis revealed a notable reduction in DNA SSBs in MSC-treated mice, especially in critical genomic regions, suggesting that HUCMSCs may mitigate age-related DNA damage. The functional annotation of the DNA breaktome indicated a potential link between reduced DNA damage and altered metabolic pathways. Additionally, beneficial alterations in gut microbiota were observed, including an increase in short-chain fatty acid (SCFA)-producing bacteria, which correlated with improved metabolic profiles.ConclusionThe administration of HUCMSCs in SAMP8 mice not only reduces DNA damage but also induces favorable changes in gut microbiota and metabolism. The observed alterations in DNA break patterns, along with specific changes in microbiota and metabolic profiles, suggest that these could serve as potential biomarkers for evaluating the efficacy of HUCMSCs in treating age-related disorders. This highlights a promising avenue for the development of new therapeutic strategies that leverage these biomarkers, to enhance the effectiveness of HUCMSC-based treatments for aging-associated diseases.

Multifunctional Analgesic Sutures from Microfluidic Spinning Technology.

Sutures are the most commonly used wound repair method after surgery. However, addressing delayed recovery and pain management remains a significant challenge. Here, microfibers are developed from microfluidic spinning with long-lasting analgesia capabilities for sutures. By using a solvent extraction manner, the polycaprolactone (PCL) microfibers encapsulated with ropivacaine (ROP), a well-known analgesic, can be continuously obtained from microfluidics. The intrinsic property of PCL and the advantage of microfluidic spinning technique impart the microfiber with highly controlled morphologies, mechanical strengths, as well as drug release. After exploring their biocompatibility both at in vitro and in vivo levels, the microfibers are directly applied to wound suture. The results demonstrate the lasting analgesic effect of the microfiber on mice with incision pain, highlighting its potential as promising suture for post-surgery treatments. It is anticipated that the multifunctional analgesic sutures produced through microfluidic spinning will pave the way for utilizing fibers as effective sutures in clinical incision wound treatment.

LnCeCell 2.0: an updated resource for lncRNA-associated ceRNA networks and web tools based on single-cell and spatial transcriptomics sequencing data.

We describe LnCeCell 2.0 (http://bio-bigdata.hrbmu.edu.cn/LnCeCell), an updated resource for lncRNA-associated competing endogenous RNA (ceRNA) networks and web tools based on single-cell and spatial transcriptomics sequencing(stRNA-seq)data. We have updated the LnCeCell 2.0 database with significantly expanded data and improved features, including(i) 257 single-cell RNA sequencingandstRNA-seqdatasets across 86 diseases/phenotypes and 80 human normal tissues, (ii) 836581 cell-specific and spatial spot-specific ceRNA interactions and functional networks for 1002988 cells and 367971 spatial spots, (iii) 15489 experimentally supported lncRNA biomarkers related to disease pathology, diagnosis and treatment, (iv) detailed annotation of cell type, cell state, subcellular and extracellular locations of ceRNAs through manual curationand (v) ceRNA expression profiles and follow-up clinical information of 20326 cancer patients. Further, a panel of 24 flexible tools (including 8 comprehensive and 16 mini-analysis tools) was developed to investigate ceRNA-regulated mechanisms at single-cell/spot resolution. The CeCellTraject tool, for example, illustrates the detailed ceRNA distribution of different cell populations and explores the dynamic change of the ceRNA network along the developmental trajectory. LnCeCell 2.0 will facilitate the study of fine-tuned lncRNA-ceRNA networks with single-cell and spatial spot resolution, helping us to understand the regulatory mechanisms behind complex microbial ecosystems.

Deep brain stimulation for severe dystonia associated with Wilson disease: A prospective multicenter meta-analysis of an N-of-1 trial.

Disabling dystonia despite optimal medical treatment is common in Wilson disease (WD). No controlled study has evaluated the effect of deep brain stimulation (DBS) on dystonia related to WD. This study was undertaken to evaluate the efficacy of DBS on dystonia related to WD. A meta-analysis of an N-of-1 prospective, randomized, double-blind, multicenter DBS study was conducted at two French WD reference centers. Main inclusion criteria were patients with WD, stabilized for at least 6 months with significant disability due to dystonia despite optimized medical treatment. The subthalamic nucleus (STN) was targeted for bradykinetic patients with tonic dystonia, and the internal globus pallidus (GPi) was chosen for patients with hyperkinetic dystonia. Each patient underwent two periods of DBS "on" and two periods of DBS "off," each lasting 4 months. The order of stimulation conditions was randomized. The primary outcome was the change in the Canadian Occupational Performance Measure Performance (COPM-P) and Satisfaction scores after each 4-month period. Secondary outcomes were changes in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) severity and disability scores and Unified Wilson's Disease Rating Scale (UWDRS) scores. Between 12 May 2016 and 7 October 2022, three patients were included. Two patients received bilateral GPi DBS, and one received bilateral STN DBS. There was no change of COPM-P (p = 0.956), BFMDRS, and UWDRS scores. No serious adverse events were reported. STN or GPi DBS are ineffective on dystonia related to WD.

BRIVA-ONE study: 12-month outcomes of brivaracetam monotherapy in clinical practice.

This study investigated the effectiveness and tolerability of brivaracetam (BRV) monotherapy in a large series of patients with epilepsy. This was a multicenter, retrospective, observational, non-interventional study in 24 hospitals across Spain. Patients aged ≥18 years who started on BRV monotherapy, either as first-line or following conversion, at least 1 year before database closure were included. Patients were evaluated at baseline and at 3, 6 and 12 months after initiation of BRV monotherapy, in accordance with usual clinical practice at these centers. Data were collected retrospectively from patients' individual charts by participating physicians. The primary effectiveness and safety endpoints were the percentage of seizure-free patients 1 year after initiation of BRV monotherapy and the proportion of patients reporting adverse events (AEs) over the complete follow-up period. Retention rates and subpopulation analysis (levetiracetam switchers, elderly and different etiologies) were also investigated. A total of 276 patients were included (48 with BRV as first-line monotherapy and 228 who converted to BRV monotherapy). The overall retention rate in monotherapy at 12 months was 89.9% (87.5% for first-line monotherapy group; 90.4% for conversion-to-monotherapy group). Seizure-freedom rates at 12 months were 77.8% (75% for first-line monotherapy group; 78.4% for conversion-to-monotherapy group). AEs occurred in 39.5% of patients at 12 months (35.4% for first-line monotherapy group; 40.4% for conversion-to-monotherapy group). Most AEs were mild-to-moderate. The most frequent AEs were irritability (12.3%) and dizziness (10.1%). The most frequent AEs leading to BRV withdrawal were dizziness (1.8%) and memory problems (1.4%). Similar outcomes in terms of effectiveness and tolerability of BRV monotherapy were observed in patients switching from levetiracetam, those with different epilepsy etiologies, and elderly patients. BRV was effective and well tolerated both as first-line monotherapy and following conversion to monotherapy in a real-world setting of patients with epilepsy. The goal of the medical treatment of epilepsy is to ensure best possible patient quality of life, by maximizing seizure control and minimizing medication toxicity. Brivaracetam (BRV) is a new-generation epilepsy treatment that is well tolerated by patients. In our study, monotherapy with BRV reduced seizures in patients who had not received other treatments and in patients who switched from a previous treatment to BRV monotherapy. BRV was well tolerated and also effective in sensitive patients (i.e., the elderly and those who had epilepsy caused by a brain tumor or a brain injury).

Influencing factors and repair advancements in rodent models of peripheral nerve regeneration.

Peripheral nerve injuries lead to severe functional impairments, with rodent models essential for studying regeneration. This review examines key factors affecting outcomes. Age-related declines, like reduced nerve fiber density and impaired axonal transport of vesicles, hinder recovery. Hormonal differences influence regeneration, with BDNF/trkB critical for testosterone and nerve growth factor for estrogen signaling pathways. Species and strain selection impact outcomes, with C57BL/6 mice and Sprague-Dawley rats exhibiting varying regenerative capacities. Injury models - crush for early regeneration, chronic constriction for neuropathic pain, stretch for traumatic elongation and transection for severe lacerations - provide insights into clinically relevant scenarios. Repair techniques, such as nerve grafts and conduits, show that autografts are the gold standard for gaps over 3cm, with success influenced by graft type and diameter. Time course analysis highlights crucial early degeneration and regeneration phases within the first month, with functional recovery stabilizing by three to six months. Early intervention optimizes regeneration by reducing scar tissue formation, while later interventions focus on remyelination. Understanding these factors is vital for designing robust preclinical studies and translating research into effective clinical treatments for peripheral nerve injuries.

Drug–drug interaction extraction based on multimodal feature fusion by Transformer and BiGRU

Understanding drug–drug interactions (DDIs) plays a vital role in the fields of drug disease treatment, drug development, preventing medical error, and controlling health care-costs. Extracting potential from biomedical corpora is a major complement of existing DDIs. Most existing DDI extraction (DDIE) methods do not consider the graph and structure of drug molecules, which can improve the performance of DDIE. Considering the different advantages of bi-directional gated recurrent units (BiGRU), Transformer, and attention mechanisms in DDIE tasks, a multimodal feature fusion model combining BiGRU and Transformer (BiGGT) is here constructed for DDIE. In BiGGT, the vector embeddings of medical corpora, drug molecule topology graphs, and structure are conducted by Word2vec, Mol2vec, and GCN, respectively. BiGRU and multi-head self-attention (MHSA) are integrated into Transformer to extract the local–global contextual DDIE features, which is important for DDIE. The extensive experiment results on the DDIExtraction 2013 shared task dataset show that the BiGGT-based DDIE method outperforms state-of-the-art DDIE approaches with a precision of 78.22%. BiGGT expands the application of multimodal deep learning in the field of multimodal DDIE.

Pluronic F127/lecithin PLGA nanoparticles as carriers of monocyte-targeted jakinibs: a potential therapeutic platform.

Aim: In this study, PLGA nanoparticles (PNPs) emulsified in Pluronic F127 (F127)/Lecithin (LEC) were designed to load Itacitinib (ITA), a selective JAK1 inhibitor, for targeting human monocytes.Materials & methods: The physicochemical characteristics of empty and ITA-loaded F127/LEC PNPs were analyzed. The binding and internalization of NPs in leukocytes were evaluated. The effect of NPs on monocyte activation and JAK1 inhibition was assessed.Results: F127/LEC PNPs were selectively bound and internalized by monocytes, sparing other leukocytes. ITA-F127/LEC PNPs significantly dampened monocyte activation. They also inhibited the monocyte's ability to promote T-cell proliferation and inhibited proinflammatory cytokine production.Conclusion: ITA-loaded F127/LEC PNPs showed potential for monocyte-targeted therapy, offering new avenues for disease treatment.