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Local injections such as bupivacaine are used to treat strabismus, although the mechanism of its clinical effects is unknown. The purpose of this study is to analyze the effects of bupivacaine on extraocular muscle regeneration in a preclinical model. Laboratory study. Three-month-old male New Zealand white rabbits with age- and sex-matched saline injection controls and uninjected controls. One superior rectus muscle per animal was injected with either 3% bupivacaine or saline control and harvested at 1 week, 1 month, or 3 months after treatment. Histomorphometric analysis was used to determine the effects of bupivacaine on extraocular muscles. Data were analyzed for the global and orbital layer separately, as well as the entire muscle cross-sectional area. Muscle morphology, markers of muscle regeneration, muscle size. Treatment with 3% bupivacaine had a myodestructive effect on the injected extraocular muscle, with disruption of myofiber organization and areas of missing myofibers. However, even 1 week after injection, we observed significantly more embryonic myosin heavy chain-positive myofibers, indicating newly regenerated myofibers, in the bupivacaine group compared with the saline group. Embryonic myosin heavy chain was still significantly expressed at 1 month after bupivacaine injection in extraocular muscles, in stark contrast to skeletal muscles elsewhere in the body where embryonic myosin heavy chain expression decreases 1 to 2 weeks after injury. There was a significant increase in the density of muscle stem cells and myofibers with centralized nuclei 3 months after bupivacaine injection compared with saline in both the orbital and global layers. Muscle size and extracellular matrix components were not increased at 3 months after bupivacaine injection compared with saline. Bupivacaine's effects on extraocular muscles may be explained in part by bupivacaine triggering a regenerative response, initially forming new myofibers and increasing the number of muscle stem cells to exert its effects as a treatment for strabismus. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Secondary injuries following spinal cord injury (SCI) are closely associated with the activation of microglia and neuroinflammation. Tanshinone IIA (TIIA), a traditional Chinese medicine monomer with anti-inflammatory and antioxidant properties, has shown neuroprotective effects after SCI. Our previous studies indicated that TIIA exhibited inhibitory effects on early inflammatory responses and microglial activation after SCI, but its underlying mechanisms remained unclear. Due to TIIA's poor water solubility and low bioavailability, its sulfonated derivative, sodium tanshinone IIA sulfonate (STS), was developed to address these issues. However, STS still faced challenges in crossing the blood-spinal cord barrier and exhibited poor stability. In this study, we utilized an emulsion electrospinning technique to load TIIA into poly (lactic-co-glycolic) acid (PLGA) microspheres, creating TIIA-loaded PLGA sustained-release microspheres (TIIA-PLGA SRMs). A single injection of an adequate amount of TIIA-PLGA SRMs was administered into the subarachnoid space through the atlanto-occipital membrane, and its regulatory effects on microglia after SCI were compared with a traditional continuous intraperitoneal injection of STS. Our experimental results demonstrated that intrathecal injection of TIIA-PLGA SRMs effectively promoted the transition of microglial phenotypes from M1 to M2 in the early stages in rats after SCI, alleviating neuroinflammation and improving motor dysfunction and neuropathic pain after SCI. Furthermore, the efficacy of TIIA-PLGA SRMs was superior to the traditional continuous intraperitoneal injection of STS. Additionally, our experiments suggested that the mechanism underlying TIIA-PLGA SRMs in regulating microglial polarization after SCI may be associated with the inhibition of the Notch signaling pathway.

Neovascular age-related macular degeneration (nAMD) is a chronic sight-threatening disease requiring repeated intravitreal antivascular endothelial growth factor (anti-VEGF) injections. Although established anti-VEGF agents have transformed the prognosis of nAMD, a proportion of patients demonstrate persistent exudation, limited durability, or inability to extend beyond short treatment intervals. Faricimab is a bispecific intravitreal antibody targeting both vascular endothelial growth factor A and angiopoietin-2, designed to improve vascular stability, reduce exudation, and increase treatment durability. This clinical audit evaluates 24-month real-world outcomes following switching to faricimab in suboptimal responders with nAMD in an NHS medical retina service. A retrospective clinical audit was conducted of 274 eyes with nAMD switched to faricimab at Sherwood Forest Hospitals NHS Foundation Trust between January 2023 and January 2025. All eyes had previously received at least one anti-VEGF agent and were switched because of persistent disease activity, inadequate anatomical response, or high treatment burden. Data were extracted from the Medisight electronic patient record and cross-checked against pharmacy records. Primary outcomes were best corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study letters and central macular thickness (CMT) on optical coherence tomography. Secondary outcomes included injection interval extension, number of injections, and safety events. Baseline mean BCVA was 58.1 letters. Mean BCVA improved to 59.7 letters at less than six months, representing a gain of +1.6 letters. At 12 months, mean BCVA was 56.9 letters, a change of -1.2 letters from baseline. At 24 months, mean BCVA was 54.4 letters, a change of -3.7 letters from baseline. Anatomical response was more consistent, with mean CMT reductions of -29.1 µm at less than six months, -34.7 µm at 12 months, and -45.7 µm at 24 months. The mean injection interval increased from 7.88 weeks before switching to 10.67 weeks after switching, representing an extension of +2.79 weeks. No cases of intraocular inflammation, retinal vasculitis, or endophthalmitis were recorded. In this real-world NHS audit, faricimab achieved meaningful anatomical improvement and reduced treatment burden in treatment-experienced nAMD eyes switched because of suboptimal response or limited durability on previous anti-VEGF therapy. Visual acuity improved modestly during early follow-up but declined slightly over 24 months, despite progressive anatomical drying. This functional-anatomical dissociation likely reflects the chronicity of disease and irreversible macular damage in a switch population. Faricimab appears to be a safe and effective second-line option for reducing exudation and extending treatment intervals, although expectations regarding long-term visual gain should be realistic.

Glyphosate is one of the most widely used herbicides in the world, whose potential effects on human health are still the subject of debate today. To assess the associated risks, reliable biomonitoring data are required using validated robust and sensitive analytical methods. In this context, an ion chromatography coupled with tandem mass spectrometry (IC-MS/MS) method was developed to quantify glyphosate in human urine. The method is based on direct injection of diluted urine samples. A labeled internal standard (13C2 15N1 glyphosate) is added prior to injection to correct for losses or matrix effects during the analysis. The method limit of quantification (LOQ) is 0.1 ng/mL in urine. The working range was validated between 0.1 and 20 ng/mL. Method trueness was assessed at three concentration levels (LOQ, 2 and 20 ng/mL), and a full validation of the method was performed to characterize the analytical performance in terms of precision and measurement uncertainty.•Direct injection ion chromatography coupled with tandem mass spectrometry•Validation of the method according to international standards.

Suprascapular neuropathy caused by nerve compression or tension at the suprascapular notch is an uncommon but often underappreciated source of shoulder pain and weakness, with limited reporting of presentation types, diagnostic algorithms, and outcomes of surgical treatment. (1) How does suspected suprascapular nerve compression without rotator cuff tear or space-occupying lesion present in a predominantly young and active military population? (2) How does arthroscopic suprascapular nerve decompression affect VAS pain scores, shoulder motor grading, and return to military duty or sport in this population? Between 2013 and 2020, two surgeons treated 29 patients for symptoms attributed to suprascapular nerve lesions with arthroscopic suprascapular nerve decompression. The diagnosis was made by a combination of history, physical examination, MRI, and selective use of EMG and diagnostic injection. Ultrasound-guided suprascapular nerve injection at the suprascapular notch with local anesthetic was performed in all patients presenting predominantly with pain to support the diagnosis. Patients who had positive findings from this work-up were offered surgical decompression, with patients presenting predominantly with pain having completed at least 7 months of nonoperative treatment at the time of final diagnosis. Although we do not have the exact numbers, the large majority of patients whose work-up suggested the presence of these nerve lesions underwent surgical decompression. We excluded nine of the original 29 patients because they had concomitant procedures and/or were over the age of 60 years. The remaining 20 patients (median [IQR] age 23 years [21 to 28]; 15 were men) were treated with isolated arthroscopic suprascapular nerve decompression at the suprascapular notch with necessary concomitant subacromial decompression, and all of them had follow-up of a minimum of 2 years (median [range] 6 years [2 to 10]) with respect to the endpoint of VAS pain, motor grading, and return to duty or sport. To answer our first research question, we characterized the patients' presentations descriptively based on whether they presented principally with pain or with weakness. Patients presenting predominantly with pain had VAS pain scores ranging from 4 to 8 with motor grades no worse than 4+ of 5, while patients presenting predominantly with weakness had a motor grading of 4 of 5 or worse and VAS pain scores ranging from 0 to 5 (median and mode 0). To answer our second research question, we collected the following outcome measures: return to active-duty military service, shoulder abduction and external rotation strength (by motor grade), and VAS pain score (worst level at rest or activity). These outcomes were compared with Wilcoxon rank sum tests. We found two clinical patterns. A primary symptom of weakness was present in 10 of 20 patients, and pain was the main symptom in 10 of 20 patients. Supraspinatus and/or infraspinatus edema and/or atrophy were present on MRI in 10 of 10 patients with weakness and 0 of 10 patients with pain. EMG had denervation changes in 8 of 8 patients with weakness and 0 of 4 patients with pain. Postoperatively, patients who primarily reported pain had improvement in median (IQR) VAS scores (6 [4 to 7] to 1 [0 to 1]; p = 0.009), whereas those who primarily reported weakness had improvement in abduction and external rotation motor grading (4.0 [3.6 to 4.0] to 5.0 [4.8 to 5.0] and 3.3 [3.0 to 3.9] to 4.3 [4.0 to 5.0], respectively; p = 0.004 and p = 0.008). Return to duty or sport occurred in 8 of 10 patients presenting predominantly with pain and 9 of 10 patients presenting predominantly with weakness at a median (IQR) of 13 weeks (13 to 17) and was maintained past at least 1-year follow-up. In this young, active cohort, suspected suprascapular neuropathy caused by compression at the suprascapular notch presented with one of two primary symptoms: pain or weakness. Diagnosis can be supported by concordant findings on history, physical examination, and MRI, with selective use of EMG for weakness and diagnostic injection for pain. Outcomes after arthroscopic suprascapular nerve release with necessary concomitant subacromial decompression involved successful pain relief and strength improvement in patients presenting with pain and weakness, respectively. Future studies could provide valuable insight into the epidemiology of suprascapular neuropathy and further define thresholds for surgical treatment, especially for patients presenting predominantly with pain. Level III, therapeutic study.

It is becoming increasingly clear that chronic exposure to lower levels of ethanol impact learning and behavior. To determine the impact of chronic low-dose ethanol exposure on sensitivity to changes in stimulus value, a conditioned taste aversion procedure was used. Adult male and female mice underwent a sucrose two bottle-choice drinking paradigm. Each day, mice received an injection of either low-dose ethanol (0.5g/kg) or saline two hours after sucrose access for 20 days. This was followed by a lithium chloride (LiCl)-induced conditioned taste aversion (CTA) paradigm in which 0.15M LiCl or vehicle injection was administered immediately after sucrose consumption for three days. On the fourth day, changes in sucrose consumption were analyzed. Chronic exposure to low-dose ethanol did not affect sucrose consumption in either female of male mice during two-bottle choice. In female mice, a history of chronic low-dose ethanol exposure blocked the development of LiCl-induced CTA. A history of chronic low-dose ethanol did not impact LiCl-induced CTA in male mice as both ethanol-naïve and -exposed male mice who underwent LiCl pairing reduced sucrose consumption. This suggests that low-dose ethanol alters aversion-related learning in female mice which may have implication for development of aberrant behavior and risk for alcohol use disorder (AUD).

Nasal filler-related vascular compromise is uncommon but may result in serious tissue injury. Mixed fillers combining hyaluronic acid (HA) with particulate biostimulators may create emboli with dual-phase rheologic behavior that is not fully addressed in current management algorithms derived largely from HA-only events. To present an illustrative case and case-derived technical algorithm integrating high-dose hyaluronidase with superficial micropuncture decompression for early nasal ischemia following injection of a mixed HA-biostimulator filler. We describe an illustrative case of dorsal nasal artery ischemia following injection of a premixed HA-calcium hydroxylapatite (CaHA) formulation containing lidocaine with epinephrine. Early-stage ischemia was managed using a dual-approach rescue strategy consisting of track-based high-dose hyaluronidase for enzymatic debulking, followed by tension-guided superficial micropuncture for mechanical decompression, together with adjunctive supportive measures. Clinical improvement with reperfusion was observed within 24 to 48 h, with marked improvement by Day 5 and near-complete recovery by Day 7. At 4-week follow-up, the patient showed near-complete recovery without clinically evident scarring, contour irregularity, or atrophy. Pain improved markedly, and patient satisfaction was high. In this illustrative case, a dual-approach rescue strategy combining high-dose hyaluronidase with superficial micropuncture was associated with favorable early recovery. This case-derived technical framework may be considered in selected early cases of mixed-filler nasal ischemia, but its independent benefit and generalizability remain uncertain and require further evaluation in larger series. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

100 years ago, the main treatments for asthma were the sympathomimetic ephedrine, theophylline tablets, inhaled anticholinergics in the form of "asthma cigarettes". Together with adrenaline injections for acute exacerbations, these treatments were all bronchodilators derived from natural products. Adrenaline injections evolved into inhaled β2-agonists as the most effective bronchodilators in asthma, whereas theophylline and inhaled anticholinergics are less useful treatments. The efficacy of desiccated adrenal glands extract, used since 1900, is likely due to steroids derived from the adrenal cortex. Corticosteroids are the most effective treatment for asthma and target the underlying eosinophilic airway inflammation. Combination inhalers of corticosteroid and long-acting β2-agonist are now the mainstay of asthma therapy. Recently, short-acting β2-agonists as relievers have been replaced by relievers containing an inhaled corticosteroid, together with a rapid onset long-acting β2-agonist formoterol (anti-inflammatory reliever). This addresses the major issue of poor adherence with inhaled corticosteroids. Poor inhaler technique is being addressed with the development of smart inhalers. In patients with severe asthma not controlled by inhaled therapy, antibodies that block cytokines involved in eosinophilic inflammation have been very effective. In the future, longer acting antibodies will simplify the treatment of these patients. New drugs are also in development for severe non-eosinophilic asthma. There have been remarkable advances in asthma therapy over the last century, although our current treatments have their origins in the therapies used in 1925.

The use of dermal fillers has emerged over the past two decades as one of the fastest-growing interventions in aesthetic medicine. While hyaluronic acid-based fillers account for the largest market share, alternative materials such as calcium hydroxylapatite, poly-L-lactic acid, and polymethylmethacrylate-based products are gaining increasing importance. Advances in injection strategies, anatomical precision, rheological product differentiation, and safety standards have led to a marked improvement in clinical outcomes. However, the profile of rare but potentially severe complications-particularly vascular occlusions-remains a central challenge. The aim of this review is to provide a comprehensive, evidence-based analysis of the current literature regarding materials, mechanisms of action, anatomical risk zones, injection techniques, indications, complication management, and future developments in filler therapy. Die Anwendung von injizierbaren Fillern hat sich in den letzten 20 Jahren als eine der am stärksten wachsenden ästhetisch-medizinischen Interventionen etabliert. Hyaluronsäurebasierte Filler machen den größten Marktanteil aus, aber alternative Materialien wie Calciumhydroxylapatit, Poly-L-Milchsäure und polymethylmethacrylatbasierte Präparate gewinnen an Bedeutung. Fortschritte in Injektionsstrategien, anatomischer Präzision, rheologischer Produktdifferenzierung und Sicherheitsstandards haben zu deutlich besseren klinischen Ergebnissen geführt. Doch das Risiko seltener, jedoch potenziell schwerwiegender Komplikationen – v. a. vaskulärer Okklusionen – bleibt eine zentrale Herausforderung. Ziel der vorliegenden Arbeit ist eine umfassende, evidenzgestützte Analyse der aktuellen Evidenzlage zu Materialien, Mechanismen, anatomischen Risikozonen, Injektionstechniken, Indikationen, Komplikationsmanagement und zukünftigen Entwicklungen in der Gesichtsfillertherapie.

SiO2 nanofluid has significant potential for weakening coal mechanical properties and improving coal seam water injection efficiency, while prewetting time critically governs its modification outcomes. Accordingly, this study systematically investigated the effects of nanofluid prewetting time on coal mechanical performance, energy dissipation, and fracture propagation. Furthermore, Langmuir adsorption theory and Young's equation were employed to elucidate the fluid dynamic mechanism underlying time-dependent structural weakening of the modified coal. Results demonstrate that nanofluid prewetting treatment significantly reduces dynamic contact angles on coal surfaces and effectively enhances hydrophilicity. Nanofluid prewetting diminishes coal resistance to deformation, with the maximum reduction rate occurring at 2 h prewetting, corresponding to the lowest elastic modulus and peak stress alongside intensified lateral expansion. Post-treatment cumulative and maximum ring-down counts decrease substantially, indicating that internal cracks slide and propagate more readily during loading, thereby alleviating instantaneous elastic energy release upon failure. Moreover, fracture development reaches its maximum at 2 h prewetting, with failure mode transitioning from tensile-dominated to shear-dominated behavior. Nanoparticle adsorption on coal surfaces initially increases and subsequently stabilizes with prolonged prewetting time. However, prolonged prewetting time leads to aggregation and deposition of the nanofluid. The channels for water infiltration become narrowed. The enhancement of wetting modification is thereby restricted. In summary, prewetting time modulates nanoparticle adsorption and aggregation behavior, thereby influencing coal water absorption and structural weakening degree, ultimately determining the failure mode transition of the modified coal. The research findings provide foundations for optimizing prewetting time in coal seam water injection.

We investigated the effects of hochuekkito (HET), a traditional Japanese herbal medicine, on anxiety-like behavior induced by the intraperitoneal administration of polyinosinic-polycytidylic acid (poly(I:C)), a synthetic double-stranded RNA that is widely used to mimic viral infection-associated inflammation, in mice. HET (1 g/kg) was orally administered to the mice once daily for two weeks prior to the injection of poly(I:C). Anxiety-like behavior was assessed for 24 h after the poly(I:C) injection using the light-dark box test. The repeated administration of HET significantly attenuated poly(I:C)-induced anxiety-like behavior. Diazepam failed to exert significant effects in poly(I:C)-treated mice. Poly(I:C) significantly increased serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentrations, as well as Il6 and Tnfa mRNA expression levels in the hippocampus and frontal cortex. HET significantly suppressed the poly(I:C)-induced elevation of serum IL-6 and TNF-α concentrations; however, it did not affect the poly(I:C)-induced increases in Il6 and Tnfa mRNA expression in the hippocampus and frontal cortex. Furthermore, poly(I:C) significantly reduced the hippocampal brain-derived neurotrophic factor (BDNF) concentration, and this reduction was significantly reversed by HET treatment. In addition, the administration of 7,8-dihydroxyflavone, a tropomyosin receptor kinase B receptor agonist, significantly increased the time spent in the light compartment in the light-dark box test and ameliorated poly(I:C)-induced anxiety-like behavior. These findings suggest that the anxiolytic-like effects of HET may be associated with the suppression of peripheral inflammatory cytokine responses and restoration of hippocampal BDNF signaling under conditions mimicking viral infection-induced inflammation.

Recombinant adeno-associated virus (rAAV)-mediated delivery of neutralizing antibodies is a promising strategy for rapid and durable prophylaxis against SARS-CoV-2. We evaluated the long-term expression, pharmacokinetics, immunogenicity, biodistribution, and protective efficacy of an rAAV vector of serotype DJ encoding the single-domain antibody P2C5 fused to a human Fc fragment (P2C5-Fc) in mice and common marmosets (Callithrix jacchus). Animals received a single intramuscular administration of rAAV-P2C5-Fc at a dose of 1 × 10¹³ vector genome copies per kg. Rapid antibody detection in serum was observed, reaching peak concentrations (Cmax) by approximately 120 days and remaining at protective levels for >480 days in mice and up to 1,120 days in marmosets. Neutralizing titers closely paralleled serum P2C5-Fc concentrations and provided complete protection against lethal intranasal challenge with SARS-CoV-2 variants B.1.1.1 (Wuhan D614G) and BA.5 (Omicron) even at late time points (216 and 460 days post-administration in mice). Biodistribution analysis showed predominant localization of rAAV at the injection site and regional lymph nodes with minimal off-target spread. Moderate anti-AAV capsid antibody responses were detected, while anti-drug antibodies against P2C5-Fc remained undetectable in both species. These findings demonstrate that a single intramuscular injection of rAAV-P2C5-Fc results in rapid onset, sustained expression, and long-term protective efficacy against SARS-CoV-2 variants in two preclinical models, supporting the potential of this platform for durable vectored immunoprophylaxis.

Previous study demonstrated that Hypnea cervicornis lectin (HCA) reduces inflammation and nociception via interaction with the lectin carbohydrate-binding site, modulating gene expression of the interleukins IL-1β, TNF-α and of iNOS. This study evaluated the effect of HCA in the rat model of arthritis induced by zymosan in the tibiotarsal joint and the involvement of macrophage-derived mediators. In vitro, macrophages were stimulated with zymosan before being incubated with HCA and the supernatant was injected into the joint. In vivo, HCA was administered by intravenous route after intra-articular injection of zymosan, fMLP, or macrophages supernatant. Hypernociception, edema and leukocyte influx were evaluated in the joints, and inflammatory mediators in the macrophage supernatant or periarticular tissue. In vitro, HCA (100 µg/ml) reduced NO2- and IL-1β in the supernatant of macrophages. In vivo, HCA (3 mg/kg) reduced articular hypernociception, edema and leukocyte influx elicited by zymosan, fMLP or by the supernatant of zymosan activated macrophages, as well as the zymosan-induced rolling and adhesion, and gene expression of iNOS and IL-1. HCA attenuated edema and leukocyte influx in the periarticular tissue, revealing preserved chondrocytes in the cartilage. In conclusion, HCA exerts anti-inflammatory effect in the arthritis induced by zymosan in rat tibio-tarsal joints, involving NO and IL-1 released by resident macrophages.

Oxygen-ozone autohaemotherapy (O2-O3-AHT) has gained clinical interest as an adjunctive treatment for fibromyalgia (FM) based on its anti-inflammatory and anti-oxidative properties. However, comprehensive data on safety and adverse events remain limited. This scoping review aimed to systematically evaluate documented adverse events associated with O2-O3-AHT and assess risk stratification. Following PRISMA-ScR guidelines, we searched Medline, EMBASE, AMED, Cochrane Library, CINAHL, Web of Science, TRIP, Clinical Evidence, and ROAD databases for relevant articles published in the last decade. Search terms included "ozone autohaemotherapy," "GAET," "autologous blood transfusion," "systemic ozone therapy," combined with "adverse effects," "side effects," "contraindications," and "iatrogenic complications." Studies involving local injections, hyperbaric oxygen therapy, veterinary applications, or non-systemic routes were excluded. The literature search identified predominantly case reports documenting rare but potentially serious adverse events. Major categories included: haemolysis and renal failure (associated with excessive ozone concentrations >60 &#x3bc;g/mL), hyperkalaemia in patients with complex comorbidities (hypertension, diabetes, chronic kidney disease), myocardial infarction and ischaemic events (attributed to vasoconstrictive and pro-thrombotic effects), cerebral gas embolism in patients with patent foramen ovale, autonomic reactions related to rapid reinfusion rates, anaphylactic reactions (linked to equipment materials), and infectious complications due to protocol breaches. The overall incidence of serious adverse events cannot be reliably quantified given the absence of prospective registries and reliable denominator data: A frequent cited historical low estimation of uncertain methodology should be interpreted with considerable caution. Most safety data were derived from mixed clinical populations and not specifically from fibromyalgia cohorts, although they are relevant for clinical decision-making in this setting. Current evidence does not identify a pattern of frequent serious unexpected harm when standardised protocol is followed. Key safety measures include mandatory glucose-6-phosphate dehydrogenase screening, adherence to recommended ozone concentrations (10-40 &#x3bc;g/mL), controlled reinfusion rates (<50 drops/minute), pre-treatment cardiovascular evaluation in selected cases, and strict aseptic technique. The estimated incidence of serious complications derived from historical global data on O2-O3 autohaemotherapy may be only inferred in a fibromyalgia population. Standardisation of treatment protocols and prospective adverse event registries are needed to further optimise safety.