Lesion Site Research Articles

Integrin‐Targeted, Activatable Nanophototherapeutics for Immune Modulation: Enhancing Photoimmunotherapy Efficacy in Prostate Cancer Through Macrophage Reprogramming

ABSTRACTProstate cancer is an epithelial malignancy with a high incidence among elderly men. Photochemistry‐based dye photodrugs (known as photosensitizers) offer a promising clinical approach for treating tumors. These agents work by inducing immunogenic cell death (ICD), which activates antitumor immune response. This approach is favored owing to its minimal invasiveness, low toxicity, and high efficiency. However, the immunosuppressive microenvironment of characteristics of “cold” tumors significantly restricts the clinical efficacy of photodrugs. Developing an advanced nanocarrier system to deliver photodrugs and immune agonists for efficient drug delivery to tumor lesion sites and to reshape the immunosuppressive microenvironment is crucial in clinical practice. Therefore, in this study, we designed an integrin‐targeted, activatable nano photodrug co‐assembly with an immune agonist (RPST@IMQ) for enhancing photoimmunotherapy in prostate cancer via the reprogramming of tumor‐associated macrophages. The active‐targeted nanosystem enhanced the dosage of photodrug at the lesion site through systemic administration. High doses of glutathione at the tumor site cleaved the disulfide bonds of RPST@IMQ, releasing the photodrug and the immune agonist imiquimod (IMQ). Under photoirradiation, the photodrug generated significant doses of singlet oxygen to eliminate tumor cells, thereby inducing ICD to activate antitumor immune responses. Simultaneously, the released IMQ reprograms immunosuppressive M2‐type tumor‐associated macrophages (TAMs) in the tumor microenvironment into M1‐type TAMs with tumor‐killing capabilities, thereby converting “cold” tumors into “hot” tumors. This conversion enhances the therapeutic efficacy against primary and distant tumors in vivo. This study offers new insights into the development of innovative, smart, activatable nano photodrugs to enhance anticancer therapeutic outcomes.

Abstract TP105: Non-invasive Brain Stimulation Alters Resting-State Brain Activity in Ischemic Stroke

Stroke is the leading cause of serious long-term disability in the United States. Stroke recovery is greatly varied since the long term effect is determined by the site and size of the initial lesion. Specifically, post stroke motor impairments occur due to damage to the corticospinal tract and maladaptive upregulation of the cortico-reticulospinal tract. Transcranial direct current stimulation (tDCS) may be an effective treatment for stroke rehabilitation. However, conventional tDCS is limited by spatial resolution to precisely target a specific brain region. To improve its spatial resolution, this study used targeted high-definition tDCS (HD-tDCS) navigated by paired-pulse transcranial magnetic stimulation. In a double-blind randomized crossover study, stroke participants (n=12) had three visits 1) anodal HD-tDCS stimulation of the arm region of the primary motor cortex (M1) to improve function of the corticospinal tract in the lesioned hemisphere, 2) cathodal stimulation of the arm region of the dorsal premotor (PM) cortex to inhibit maladaptive use of the cortico-reticulospinal tract in the contralesional hemisphere, and 3) sham. The effect was measured by quantitative electroencephalogram (qEEG) metrics delta alpha ratio (DAR) and delta theta alpha beta ratio (DTABR), calculated from a pre and post 3-minute EEG. Acute changes in brain activity of these power bands have been associated with the severity of motor impairment post stroke. The results demonstrate that anodal (p=0.026) and cathodal (p=0.0108) stimulation significantly decreased the DAR compared to the sham. The reducation of DAR value is associated with the improvement of Fugl-Meyer Upper Extremity score. However, there were no significant differences found in the DTABR. These results indicate that both anodal and cathodal HD-tDCS may improve brain function following stimulation. However, future work is required on the use of qEEG metrics and its use as a marker of stroke recovery. This work is important as qEEG could be used as a more objective method, compared to clinical assessments, to track stroke rehabilitation.

Modulation of β secretase and neuroinflammation by biomimetic nanodelivery system for Alzheimer's disease therapy.

Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. The vicious circle between amyloid-β peptide (Aβ) overgeneration and microglial dysfunction is an important pathological event that promotes AD progression. However, therapeutic strategies toward only Aβ or microglial modulation still have many problems. Herein, inspired by the Aβ transportation, an Aβ-derived peptide (CKLVFFAED) engineered biomimetic nanodelivery system (MK@PC-R NPs) is reported for realizing BBB penetration and reprogram neuron and microglia in AD lesion sites. This hollow mesoporous Prussian blue-based MK@PC-R NPs carrying curcumin and miRNA-124 can down-regulate β secretase expression, thereby inhibiting Aβ production and reducing Aβ-induced neurotoxicity. Meanwhile, MK@PC-R NPs with excellent antioxidant and anti-inflammatory properties could normalize the microglial phenotype and promote Aβ degradation, providing neuroprotection. As expected, after treatment with MK@PC-R NPs, the Aβ burdens, neuron damages, neuroinflammation, and memory deficits of transgenic AD mice (APP/PS1 mice) are significantly attenuated. Overall, this biomimetic nanodelivery system with anti-Aβ and anti-inflammatory properties provides a promising strategy for the multi-target therapy of early AD.

Effects of early supplemental parenteral nutrition on new-onset infection in adults with acute severe stroke: a single-center retrospective case–control study

BackgroundEarly adequate feeding reduces mortality in patients with acute severe stroke. Supplemental parenteral nutrition (SPN) may address enteral nutrition (EN) deficiency and mitigate the risk of nosocomial infection. The benefit of the EN plus early SPN strategy over the full EN strategy is unknown in acute severe stroke patients.MethodsWe retrospectively enrolled 20 patients with acute severe stroke in the SPN group who received EN plus early SPN (more than 50% of the energy target within 72 h after admission). Forty control patients in the EN group who received full EN were matched by age, sex and lesion site. The time to new-onset pneumonia or nosocomial infections was analyzed by Student’s t test and the Breslow generalized Wilcoxon test.ResultsThe baseline characteristics did not differ significantly between the SPN group and the EN group, except for higher serum leukocyte counts, neutrophil counts, and neutrophil-to-lymphocyte ratios in the SPN group (P < 0.05). Compared with that in the EN group, the time to new-onset pneumonia was significantly delayed in the SPN group (7.6 days vs. 5.2 days; mean difference, 2.5 days; 95% CI, 0.65 to 4.31; P = 0.009), as was the time to new-onset nosocomial infections (7.1 days vs. 4.8 days; mean difference, 2.3 days; 95% CI, 0.46 to 4.07; P = 0.015). Kaplan–Meier analysis revealed similar cumulative probabilities of new-onset pneumonia and new-onset nosocomial infections in the two groups (P > 0.05). The rates of digestive intolerance events were similar between the two groups (40% in the SPN group vs. 52.5% in the EN group, P = 0.361).ConclusionsIn patients with acute severe stroke, the application of EN plus early SPN could delay the onset of pneumonia and nosocomial infections especially in the early phase.

Monkeypox outbreak 2023 in Chengdu, China: an observational study

Monkeypox is a zoonotic viral disease caused by monkeypox virus infection and formerly this disease had been endemic mainly in Africa. Since May 2022, the disease has rapidly spread across the world and some imported case was confirmed sporadically in China. Under these circumstances, data of confirmed cases were collected consecutively in Chengdu, southwest China to investigate clinical and epidemiological characteristics. In this study, 28 male patients were confirmed to have monkeypox infection, with 26 identifying as MSM (men who have sex with men). Typical lesions included papules, pustular papules, vesicles, scabs and ulcerations. The most common sites of skin lesions were anogenital and perineal areas, three patients developed a widespread exanthem. Seven patients reported a history of sexual transmitted diseases, no one was hospitalized and there were no deaths. Three instances of secondary transmission were identified among close contacts, all of them were sexual partners of our participants. Furthermore, this observation provides insights of the public health for surveillance of this emerging disease and raises awareness among people at risk.

Cathelicidin-HG Alleviates Psoriasis by Targeting Glycoprotein VI to Inhibit Platelet-Neutrophil Complexes Formation.

Psoriasis, a chronic inflammatory skin disorder, is characterized by a complex interplay among immune cells. Although the specific mechanisms of platelet involvement in psoriasis are not fully elucidated, platelet activation is considered a major pathogenic factor. In this study, we investigated the role of Cathelicidin-HG (Cath-HG), a peptide derived from Hylarana guentheri skin that exhibits potent inhibitory activity against platelet glycoprotein VI (GPVI), in an imiquimod-induced psoriasis mouse model. Our experimental findings demonstrated that Cath-HG significantly alleviates psoriasis symptoms, reduces platelet-neutrophil complexes (PNCs) formation, and attenuates neutrophil activation at lesion sites. In vitro studies confirmed that Cath-HG inhibits collagen-induced platelet activation via GPVI, thereby disrupting PNCs formation and suppressing subsequent inflammatory responses. These findings not only establish GPVI as a key regulator of PNC-mediated inflammation in psoriasis but also identify Cath-HG as a promising therapeutic candidate. This study provides a novel mechanistic insight into platelet-neutrophil interactions in psoriasis and highlights the potential of GPVI as a therapeutic target for innovative psoriasis treatments.

216. Effectiveness of JYNNEOS Vaccination in Preventing Lesion Dissemination Among Individuals with Confirmed Mpox Infection

Abstract Background Observational studies during the global mpox clade IIb outbreak associated with male-to-male sexual contact have demonstrated the JYNNEOS vaccine prevents diagnosed mpox disease. However, effects of vaccination on mpox clinical presentations remain uncertain. Data Flow Chart Flow chart characterizing the mpox cases in California’s eligibility for inclusion in the present analysis in relation to their genders, clinical presentations, and vaccination statuses. Methods Male cases with confirmed mpox infection reported to the California Department of Public Health between May 12, 2022 and December 31, 2023 were interviewed about anatomical lesion sites. We ascertained cases’ vaccination statuses via linkage to the California Immunization Registry. We estimated JYNNEOS vaccine effectiveness (VE) against progression to disseminated disease via the adjusted odds ratio of vaccination among cases with lesions across multiple anatomical regions versus cases with lesions contained to a single anatomical region. Body Regions Anatomical regions of the body used to characterize lesion spread. Spread was defined&amp;gt;1 groups with lesions. Results Analyses included 4,613 mpox cases; 3,045 (66.0%) reported lesions disseminated across multiple anatomical regions and 1,956 (42.4%) were living with HIV infection. Among cases with disseminated lesions, 114 (3.7%) had received any pre-exposure vaccination and 43 (1.4%) received post-exposure vaccination, compared with 286 (18.2%) and 146 (9.3%), respectively, of 1,568 cases with lesions contained to a single region. VE against progression to disseminated disease was 58.9% (95% confidence interval: 50.4-65.9%) for any pre-exposure immunization with JYNNEOS, and 57.6% (46.3-66.5%) and 61.0% (47.3-71.1%), respectively, for 1 and 2 dose JYNNEOS series. VE against progression to disseminated disease was 15.9% (3.3-26.8%) for cases who received JYNNEOS only as post-exposure prophylaxis. Pre-exposure VE against progression to disseminated disease was 66.4% (56.6-74.0%) for HIV-negative cases and 45.3% (28.0-58.5%) for cases living with HIV. Proportion of Individuals with Regions Affected by Lesions The proportion of mpox cases in California in each subpopulation who reported anywhere from 1-6 body site groups, as defined in figure 2, affected with lesions. A-D represent the unvaccinated population of mpox cases, E-H is the population given PEP, and I-L the vaccinated population (either single or double vaccinated). The first column A, E and I show the HIV- negative population, B, F, and J are persons with HIV (PWH), C, G, and K are PWH with CD4 &amp;lt;500, and D, H, and L are PWH with CD4 ≥ 500. Conclusion All persons at risk for mpox should receive JYNNEOS vaccine series to reduce the odds of disseminated disease. Among persons infected with mpox, including those living with HIV, vaccination with JYNNEOS is associated with less severe clinical presentation. Protection was greatest when the vaccine was administered prior to exposure. Strategies are needed to ensure continuous access to JYNNEOS vaccination among all at-risk persons. VE of JYNNEOS in Preventing Lesion Spread VE of JYNNEOS for PEP, single, double, and any pre-exposure vaccination in reference to a nonvaccinated counterpart. Conditional logistic regression models matching individuals in the “all cases” category on HIV status to estimate VE given number and timing of doses received. Additionally, individuals were stratified by HIV status. All vaccinated groups were calculated in reference to an unvaccinated population. Disclosures All Authors: No reported disclosures

An examination of noun and verb naming differences in aphasia: effects of lesion site, aphasia type and the use of static or dynamic stimuli

ABSTRACT Background Anomia has been extensively researched within the aphasia literature and a dissociation in naming nouns and verbs has been used in diagnostic classifications and related to lesion location. However, there is evidence that action naming is more difficult for many clinical populations as well as for healthy speakers. Confrontation naming tests have often been used to evaluate anomia, but static depiction has been considered a potential source of error in evaluations of verb naming, since actions are dynamic. Aims The first aim of this study was to examine the ability to name objects and actions in a stroke population and non-brain damaged controls and to explore naming ability in relation to lesion location and aphasia type (fluent or non-fluent). A second aim was to determine if action naming is facilitated by using dynamic rather than static stimuli. Methods & Procedures A cross-sectional study was carried out, where 19 participants with aphasia after stroke and 19 matched controls were included. Type of aphasia was based on connected speech samples. Naming performance was compared on two Swedish naming tests consisting of line drawings of high frequency nouns and verbs respectively, and a subset of action pictures was compared to a test using video depictions of actions as verb stimuli. Outcomes & Results There was a significant difference between nouns and verbs in 11 of 19 participants with aphasia. Only one participant, with a temporo-occipital lesion, had a substantial noun-verb difference (≥30%). Individual results showed some agreement with the fluent-nonfluent classification. However, at group level, there was no significant difference between scores on action and object naming for participants with aphasia. While only the control group achieved significantly higher scores on object than action naming, response latencies were longer for action than object naming for both groups. There was no difference in action naming performance that could be related to the use of dynamic or static stimuli. Conclusions The results suggest that a dissociation in naming nouns and verbs is common in aphasia. This finding underscores the importance of testing action as well as object naming. Even though there was some agreement with aphasia type, the relationship between noun-verb dissociation, lesion location and aphasia type is not straight forward. The study adds to previous findings suggesting that action naming is more difficult than object naming. The question whether action naming is facilitated by using dynamic stimuli needs to be further investigated.

Remote neurodegeneration in the lumbosacral cord one month after spinal cord injury: a cross-sectional MRI study.

To characterize structural integrity of the lumbosacral enlargement and conus medullaris within one month after spinal cord injury (SCI). Lumbosacral cord MRI data were acquired in patients with sudden onset (<7 days) SCI at the cervical or thoracic level approximately one month after injury and in healthy controls. Tissue integrity and loss were evaluated through diffusion tensor (DTI) and T2*-weighted imaging (cross-sectional area [CSA] measurements). Associations with the degree of neurological impairment were assessed using linear mixed-effects models. Twenty-one patients with SCI showed lower white matter (WM) fractional anisotropy (FA) (≤-13.3%) and higher WM radial diffusivity (≤14.6%) compared to 27 healthy controls. Differences were most pronounced in the lateral columns of WM. CSA measurements revealed no group differences. For the lateral columns, lower FA values were associated with lower motor scores and lower amplitudes of motor evoked potentials. For the dorsal columns, lower FA values were associated with lower amplitudes of somatosensory evoked potentials from the lower extremities. One month after SCI, first signs of WM degeneration were apparent, without indication of tissue loss. The more pronounced differences observed in the lateral column could be attributed to anterograde degeneration of the motor tracts. The variability among DTI measurements remote from the lesion site can be partially explained by the degree of the SCI-induced neurological impairment. Together with previous studies, our findings indicate that impaired tissue integrity precedes tissue loss. The presented techniques have potential applications in monitoring the progression of various neurological diseases.

Epilepsy Stands Nearby: A Pilot CT Perfusion Study on Post-Stroke Non-Convulsive Status Epilepticus.

To investigate the relevance of hyperperfusion on computerised perfusion imaging (CTP) in the emergency setting in people with non-convulsive status epilepticus (NCSE) and previous stroke, to derive relevant aspects on the epileptogenic focus and the network recruited for NCSE propagation. We enrolled consecutive adult patients with acute-onset NCSE and a previous stroke at a single institution undergoing CTP and EEG during symptoms. All patients underwent standard imaging including CT, CTP, CT angiograms and standard EEG within 30 min from hospital arrival. Age-/sex-matched NCSE without previous stroke cases and recurrent ischaemic stroke cases were included to test for accuracy of hyperperfusion rates. Overall, 15 patients had a previous stroke and developed NCSE (mean age 78 years, 46.7% female). All patients had hyperperfusion on CTP imaging (mean onset-to-CTP 184 min). Only one case showed hyperperfusion limited to the previous stroke lesion, and one had a combination of lesional and peri-lesional hyperperfusion. All remaining cases (n = 13) had exclusive extra-lesional involvement. Five cases had multiple separated hyperperfused areas, and five had ipsilateral intra-thalamic hyperperfusion. No correlation emerged between onset-to-CTP timing and hyperperfusion (p value for CTP = 0.66, CBV = 0.28, MTT = 0.28, reverse Tmax = 0.66). Hyperperfusion was present in NCSE cases only and in none of age-/sex-matched ischaemic stroke cases (n = 18). Hyperperfusion involves cortical areas external to the previous lesion site during NCSE, supporting the relevance of networks for the spatial evolution of epileptic activity and limited relevance of the lesion site for the propagation of the epileptiform activity.

Neutrophil-macrophage hybrid membrane-coated prussian blue nanozyme for ulcerative colitis treatment and mechanistic insights

BackgroundUlcerative colitis (UC) is a chronic and recurrent digestive tract disease that can lead to significant morbidity and mortality. The pathogenesis of UC is intricately associated with the presence of reactive oxygen species (ROS). Prussian blue (PB), an inorganic nanozyme with potent antioxidant properties, has been extensively applied in the treatment of various inflammatory conditions and tumors. However, despite the explicit antioxidant properties, the underlying molecular mechanism of PB nanozyme in the treatment of UC remains poorly understood. Furthermore, there is a deficiency in antioxidants that possess specific targeting capabilities towards UC lesions. The present study pioneered the fabrication of neutrophil (N)-macrophage (M) hybrid membrane-coated PB (NM-PB) nanozyme for the treatment of UC and investigated its underlying molecular mechanism.ResultsWe have successfully constructed PB, N-PB, M-PB, and NM-PB nanozymes. In both the colitis cell model and UC mouse model, compared with PB, N-PB, and M-PB nanozymes, NM-PB nanozymes exhibited remarkable targeting capabilities, significantly enhancing the localization and uptake of PB nanozymes at the lesion site. NM-PB nanozymes significantly reduced levels of ROS (•OH, •OOH, and H2O2) and decreased the production of proinflammatory cytokines (TNF-α, IL-6, IL-1β). Meanwhile, these nanozymes regulated the expression of intestinal mucosal barrier-related proteins (ZO-1, E-cadherin, and Occludin) and apoptosis-related proteins (Bcl2, Bax). Furthermore, NM-PB nanozymes facilitated the polarization of proinflammatory M1-phenotype macrophage towards an anti-inflammatory M2-phenotype. The mechanistic studies demonstrated that NM-PB nanozymes mitigated the progression of UC by inhibiting the pathway of cytokine-cytokine receptor interaction.ConclusionThe NM-PB nanozymes provide a promising and innovative alternative for the treatment of UC, offering enhanced targeting and efficacy through their unique design and mechanism of action.Graphical

Clinical characteristics and outcomes of patients with chondroblastoma undergoing surgery with various adjuvant procedures: a retrospective study of 59 cases

BackgroundChondroblastoma is classified as a benign bone tumor. However, postoperative local recurrence remains a concern. We analyzed the factors contributing to chondroblastoma local recurrence and the clinical challenges associated with treating these patients.MethodsThis retrospective study examined 59 patients followed up at our hospitals for ≥ 1 year after surgery during 1990–2020. The most common lesion site was the epiphyses of long bones (42 cases, 71%), including the femur, tibia, and humerus. Curettage was performed in 57 cases; 2 cases with an iliac lesion underwent resection. The median postoperative follow-up period was 47 months. Clinical features of chondroblastoma were retrospectively investigated, and local recurrence and postoperative functional outcomes were assessed.ResultsLocal recurrence occurred in 9% (5/57) of patients after curettage but not in the resected cases. The median time to local recurrence was 14 months. The local recurrence-free survival (LRFS) rate for all patients was 92.7% at 2 years and 88.3% at 5 years. All patients with local recurrence were aged < 17 years at the time of surgery. Local recurrence was observed in the proximal humerus in two cases and the calcaneus, acetabulum, and distal femur in one case each. None of the adjuvant procedures (high-speed burr, ablation, bone replacement materials, and preoperative denosumab) helped reduce local recurrence risk (P > 0.05). Trends toward fewer local recurrences were observed in the group treated using the high-speed burr and in the group not treated using bone replacement materials. Among the groups treated with bone replacement materials, artificial bone achieved the best LRFS rate, followed by allograft and autograft. At the final follow-up, the mean Musculoskeletal Tumor Society score was 29.8 (range: 25–30), indicating excellent postoperative functional outcomes. Joint degeneration was observed in five patients. Patients with local recurrence had a high degree of disability and joint deformity (P < 0.05). Two patients received preoperative denosumab and neither experienced local recurrence nor functional impairments.ConclusionsGood oncological and functional outcomes were achieved. Age < 17 years was associated with a high risk of local recurrence after curettage (P = 0.0198). Patients with local recurrence exhibited poorer functional outcomes. High-speed burr may help reduce the recurrence risk. If bone grafts are necessary, materials with low biocompatibility, including artificial bone, may be optimal. Managing patients with chondroblastoma should encompass curative and functional aspects.

Accessory uterine cavities: a review of cases and an appeal for standard terminology.

To study and address the diagnostic, management, and classification challenges of unilocular myometrial cystic lesions adjacent to a normal uterine cavity. Describe 23 further cases, and undertake a systematic review using Medline, PubMed and Ovid for similar lesions. 23 cases of accessory uterine cavities presenting to pediatric and adolescent gynecologists in Australia and New Zealand. 92 similar cases of cavitated myometrial masses were identified in the literature. The cases in our series and in the literature were examined for age at presentation, site of lesion, pathology, and presence of other anomalies. All patients in our series were aged ≤ 32 years. All presented with unilocular blood-filled myometrial lesions that did not communicate with the uterine cavity. All were located on the lateral aspect of the uterus in proximity to the round ligament. Of the 22 that have been resected, all were lined by endometrium and smooth muscle. These characteristics are mirrored in the previously described cases in the literature. The frequency of these myometrial cystic masses is such that they can no longer be considered rare. Nevertheless, their etiology remains unclear. These lesions have often been given names suggesting that they are an early representation of adenomyosis. The alternative possibility of a Müllerian anomaly is supported by consistent anatomical location and young age of presentation in most reported cases. Yet the absence of documented associated anomalies raises concerns about this theory. To progress understanding of these lesions, consistent reporting of features including location and the presence or absence of other anomalies is required. In view of this ongoing uncertainty, we recommend the use of the term "accessory uterine cavity (AUC)." This terminology avoids the implication of either a pathological process or a congenital anomaly.

Immunoglobulin E, the potential accelerator of comorbid psoriasis and atherosclerosis.

Immunoglobulin (Ig) E is a key mediator in the induction and maintenance of allergic inflammation, characterized by a Th2-dominated immune response. Recently epidemiological studies have showed that elevated serum total IgE levels or an increased abundance of mast cells (MCs) at the lesion site are observed in psoriatic patients with cardiovascular diseases (CVD), such as atherosclerosis. Although the underlying mechanisms by which IgE synergizing with MCs in promoting these chronic immune-inflammatory diseases remain unclear, the interleukin (IL)-23/IL-17 axis appears to play a crucial role in comorbidity of psoriasis and atherosclerosis. High IgE production may result from IL-17A response, further exacerbating inflammatory pathways involved in both psoriasis and atherosclerosis. This review explores the possible mechanisms of IgE in these comorbid conditions, reinforcing the rationale for IL-17A targeted biologics in the treatment of psoriasis andatherosclerosis comorbidity. Additionally, IgE is proposed as a potential therapeutic target for alleviating patients suffering from these comorbidity conditions.

Smart core-shell microneedles for psoriasis therapy: In situ self-assembly of calcium ion-coordinated dexamethasone hydrogel.

Psoriasis is a prevalent relapsing dermatological condition that often necessitates lifelong treatment. The distinctive thickening of the stratum corneum presents a challenge to drug penetration. The employment of microneedles has been demonstrated to enhance the transdermal drug delivery efficacy by creating multiple microchannels in the skin. Nevertheless, polymeric microneedles often encounter difficulties in meeting the requirements for sustained drug release. It is imperative to acknowledge that sustained-release hydrogel microneedles are invariably fabricated under harsh crosslinking conditions. In addressing these challenges, a core-shell microneedles (CSMNs) system was customized at a facile, accessible process, enabling the in situ formation of supramolecular microhydrogels within the skin. This concept was realized by leveraging the interaction between the therapeutic drug dexamethasone sodium phosphate (DexP) and calcium chloride (CaCl2), combined with the differential biphasic release technology (DexP HMNs). Upon insertion into the skin, the core of the microneedles rapidly released CaCl2, which diffused to the shell and formed a hydrogel with DexP, creating multiple reservoirs for the sustained release of DexP. In vitro transdermal permeation experiments demonstrated that DexP HMNs greatly prolonged the skin retention time of DexP. In the context of psoriasis treatment, DexP HMNs were demonstrated to be more effective than DexP CSMNs in inhibiting keratinocyte proliferation and significantly reducing the levels of inflammatory factors and immune cell infiltration at the lesion site. This study provides a new direction for the development of intelligent microneedle drug delivery systems for sustained drug release and enhanced management of chronic skin diseases.

Repetitive Mild but Not Single Moderate Brain Trauma Is Associated with TAR DNA-Binding Protein 43 Mislocalization and Glial Activation in the Mouse Spinal Cord.

Background/Objectives: Traumatic brain injury (TBI) occurs after a sudden mechanical force to the skull and represents a significant public health problem. Initial brain trauma triggers secondary pathophysiological processes that induce structural and functional impairment of the central nervous system, even in the regions distant to the lesion site. Later in life, these changes can be manifested as neurodegenerative sequalae that commonly involve proteinopathies, such as transactive DNA-binding protein 43 (TDP-43). The progression of pathophysiological changes to the spinal cord motor neurons has been detected after repetitive TBI, while such changes have been less investigated after single TBI. Methods: Single TBI was applied over the left parietal cortex of mice by using the lateral fluid percussion injury apparatus and a separate cohort of animals received repetitive mild TBI by weight drop apparatus, with two mild injuries daily, for five days in a row. Mice were sacrificed after single moderate or last mild TBI and their spinal cords were prepared for the analyses. For both types of injury, sham-injured mice were used as a control group. Results: Here, we found an early formation of toxic phosphorylated TDP-43 species on the 3rdday post-injury which, together with TDP-43 cytoplasmic translocation, remained present in the subacute period of 14 days after repetitive mild but not single moderate TBI. During the subacute period following a repetitive brain trauma, we found an increased choline acetyltransferase protein expression and significant microgliosis in the cervical part of the spinal cord, which was not detected after single TBI. Astrogliosis presented similarly after both experimental procedures. Conclusions: This study demonstrates the differences in the spinal cord TDP-43 pathology and inflammation, depending on the brain trauma type, and may contribute to the development of targeted therapeutic strategies.

Cerebellar Volume Measures Differentiate Multiple Sclerosis Fallers from Non-Fallers.

The cerebellum is a common lesion site in persons with multiple sclerosis (PwMS). Physiologic and anatomic studies have identified a topographic organization of the cerebellum including functionally distinct motor and cognitive areas. In this study, a recent parcellation algorithm was applied to a sample of PwMS and healthy controls to examine the relationships among specific cerebellar regions, fall status, and common clinical measures of motor and cognitive functions. Thirty-one PwMS and twenty-nine age- and sex-matched controls underwent an MRI scan and motor and cognitive testing. The parcellation algorithm was applied to all images and divided the cerebellum into 28 regions. Mann-Whitney U tests were used to compare cerebellar volumes among PwMS and controls, and MS fallers and MS non-fallers. Relationships between cerebellar volumes and motor and cognitive function were evaluated using Spearman correlations. PwMS performed significantly worse on functional measures compared to controls. We found significant differences in volumetric measures between PwMS and controls in the corpus medullare, lobules I-III, and lobule V. Volumetric differences seen between the PwMS and controls were primarily driven by the MS fallers. Finally, functional performance on motor and cognitive tasks was associated with cerebellar volumes. Using the parcellation tool, our results showed that the volumes of motor and cognitive lobules impact both motor and cognitive performance, and that functional performance and cerebellar volumes distinguishes the MS fallers from non-fallers. Future studies should explore the potential of cerebellar imaging to predict falls in PwMS.

A quantitative polymerase chain reaction (qPCR) protocol predictive of treatment outcome in cutaneous leishmaniasis caused by Leishmania braziliensis

Abstract Leishmania braziliensis is the most prevalent agent causing cutaneous leishmaniasis (CL) in Brazil. While inflammation is a hallmark of CL, few parasites are found at the lesion site, leading to challenges regarding diagnosis. Using L. braziliensis kDNA and human 18S rRNA as targets, the present study developed a qPCR assay to determine parasite load in biopsies from CL patients residing in an endemic area in northeastern Brazil. In addition, we investigated whether parasite load correlated with clinical outcome and observed that patients with higher parasite load were more likely to fail therapy. Moreover, CL patients in the early phase of infection presented higher levels of parasite transcripts than individuals in later phases. Thus, our results suggest that parasite load as determined by qPCR may constitute a valuable prognostic tool to aid in both the determination of disease severity and treatment outcome.

Clopidogrel combined with rivaroxaban in peripheral artery disease after revascularization.

To evaluate the efficacy and safety of clopidogrel-rivaroxaban combination compared to aspirin-rivaroxaban combination in patients with symptomatic peripheral artery disease (PAD). Consecutive patients with symptomatic PAD patients were analyzed from January, 2018 to June, 2022at Nanjing Drum Tower Hospital. Patients were divided into two groups based on the antithrombotic therapy. The primary efficacy outcome was a composite of major adverse cardiovascular events (MACE) and major adverse limb events (MALE), and the primary safety outcome was major bleeding. Patients were followed until the first occurrence of any outcomes or the study end date (30 June 2024). A total of 695 patients were enrolled into this study. The clopidogrel-rivaroxaban combination significantly reduced the risk of composite outcome (HR: 0.59, 95%CI: 0.41-0.83) without increasing the risk of major bleeding (HR: 0.68, 95%CI: 0.27-1.69). When analyzed separately, clopidogrel-rivaroxaban combination was associated with a reduced risk of MALE (HR: 0.61, 95%CI: 0.41-0.91), although no significant differences were observed in terms of MACE (HR: 0.64, 95%CI: 0.34-1.20) or all bleeding events (HR: 1.00, 95%CI: 0.52-1.93). In the subgroup analysis, there were no significant interactions between the treatment groups and the subgroups of age, diabetes, lesion sites, Rutherford classifications and renal function for composite outcome, MACE and MALE. The clopidogrel-rivaroxaban combination in PAD patients may offer enhanced cardiovascular protection without increasing the risk of bleeding complications. These findings suggested that clopidogrel could be a superior alternative to aspirin in dual antithrombotic therapy for PAD management.

Therapeutic Effect of a Near‐Infrared Responsive MTX‐Mn3O4@PDA Nano‐Delivery System on Rheumatoid Arthritis

AbstractRheumatoid arthritis (RA) is an autoimmune disease associated with chronic inflammatory processes. RA, which is typically associated with the accumulation of hyperactive immune cells (HICs), particularly M1 proinflammatory macrophages, is accompanied by elevated levels of reactive oxygen species (ROS) and decreased pH in the synovial membranes of the joints. In this work, a nano‐delivery system (MTX‐Mn3O4@PDA) is designed that can deliver photothermal materials, ROS scavengers, and synovial fibroblast inhibitors at the joint site for the treatment of RA. After injecting MTX‐Mn3O4@PDA into the inflamed site of RA, photothermal therapy is initiated by near‐infrared (NIR) laser irradiation, which resulted in the death of activated inflammatory cells at the lesion site. While polydopamine (PDA) slowly dissociates under stimulation by a low pH microenvironment. Subsequently, excess ROS interacts with the Mn3O4 nanozyme and the undissociated PDA nanozyme, promoting ROS clearance, while Methotrexate (MTX) inhibits the proliferation of synovial fibroblasts. Intra‐articular injection of MTX‐Mn3O4@PDA (7 mg kg−1) into collagen‐induced arthritis mice demonstrated efficacy in reducing toe swelling and significantly alleviating synovial inflammation, bone erosion, and cartilage degeneration. This nano‐delivery system has potential clinical applications for treating RA.