Post hoc analysis of the PULSAR Phase 3 trial (NCT04423718) to describe whether dosing interval outcomes were associated with key baseline disease characteristics. Exploratory post hoc analysis of PULSAR, a 96-week, double-masked, active-controlled, randomized clinical trial in patients with treatment-naïve neovascular age-related macular degeneration (nAMD) treated with aflibercept 8 mg or aflibercept 2 mg. For the main analysis, patients receiving aflibercept 8 mg were grouped according to their last assigned dosing interval at Weeks 48 and 96. Patients with treatment-naïve nAMD who were randomly assigned to receive aflibercept 8 mg in PULSAR. Aflibercept 8 mg was administered every 12 weeks (8q12) or 16 weeks (8q16) following 3 initial monthly injections. Dosing intervals could be shortened in Year 1 based on prespecified disease activity criteria, whereas in Year 2, both interval shortening and extension were allowed. Patients were monitored every 4 weeks but assessed for interval modification at dosing visits only. Baseline best-corrected visual acuity (BCVA), central retinal thickness (CRT), and macular neovascularization (MNV) area were assessed in patients grouped by their last assigned dosing interval (Q8, Q12, Q16, Q20, or Q24) at Weeks 48 and 96. In 86.6% and 78.4% of patients assigned to the 8q12 and 8q16 arms in PULSAR, respectively, randomized dosing intervals were maintained or extended through Week 96. In the 8q12 arm, no trends were observed in baseline BCVA, CRT, and MNV area across groups based on patients' last assigned dosing intervals. In the 8q16 arm, no trends were observed in baseline BCVA across treatment arms; however, patients with shorter last assigned dosing intervals (Q8 and Q12) at Weeks 48 and 96 tended to have a greater baseline CRT or MNV area compared with patients with longer dosing intervals (Q16 to Q24). Overall, findings from this PULSAR post hoc analysis of key baseline characteristics in patients grouped by dosing interval suggest that the aflibercept 8q12 and 8q16 regimens were suitable for most patients across a broad range of baseline BCVA, CRT, and MNV area values, with a large proportion of patients able to achieve and maintain extended dosing intervals through Week 96.
Local Anesthetic Systemic Toxicity (LAST) is a rare but potentially fatal complication of regional anesthesia and local anesthetic infiltration. Despite established treatment protocols, the extent of clinician awareness and institutional preparedness across surgical specialties remains poorly characterized. This descriptive cross-sectional study enrolled 192 physicians from eight surgical specialties across five tertiary-level training and research hospitals in Türkiye (April-May 2025). A validated, structured questionnaire assessed LAST knowledge, clinical practices, and institutional readiness. Multivariable logistic regression identified independent predictors of correct lipid emulsion dosing knowledge, adjusting for specialty, seniority, and training status. Only 41.1% of participants had received formal LAST training. Correct identification of the recommended lipid emulsion bolus dose (1.5 mL/kg) was reported by 34.4% overall, rising to 58.2% among trained participants versus 18.1% among untrained participants (p < 0.001). On multivariable analysis, formal training (OR 6.38; 95% CI 3.21-12.68), anesthesiology specialty (OR 3.14; 95% CI 1.67-5.91), and senior academic title (OR 2.07; 95% CI 1.08-3.96) were independent predictors of correct dose knowledge. Early symptom recognition was reported by 49.5%. Aspiration before injection was performed consistently by 53.1%, and ultrasound guidance by 38.5%. Lipid emulsion was readily available in only 29.2% of departments. Significant gaps exist in LAST knowledge, preventive practices, and institutional preparedness across surgical specialties. Targeted simulation-based education, mandatory availability of lipid emulsion, and standardized institutional protocols are warranted to improve patient safety.
Most patients with brain arteriovenous malformations (bAVMs) present with or eventually develop symptoms, while facing a persistent risk of rupture. Management remains challenging, and treatment practices continue to evolve. In this study, the safety and efficacy of embolization with the SQUID (BALT Group, Gland,Switzerland) embolic agent, used either as a standalone therapy or in combination with other modalities, were assessed. CHOICE is a prospective, observational, multicenter study conducted at 21 mainly European centers. Adults with previously untreated bAVMs were treated with SQUID, either as embolization alone or before neurosurgery or radiosurgery. The primary endpoint was SQUID- or procedure-related morbidity-mortality, at 3-6 months after last embolization or before further therapy. Secondary endpoints included bAVM occlusion at 3-6 months post-last embolization and safety at 12 months. Among the 109 patients included (46.3±15 years, 50.5% male), 80.7% underwent embolization alone and 19.3% had further therapy. Most bAVMs were Spetzler-Martin grade I-II (67%) and <3 cm in diameter (78.9%). Morbidity-mortality related to SQUID and/or procedure at 3-6 months were 11% and 0% respectively, including 6.4% SQUID-related morbidity. At 12 months, these rates were 7.8% and 0% respectively, including 4.9% of SQUID-related morbidity. Complete bAVM occlusion at 3-6 months post-last embolization was achieved in 63.2% in embolization alone patients and 19.0% in patients with embolization before further therapy. The overall complete occlusion rate was 53.6%. CHOICE study results suggest good safety and efficacy of SQUID as a standalone treatment or in association with surgical treatment. NCT03413852.
High-quality cardiopulmonary resuscitation (CPR) is essential for improving outcomes in emergency patients treated in medical practices. Although regular emergency training is recommended, its measurable impact on resuscitation quality parameters in this setting has not been sufficiently investigated. The aim of this study was to examine the effects of emergency training on the quality of resuscitation measures in medical practices. Specifically, it sought to determine which resuscitation parameters could be influenced by the intervention and whether the quality of care was associated with emergency patient management. Seventeen medical practices participated. Each completed a 5-minute resuscitation simulation before (T1) and after (T2) emergency training. Quantitative data were collected on compression rate, compression depth, ventilation frequency, ventilation volume, no-flow time, incorrect hand position and missing defibrillation discharges. Due to small sample size and non-normal distribution, Wilcoxon signed-rank tests were applied. Spearman correlation analysis assessed the association between baseline performance and time since last emergency training. Significant improvements were observed in ventilation frequency (p = 0.007), ventilation volume (p < 0.001), ventilation volume per minute (p = 0.003), compression depth (p < 0.001), and incorrect hand position (p = 0.001). Compression rate, no-flow time, and missing discharges did not change significantly. Compression depth increased from 31 [27.5-36.5] mm to 48 [45-56] mm, while ventilation frequency increased from 1.00 [0.00-3.50] to 3.00 [3.00-4.00]. Compression rate remained unchanged (p = 0.570). Time since last emergency training correlated with baseline performance (rs = -0.516, p = 0.034). Emergency training significantly improves key resuscitation quality parameters in medical practices. Performance declines with increasing time since last training, underscoring the need for regular repetition. Structured, hands-on emergency training appears essential to maintain high-quality CPR performance. Not applicable.
Objective: To investigate the clinical efficacy of intraoral approach combined with submandibular minor-incision for simultaneous mandibular resection and precise reconstruction using vascularized iliac bone-muscle flap in patients with benign mandibular lesions. Methods: From January 2023 to January 2026, 19 patients with benign mandibular lesions were enrolled. The cohort comprised 8 males and 11 females, aged 15 to 75 years (mean 46.5 years). Pathological diagnoses included ameloblastoma (n=13), recurrent odontogenic keratocyst (n=2), sclerosing osteomyelitis of the jaw (n=2), giant cell lesion (n=1), and recurrent ossifying fibroma (n=1). All procedures employed an intraoral approach combined with a submandibular minor-incision. Preoperatively, spiral CT scans of the mandible and iliac bone were utilized to construct a mandibular model, and a reconstruction titanium plate was pre-bent using computer-aided design/computer-aided manufacturing (CAD/CAM) technology. All 19 patients underwent unilateral segmental mandibulectomy with in-situ fixation of the pre-bent reconstruction plate, followed by mandibular defect reconstruction using a vascularized iliac bone-muscle flap. Immediate implant placement was performed in 12 cases. Results: Vascularized iliac bone-muscle flaps survived in 18 patients (success rate 95%), while 1 flap failed due to necrosis. All incisions healed primarily. Twelve patients underwent simultaneous implant placement. During the 1-year follow-up, all patients demonstrated satisfactory functional recovery without facial nerve injury. The occlusal relationship of the remaining dentition was basically maintained at the preoperative level. Masticatory function was satisfactory. Mouth opening ranged from 31 to 36 mm. Swallowing and speech functions were normal. Only minor scars (mean length 1.5 cm) were observed extraorally, and patients were satisfied with their facial appearance. The mean initial implant stability quotient value in the 12 implanted patients was (72.5±6.3). CBCT evaluation at 6 months postoperatively revealed an osseointegration rate of 100%. No recurrence was observed up to the last follow-up. Conclusions: Intraoral approach combined with submandibular minor-incision for simultaneous mandibular resection and vascularized iliac bone-muscle flap reconstruction, as preliminarily demonstrated in this small-sample cohort, can shorten operative time, enhance reconstructive precision, reduce maxillofacial scarring, and significantly improve patient satisfaction. It represents a reliable surgical strategy for precise simultaneous mandibular resection and reconstruction. 目的： 探讨采用口内入路联合颌下小切口进行下颌骨切除同期血管化髂骨肌皮瓣精准修复重建的临床效果。 方法： 纳入2023年1月至2026年1月南京大学医学院附属口腔医院口腔颌面头颈外科收治19例下颌骨良性病变患者。其中男性8例，女性11例；年龄15~75岁，平均46.5岁。病理诊断为成釉细胞瘤13例，复发性牙源性角化囊肿2例，颌骨硬化性骨髓炎2例，巨细胞性病变1例，复发性骨化纤维瘤1例。手术均采用口内入路联合颌下小切口。术前利用螺旋CT扫描获取的下颌骨及髂骨数据，通过计算机辅助设计及制作技术制作下颌骨模型，并在该模型上对重建钛板进行预弯塑形。19例患者均行单侧下颌骨节段性切除，同时将弯制重建钛板原位固定，下颌骨缺损区采用血管化髂骨肌瓣修复重建，其中12例行同期即刻种植体植入。 结果： 18例血管化髂骨肌瓣成活（成功率95%），1例髂骨肌瓣坏死，切口均一期愈合；12例行同期种植体植入；随访时间1年，患者功能均恢复良好，无面神经损伤表现，余留牙列咬合关系基本维持术前状态；咀嚼功能满意；开口度31~36 mm；吞咽及语言功能正常。口外仅有轻微瘢痕，长度1.5 cm，患者对面部外形满意。12例同期种植患者种植体的初始稳定性值（72.5±6.3）；术后6个月锥形束CT评估骨结合率100%。截至末次随访均无复发。 结论： 口内入路联合颌下小切口进行下颌骨切除同期血管化髂骨肌瓣修复重建在本小样本队列中初步显示可以缩短手术时间，增加重建精确性，减小颌面部瘢痕，明显提高患者满意度，是下颌骨切除同期精准修复重建的可靠手术方案。.
Migraine is common in people with multiple sclerosis (PwMS) and substantially contributes to disability and impaired quality of life. Although (CGRP)-targeting therapies have reshaped migraine prevention, evidence on their use in PwMS remains scarce, particularly in people receiving concomitant disease-modifying therapies (DMTs). We retrospectively collected data from 17 Italian multiple sclerosis (MS) centers on adult PwMS with comorbid migraine treated with anti-CGRP monoclonal antibodies or gepants in addition to stable DMTs. Monthly headache days (MHDs) and total number of analgesics per month were compared between treatment initiation and last follow-up. MS activity was assessed through clinical relapses, Expanded Disability Status Scale (EDSS), and MRI findings. A ≥ 50% reduction in MHDs defined treatment response. Multivariate regression models were used to explore predictors of response to anti-CGRP therapies. Fifty-four patients were included (46 women; mean age 42.3 years; 85% relapsing MS). Baseline MHDs averaged 19.87 ± 6.97 and declined to 11.40 ± 9.35 at follow-up (p < 0.001), with a parallel decrease in analgesic use (p < 0.001). Responder rate at the last follow-up was 53.7%. MS disease activity remained stable, with no significant changes in relapse rate, EDSS score, or MRI activity. Higher baseline headache burden was associated with greater reduction in MHDs (β=+0.685, p < 0.001), whereas longer MS duration predicted poorer response (OR1.43, 95%CI 1.06-1.92, p = 0.016). Mild adverse events occurred in four patients (7%), without treatment discontinuation. Anti-CGRP pathway therapies provided meaningful migraine improvement in PwMS while maintaining MS stability. MS disease duration and baseline headache frequency may influence therapeutic response to anti-CGRP drugs in PwMS. Not applicable.
Genitourinary syndrome of menopause (GSM) affects a significant proportion of postmenopausal women, leading to symptoms such as vaginal dryness, irritation, dyspareunia, and urinary symptoms. Hormonal therapies are not suitable for all patients, particularly those with contraindications to hormone use. This study aims to compare the efficacy and safety of two non-hormonal therapies-fractional CO₂ laser (CO₂ laser) and fractional microablative radiofrequency (MAFRF)-for the treatment of GSM. This protocol describes a randomised, double-blind, non-inferiority clinical trial that will enrol 40 postmenopausal women diagnosed with GSM. Participants will be randomised to receive either fractional CO₂ laser or fractional microablative radiofrequency in three monthly sessions. The primary outcome will be the Vaginal Health Index Score (VHIS), assessed 30 days after the last treatment session (day 90). Secondary outcomes include sexual function, GSM symptom severity, and urinary symptoms. Follow-up assessments will be conducted at 120 and 300 days after the last session (days 180 and 365, respectively). Histological analysis of vaginal biopsies will be performed in a predefined subsample of participants as an exploratory analysis. This study is expected to contribute to the comparative understanding of the efficacy and safety of CO₂ laser and MAFRF as non-hormonal therapeutic options for the treatment of GSM, potentially supporting clinical decision-making for women who are not candidates for hormonal therapy. Brazilian Clinical Trials Registry (ReBEC): RBR-2hgwvgy. The trial was registered retrospectively due to administrative delays in the registration process. However, no outcome data were accessed, analysed, or used to inform any decisions prior to registration, and no interim analyses were performed. Additionally, no modifications were made to the study design, outcomes, or planned analyses after the initiation of data collection. Registered on July 2, 2023.
Epilepsia partialis continua (EPC) is a form of focal motor status epilepticus (SE), which is commonly drug-resistant requiring treatment with multiple antiseizure medications (ASM). There are no established guidelines for pharmacological management. Perampanel (PER), an AMPA receptor antagonist, has gained attention in treating SE based on limited case reports. This study evaluates the efficacy of PER in treating EPC. We retrospectively analyzed the treatment response and adverse effects of PER in patients with EPC at our local centre between January 2024 and March 2025. Eight patients with EPC were included. The loading dose of PER ranged from 6 mg to 20 mg. A clinical response was defined as seizure freedom within 72 h of initiating PER, with PER being the last ASM added. PER resulted in seizure termination in eight out of eight patients. Time to response ranged from less than 24 h to 72 h. Oral PER, up to a dose of 16 mg, was well-tolerated in conscious patients. Common side effects included sedation, delirium, agitation, and nausea. Our real-world data suggest that PER is an effective and well-tolerated early adjunct therapy in EPC, particularly at higher oral loading doses in conscious patients.
Among donor-acceptor dyes, merocyanines (MCs) stand out as their absorption and emission wavelengths can be tuned over a wide visible and near-infrared (NIR) spectral range by proper choice of donor and acceptor end groups and length of the polymethine chain. Concerning emission properties, however, non-radiative relaxation channels enabled by the floppy nature of the polymethine chain and changes in bond lengths upon optical excitation are problematic but offer perspectives for environmentally sensitive fluorescent probes. In the first part of this review, we analyse the fundamental properties of MCs and point out the special case of MCs whose electronic structure is located in the cyanine limit, where structural changes upon optical excitation are minimized, thereby establishing the best starting point for emitter design. Subsequently, we show examples of highly fluorescent MC dyes and discuss the solvent dependency of emission wavelength and quantum yield. This discussion will not only provide insights into common relaxation pathways via twisted intramolecular charge transfer (TICT) states and conical intersections (CIs) but also highlight unexpected improvements in fluorescence intensity with chain elongation, providing MC emitters for the NIR spectral range. In the following, examples of the utilization of MCs as fluorescent molecular probes and for biomolecular imaging will be discussed. In the former case, probes that exhibit fluorescence turn-on upon rigidification are particularly desirable, as they enable the detection of ligand binding, protein activation, or other biochemical events, based on MCs being either covalently or non-covalently attached to nucleic acid or protein scaffolds. For the latter, a more constant luminescence intensity is preferred as a marker of a tagged biomacromolecule, e.g., in live cell imaging. In the last part, counteracting effects on fluorescence originating upon aggregation will be elucidated which consist of (desired) slow-down of non-radiative relaxation channels of photoexcited MCs due to rigidification vs. reduced radiative rates due to co-facial stacking, leading to (undesired) H-type coupling with the concomitant decrease of oscillator strength for the lowest excitonic state. Here, we will highlight examples where the first process prevails, leading to emission enhancement, as demonstrated for solid state materials as well as self-assembled aggregates and foldamers in solution.
This paper examines the quality impact of technology on health care services and attitudes, focusing on telemedicine (TM) and artificial intelligence (AI). The aim is to systematically review in the last five years international literature to analyze the benefits and challenges associated with the implementation of these technologies. Emphasis is given to the role of AI and TM, concerning improving accessibility in healthcare and managing economic impact and health challenges through data and coordination of activities. Following PRISMA guidelines, 25 systematic reviews published between 2021 and 2026 were analyzed using a structured data extraction process. This study aspires to provide valuable insights to healthcare professionals and researchers, contributing to the development of best practices for continuous improvement of healthcare quality.
The launch of ChatGPT has raised interest in Generative Artificial Intelligence models and the way they can be applied across domains. In this study we focused on dermoscopic image labeling, using OpenAI's GPT-5 series to determine if there are improvements in labeling between the last versions: GPT-5, GPT-5.2 and GPT-5.4. The testing process uses three different formats: free answer, choosing between labels, and choosing between labels after providing patient metadata together with the images. The evaluation was carried out with paid ChatGPT Plus subscription deactivating the option "Improve the model for everyone" ensuring an unbiased testing. The models were tested using the Thinking variant during different timeframes. The results underline improvements in distinguishing melanoma across model iterations.
Self-injury behavior is a prevalent mental health problem among adolescents. Childhood maltreatment is closely associated with the development of alexithymia, impulsivity, and self-injury behavior in adolescents and young adults with mental disorders; however, the underlying mechanisms remain unclear. This study aims to classify psychiatric patients aged 12 to 24 years into psychological subtypes based on alexithymic and impulsive traits, to explore differences in self-injury behavior among these subtypes, and to examine whether different forms of childhood maltreatment are associated with specific psychological subtypes, thereby providing evidence for clinical intervention and prognosis improvement. Clinical data of adolescents and young adults with mental disorders treated between 2021 and 2022 were retrospectively collected. Principal component analysis (PCA) was performed using 6 dimensions derived from the Toronto Alexithymia Scale (TAS)-20 and the Barratt Impulsiveness Scale (BIS)-11, including difficulty identifying feelings (DIF), difficulty describing feelings (DDF), externally oriented thinking (EOT), attentional impulsiveness, motor impulsivity, and non-planning impulsivity. Principal components with eigenvalues (λ) ≥1 were retained, and their scores were subjected to 2-step cluster analysis for automatic subtype classification. Differences among the subtypes were compared with respect to demographic characteristics, clinical features, and self-injury behavior-related characteristics. Multivariate Logistic regression models were subsequently used to examine associations between the identified psychological subtypes and different forms of childhood maltreatment. A total of 634 adolescents and young adults with mental disorders were included, among whom 459 (72.4%) had a history of self-injury behavior. The diagnostic distribution comprised depressive disorders (n=295, 46.5%), bipolar disorder (n=136, 21.5%), anxiety disorders (n=61, 9.6%), schizophrenia (n=14, 2.2%), and other disorders (n=128, 20.2%), including personality disorders, obsessive-compulsive disorder, post-traumatic stress disorder, somatoform disorders, and eating disorders. PCA reduced the 6 dimensions related to alexithymia and impulsivity into 2 independent principal components (Z1 and Z2). Based on individual scores on Z1 and Z2, 2-step cluster analysis automatically classified participants into 3 clusters (K1, K2, and K3). The psychological characteristics of the K1 group were characterized by high motor impulsivity accompanied by marked difficulties in identifying and expressing emotions. The K2 group exhibited relatively low levels of impulsivity and alexithymia. The K3 group was characterized by high attentional impulsivity, high non-planning impulsivity, and externally oriented thinking. No significant differences were observed among the 3 groups in the distribution of primary psychiatric diagnoses (P>0.05). Comparisons of self-injury behavior-related characteristics showed that the K2 group had significantly lower rates of self-injury, lower self-injury frequency, lower self-injury addiction scores, and lower self-injury motivation scores than the other 2 groups (all P<0.05). No significant differences were found between the K1 and K3 groups in self-injury prevalence, self-injury addiction scores, and external emotion regulation motives (P>0.05). However, the K1 group scored significantly higher than the K3 group on the motivational dimensions of social influence, internal emotion regulation, and sensation seeking, while exhibiting a lower frequency of self-injury behavior (P<0.05) in the last year. Multivariable Logistic regression analysis revealed that childhood emotional abuse may be a risk factor for developing the K1 psychological subtype; childhood physical abuse may be a risk factor for developing both K1 and K3 psychological subtypes; and childhood emotional neglect was associated with the development of K1 and K2 psychological subtypes. Adolescents and young adults with mental disorders can be classified into 3 distinct psychological subtypes based on alexithymia and impulsive traits. These subtypes differ in the prevalence and motivational characteristics of self-injury behavior, independent of clinical diagnosis. Furthermore, the development of different psychological subtypes may be associated with exposure to different forms of childhood maltreatment. These findings suggest that providing targeted emotional regulation and impulse-control interventions for adolescents exposed to specific childhood adversities may help reduce the occurrence and frequency of self-injury behavior. 目的: 自伤行为是青少年高发的心理健康问题，童年期虐待与青少年精神障碍患者的述情障碍、冲动性心理特征及自伤行为的发生和发展密切相关，但其机制尚不明确。本研究旨在通过依据个体述情障碍和冲动性心理特征对12~24岁青少年精神心理障碍患者进行亚型分类，探索不同亚型个体间自伤行为特征的差异，同时分析不同类型的童年期虐待是否与特定的心理特征亚型相关，以期为患者的临床治疗和预后改善提供依据。方法: 回顾性收集2021至2022年青少年精神障碍患者的临床资料，利用多伦多述情障碍量表(Toronto Alexithymia Scale，TAS)-20及Barratt冲动性量表(Barratt Impulsiveness Scale，BIS)-11的6个维度(情感辨别不能、情感描述不能、外向性思维、注意冲动性、运动冲动性和无计划冲动性)特征进行主成分分析，对λ≥1的主成分使用二阶聚类法进行自动亚型聚类。比较不同类别患者在人口学资料、临床特征及自伤行为相关特征3个方面指标上的差异。同时，利用多元Logistic回归模型探索聚类分析得到的心理亚型是否与不同类型的童年期虐待有关。结果: 共纳入634例青少年精神障碍患者资料，459例(72.4%)曾出现过自伤行为。入组患者中，抑郁障碍295例(46.5%)、双相情感障碍136例(21.5%)、焦虑障碍61例(9.6%)、精神分裂症14例(2.2%)、其他障碍128例(20.2%;包括人格障碍、强迫性障碍、创伤后应激障碍、躯体形式障碍、进食障碍等)。主成分分析可将述情障碍与冲动性相关的6个维度转化为2个互不相关且具有独立意义的主成分(Z1及Z2)，依据个案在Z1和Z2的得分，利用二阶聚类法将研究对象自动聚为3组(K1、K2、K3)，K1组患者的心理特征可归纳为高运动冲动性且存在较明显的情感辨别及情感表达障碍，K2组患者的心理特征表现为较低程度的冲动性及述情障碍，K3组患者心理特征为高注意冲动性、无计划冲动性及外向性思维。3个亚组在主要诊断构成上的差异无统计学意义(P>0.05);3个心理特征亚组的自伤行为相关特征比较结果显示，K2组的自伤发生率、自伤行为频率、自伤成瘾性评分、自伤行为动机评分均显著低于其他2组(均P<0.05);K1组和K3组患者在自伤发生率、自伤成瘾性评分、自伤的外部情绪调节等指标上的差异无统计学意义(P>0.05)，但K1组患者在自伤社会影响、自伤的内部情绪调节、感觉刺激3个动机维度上的评分均显著高于K3组患者，而近一年自伤行为频率则低于K3组(P<0.05)。多元Logistic回归分析结果显示，童年期遭受情感虐待可能是个体形成K1组心理特征的危险因素;童年期遭受躯体虐待可能是个体形成K1和K3组心理特征的危险因素;童年期遭受情感忽视与K1和K2组心理特征的形成有关。结论: 依据述情障碍和冲动性心理特征可将青少年精神障碍患者分为3种亚型，各亚型在自伤行为发生率及自伤行为出现的动机等方面存在差异，且独立于患者的临床诊断。而不同心理特征亚型的形成可能与不同类型的童年期创伤暴露有关，这提示对遭受不同童年创伤的青少年精神障碍患者提供针对性的情绪调控与冲动控制策略可能有助于降低自伤行为发生率和频率。.
Unlike in hematologic malignancies like acute promyelocytic leukemia (APL), the tumorigenic role of RARA fusions in solid tumors, including melanomas, remains largely unknown. Here, we present a comprehensive clinicopathologic and molecular analysis of two cutaneous melanomas harboring RARA fusions. Both melanomas were of the acral subtype, affecting the feet of adults (median age: 60.5 years) without sex predilection. At diagnosis, Breslow thickness ranged from 1.2 to 5.5 mm, ulceration was present in one case, and the median mitotic rate was 4/mm2. Tumor cells exhibited variable cytomorphology, including spindled and epithelioid features, with occasional rhabdoid morphology. Molecular analysis revealed a consistently low tumor mutational burden (median: 4.5 mutations/Mb). One acral melanoma was triple wild-type (lacking mutations in BRAF, NRAS, and NF1) and showed no gene amplifications, but harbored a LOC107984974::RARA fusion. The other acral melanoma carried an NF1 loss-of-function mutation and multiple gene amplifications involving 11q13.3 (CCND1, FGF3, FGF4, FGF19), 11q13.5-q14.1 (PAK1), 12q15 (MDM2), and 6q24.3 (SHPRH), along with two RARA fusions: RARA::LRP5 and RARA::RNF169. Over a median follow-up of 23 months, one patient developed a distant metastasis involving the brain approximately 20 months after the initial diagnosis. At last follow-up, one patient was alive with disease, while the other remained alive without clinical or radiological evidence of recurrence. These findings expand the current understanding of the molecular landscape of acral melanomas and may provide insights into the potential utility of targeted therapies against RARA fusions in a subset of melanomas, analogous to their therapeutic role in APL.
The estrogen receptor (ER) is the key therapeutic target for ER-positive (ER+) breast cancer. Novel ER degraders may overcome resistance to available endocrine therapy while providing consistent oral bioavailability. Imlunestrant is a novel, orally bioavailable selective estrogen receptor degrader (SERD) designed to deliver continuous ER target inhibition. A phase 1, open-label, 3-site study was conducted to characterize the pharmacokinetic (PK) profile of imlunestrant in individuals with varying degrees of hepatic impairment based on Child-Pugh and National Cancer Institute classifications. In this study, participants received a single oral dose of imlunestrant at either 200 or 400 mg in the fasted state, and the pharmacokinetics and safety were assessed in individuals with normal hepatic function and those with mild, moderate, or severe hepatic impairment. Based on Child-Pugh classification, there were no significant differences in the exposure profiles of imlunestrant in participants with mild hepatic impairment in comparison to participants with normal hepatic function. In participants with moderate and severe hepatic impairment, there were significant increases in imlunestrant AUC (but not Cmax) observed when compared with normal hepatic function (by 120% and 191% for AUC(0-tlast) and 122% and 206% for AUC(0-∞), respectively). Most treatment-emergent adverse events (TEAEs) were mild or moderate in severity. Nausea and headache were the only TEAEs reported by more than one participant. Treatment-related adverse events were reported by two participants, one each from the moderate and severe hepatic impairment groups. This data will inform the recommendations for dosing patients with hepatic impairment under treatment with imlunestrant.
The present experiment examined the effects of the number of conditioned stimulus sessions on (a) the rate of extinction of conditioned hyperactivity and (b) the subsequent expression of context-specific sensitization in mice. Male, Swiss Webster mice (n = 10/group) received methamphetamine (0.5 mg/kg) associated with locomotor activity chambers (paired) or home cages (unpaired) for five sessions (acquisition) followed by vehicle injections (saline) for either 5 (1 session/day × 5 days) or 20 (2 sessions/day × 10 days) sessions (extinction). All mice received an escalating methamphetamine-dose regimen (0.25-1.0 mg/kg, 1 dose/day for 3 days) regimen 24 h after the last extinction session (tests for context-specific sensitization). Distance traveled and vertical counts assessed locomotor activity. Both measures of locomotor activity detected between-session sensitization; however, the distance traveled measure was more sensitive in detecting conditioned hyperactivity. The vertical counts, but not the distance traveled measure, found that 5 extinction sessions compared with 20 extinction sessions produced slower extinction, perhaps owing to the trial spacing effect. However, the distance traveled measure revealed that 20, but not 5, extinction sessions completely suppressed context-specific sensitization following the 0.25 mg/kg methamphetamine challenge dose. These results suggest that increasing the number of conditioned stimulus sessions during extinction effectively suppresses the expression of context-specific sensitization, lending support to a 'Pavlovian excitatory conditioning hypothesis' of context-specific sensitization.
Anxiety and depression are highly prevalent among adolescents and young adults with eating disorders. A comorbid mental health condition is associated with worsened long-term eating disorder outcomes. While individual risk factors for comorbid anxiety or depression and eating disorders have been elucidated, the impact of external factors, such as neighborhood disadvantage, remains understudied. The purpose of this study was to examine the associations between levels of neighborhood disadvantage and comorbid anxiety and depression. This was a retrospective study utilizing data available from Epic Cosmos, an electronic health record data platform. Individuals aged 9-25 years with an eating disorder diagnosis and a healthcare encounter within the last year were included. The exposure variable of neighborhood disadvantage was measured by the Area Deprivation Index percentile ranks. Outcomes included ICD-10 diagnoses of anxiety or depression. Logistic regression models were used to assess associations between area deprivation and mental health conditions. Inclusion criteria were met in 100,924 individuals. The median age was 17 years, and the majority were female, White, and non-Hispanic. Anxiety was present in 71.2% of the cohort and depression was present in 52.5%. Higher levels of neighborhood disadvantage were associated with increased odds of anxiety and depression. Disparities based on sociodemographic characteristics were also observed. More neighborhood disadvantage is associated with increased odds of anxiety and depression among adolescents and young adults with eating disorders. These findings highlight the importance of understanding neighborhood context in eating disorder presentations.
The objective of this study was to estimate the prevalence and trends in prevalence of dysglycemia in the United States (U.S.). This is a repeat cross-sectional analysis of adults age ≥ 20 years who participated in the National Health and Nutrition Examination Survey (NHANES) between 2013-2023. Age-standardized pre-diabetes, undiagnosed diabetes, diagnosed diabetes, and total diabetes prevalence were estimated for each of the 4 survey cycles, then stratified by sociodemographic and clinical characteristics. Linear trends were estimated using logistic regression. Prevalence calculations and trend analyses were repeated to assess the proportion of participants meeting glycemic, blood pressure, and lipid control targets. Among 24 230 participants across all survey years, 6773 had pre-diabetes, and 4784 had diabetes (3826 diagnosed/958 undiagnosed). The age-adjusted prevalence of total diabetes was stable across the study period: 14.6% (95% CI 13.0%-16.2%) in 2013-2014 and 16.3% (14.6%-18.0%) in 2021-2023 (prevalence ratio (PR) 1.07 [95% CI 0.90-1.26], p-trend = 0.47). The age-adjusted prevalence of pre-diabetes increased significantly during the study period from 26.4% (23.7%-29.1%) in 2013-2014 to 30.7% (28.4%-33.0%) in 2021-2023 (p-trend = 0.04, PR 1.12 [1.02-1.23]). While the prevalence of diabetes has stabilized over the last decade, the rise in pre-diabetes signals a growing population at risk for future cardiometabolic and kidney disease.
CSF diversion through ventricular shunt placement is a mainstay of hydrocephalus treatment, and the advent of programmable shunt valves in the last 40 years has continued to improve treatment options. Programmable shunt valves allow noninvasive setting adjustment with magnetic programming devices. However, since there are objects in everyday life that emit magnetic fields, the shunt valve setting may be unintentionally changed. The authors aimed to summarize the current literature on handheld, wearable, and earpiece devices and their impact on programmable shunts, as well as explore the effect of the magnetic field of handheld and wearable electronics when actively in use in common positions on programmable shunt valve settings. The following reprogrammable shunt valves were tested: Medtronic Strata II, Codman Hakim, and Codman Certas. The electronic devices used were Apple AirPods Pro 2, Bose QC 45, Oculus Meta Quest 3, Apple iPad 6, and Apple iPhone 15. A shunt valve with a predetermined setting was attached to the skull model in the right parieto-occipital and right frontal locations. The devices in their active mode were placed on or around the ear for a minimum of 5 minutes. The shunt valve setting was then rechecked. As rotary motion may impact magnetic fields, secondary testing with various motions was performed and the shunt setting was rechecked. The programmable shunt valves were set as follows: Medtronic Strata II at 1.5, Codman Hakim at 70 mm H2O, and Codman Certas at 4. After a minimum of 5 minutes of realistic interaction with the aforementioned electronics, the shunt setting was rechecked. The shunt setting remained the same in each case tested. It is safe for children and adults with hydrocephalus and programmable shunt valves to use common handheld and wearable electronics without concern for their shunt valve setting being affected unknowingly.
Plantar fasciitis (PF) is a common musculoskeletal injury that can occur in adults of all ages and activity levels. This condition accounts for more than 1 million medical visits annually in the United States alone. Despite its name, PF is considered a degenerative condition rather than a primary inflammatory disorder. It is characterized by pain in the medial part of the heel that worsens with weight-bearing activity and prolonged standing. Treatment for PF can be conservative, including stretching complemented by formal physical therapy, NSAIDs, and orthotics. If symptoms have not improved after these options, the use of injectable treatments should be considered. If symptoms persist for more than 6 months, surgical release could be considered as a last resort. Different studies have demonstrated the efficacy and safety of high molecular weight hyaluronic acid (HA) injections in the treatment of patients with PF. The objective of the study was to evaluate the efficacy and safety of treatment with hybrid high-low molecular weight hyaluronic acid (HA) in patients diagnosed with plantar fasciitis through retrospective analysis of medical records. Patient functionality was assessed using the Spanish-validated Manchester-Oxford Foot and Ankle Questionnaire (MOXFQ), and pain level was measured with the Verbal Numeric Rating Scale (VNRS), both before the procedure and after 12 months of post-treatment follow-up, in 10 patients diagnosed with PF who were administered hybrid high-low molecular weight HA (Sinovial HL® 1 ml) through ultrasound-guided injection into the plantar fascia. In all cases, the thickness of the plantar fascia was evaluated by ultrasound before the procedure and at 12 months. A significant reduction in pain assessed by the VNRS was observed when comparing baseline data to values at 12 months post-procedure (P<.001). In all cases, patients reported total absence of pain 12 months after the HA injection. Likewise, a statistically significant reduction in MOXFQ scores was observed between baseline values and those obtained at the 12-month follow-up. The mean scores decreased from 57.2 ± 4.3 points at baseline to 2.5 ± 2.8 points at 12 months, with a median difference of -55 points (IQR: -58.2 to -50.8; P=.002). Regarding the evaluation of ultrasound changes in plantar fascia thickness, the analysis revealed a statistically significant reduction at 12 months after the procedure compared to baseline measurements (median difference: -2.25 mm, IQR: -2.85 to -1.95; P=.002). The body mass index (BMI) was 27.8%, and the predominant gender was male (70%) compared to female (30%). The baseline characteristics of the patients and the results of the tests performed are shown in table 1. Ultrasound-guided infiltration with hyaluronic acid hybrid high-low molecular weight into the plantar fascia in patients with plantar fasciitis or intrafascial fiber rupture is an effective and safe treatment that maintains its positive effects for at least one year after the procedure. The use of ultrasound plays a fundamental role both at the time of infiltration and in the follow-up of the condition.
Inspired by the neural mechanisms of conditioned fear, this paper designs a memristive neuromorphic circuit based on the Pavlovian associative memory experiment to simulate the functions of learning, forgetting, long-term memory, formation and regulation of conditioned fear, generalization and differentiation, as well as the nested generalization and differentiation. The circuit mainly consists of three modules: the Pavlovian associative memory module, the conditioned fear associative memory and fear regulation module, and the generalization and differentiation module. The Pavlovian associative memory module simulates the process of forming long-term memory through repeated associative learning between food and ring. It achieves a biological mechanism in which the natural forgetting rate approaches zero, while the forgetting rate decreased significantly under the ring stimulus. The conditioned fear associative memory and fear regulation module simulates the formation of conditioned fear, and the fear signal disconnects the synaptic between the ring and the salivation neuron, thereby inhibiting the secretion of salivary neuron. The last module simulates the generalization and differentiation processes for food-ring association and conditioned fear, and it implements the nesting of generalization and differentiation. The correctness and effectiveness of the circuit are verified through PSPICE simulations. Monte Carlo analysis and temperature analysis are operated to demonstrate the robustness of the circuit.