引言：荨麻疹是一种普遍存在的疾病，影响着全球相当一部分人口。皮肤科医生和患者都需要获取最新、准确的信息。传统搜索引擎往往无法满足这些需求。尽管人们越来越依赖人工智能进行医学咨询，但人工智能生成内容的准确性和质量仍未得到充分研究。本研究旨在评估和比较两种广泛使用的人工智能模型ChatGPT-4o和DeepSeek-R1在处理荨麻疹相关问题方面的表现。 方法：采用电子德尔菲法生成并完善一组与荨麻疹相关的问题，并为人工智能生成的回答制定评估框架。然后向ChatGPT-4o和DeepSeek-R1提出最终确定的问题，并记录它们的回答。对67名参与者（29名皮肤科医生和38名非皮肤科医生）进行了单盲比较评估。从简单性、准确性、专业性、临床可行性、可理解性和完整性等方面对两个人工智能模型的回答进行评估。 结果：在大多数指标上，DeepSeek-R1的表现优于ChatGPT-4o。皮肤科医生对DeepSeek在简单性（p<0.001）、准确性（p<0.001）、完整性（p=0.001）、专业性（p<0.001）和临床可行性（p<0.001）方面的评分显著更高。非皮肤科医生发现DeepSeek的回答更简洁（p<0.001）且更易于理解（p<0.001）。两种模型在前沿知识整合方面表现相当（p=0.06），不过DeepSeek的输出稳定性更高，标准差更低就证明了这一点。与指南相比，DeepSeek-R1提供的答案没有错误，而ChatGPT-4o在三个临床问题上出现了错误。 结论：人工智能生成的答案需要经过严格评估，以确保其可靠性和在医学应用中的适用性。根据目前的研究，DeepSeek-R1在处理荨麻疹相关问题方面优于ChatGPT-4o，在临床和患者使用方面都显示出更高的潜力。
前列腺素E2（PGE2）是肿瘤微环境（TME）中一种重要的免疫抑制因子。通过前列腺素E受体2型（EP2）和EP4发出信号，PGE2可促进免疫抑制细胞表型并损害抗肿瘤免疫力。人们正在探索用EP2和EP4拮抗剂阻断PGE2信号传导，以对抗肿瘤诱导的免疫抑制。虽然已知肿瘤来源的PGE2可调节人类髓细胞亚群，但其对巨噬细胞的具体作用仍不清楚。虽然小鼠模型显示PGE2可诱导促肿瘤巨噬细胞表型，但PGE2-EP2/4信号传导对人类巨噬细胞的作用尚不清楚。本研究评估了PGE2对人类巨噬细胞表型和功能的影响，以及用可溶性和纳米颗粒包裹的拮抗剂靶向EP2和EP4的有效性。我们发现，单核细胞分化为巨噬细胞过程中暴露于PGE2会诱导出一种独特的表型并影响巨噬细胞功能。肿瘤来源的PGE2主要通过EP2发出信号；然而，对EP2和EP4的双重阻断能更有效地抵消PGE2诱导的变化。值得注意的是，EP2/4拮抗剂的包裹增强了对肿瘤来源的PGE2信号传导对巨噬细胞表型的阻断作用，以及它们调节患者来源的肿瘤类器官内T细胞增殖的能力。这些发现强调了肿瘤来源的PGE2对人类巨噬细胞的影响，并支持在癌症治疗中靶向PGE2-EP2/4轴。
意义：对小鼠玻璃体视网膜血管系统进行全深度光学相干断层扫描（OCT）在技术上具有挑战性。传统的OCT技术采用轴向共焦选通，这会导致信号衰减，并限制瑞利范围之外的空间分辨率。 目的：我们的目的是开发一种使用可调谐透镜和配准方法的多焦点OCT成像方法，该方法能够生成玻璃体视网膜血管系统的合成图像，同时在全深度范围内保持高且均匀的横向空间分辨率、信号强度和图像对比度。 方法：开发了一个校准目标来表征多焦点光学系统，并量化信号强度、对比度和分辨率。利用这些光学规格对出生后第14天的小鼠进行成像。需要采用体积内和体积间配准方法来校正运动，并使用加权平均从单焦点图像生成合成图像。 结果：在校准目标中，合成图像的信号强度和对比度比单焦点图像高20 dB。横向分辨率保持均匀（4至 ）。在动物中，合成图像的信号强度和对比度比单焦点图像高10至15 dB，在玻璃体血管系统中最高。 结论：该技术在研究眼睛发育和疾病过程中的小鼠玻璃体视网膜血管系统方面具有前景。
本研究旨在比较不同肾去神经支配（RDN）技术的降压疗效和安全性。我们系统检索了截至2025年9月4日的PubMed、Ovid和Embase数据库。主要结局是24小时动态收缩压从基线到随访结束的变化。次要结局包括24小时动态舒张压的变化以及主要不良事件的发生率。两名研究者独立进行研究筛选、数据提取和偏倚风险评估。进行了网络荟萃分析以及敏感性和亚组分析。我们的分析表明，主肾动脉及其分支的射频RDN（RFB-RDN）和超声RDN（US-RDN）均与24小时动态血压的显著降低相关，两种方法疗效相当，而主肾动脉射频RDN（RFM-RDN）和酒精介导的RDN（ALC-RDN）疗效有限。与假手术相比，US-RDN和RFM-RDN不良事件有减少趋势，而RFB-RDN和ALC-RDN不良事件风险在数值上更高；然而，这些差异未达到统计学意义。亚组分析表明，高血压亚型、种族和基线血压可能影响治疗效果，特别是对于RFB-RDN。
刺激性接触性皮炎是一种常见的造口周围皮肤并发症。由于肠液和粪便的持续刺激，这种皮炎的愈合缓慢，病情严重影响患者的生活质量。该研究旨在评估一种改良的可插入式造口器具在促进愈合和改善患者预后方面的疗效。2022年1月至2024年12月在一家三级医院进行了一项随机对照试验。所有入选患者均被诊断为刺激性接触性皮炎，随机分为两组。对照组佩戴传统的两件式造口器具，而实验组佩戴改良的可插入式造口器具。在第3、7、14和28天评估结果。主要结局是第28天的愈合率（色素沉着、糜烂和组织过度生长[DET]评分≤2）。次要结局包括DET评分、视觉模拟量表（VAS）疼痛评分、造口生活质量问卷（Stoma-QOL）评分和器具渗漏发生率。共有89名符合条件的参与者完成了试验。实验组的28天愈合率显著更高（73.3%对29.5%，p<0.001），DET评分更低（第28天：2.0对4.5，p<0.001），VAS评分降低（第28天：1.5对2.0，p<0.001），Stoma-QOL评分更高（第28天：55.67对51.64，p<0.001），渗漏率更低（13.3%对93.2%，p<0.001）。改良的造口器具显著改善了愈合情况，减轻了疼痛，提高了生活质量，是临床实践的一种新解决方案。
星形胶质细胞，曾被仅仅视为大脑中的被动支持细胞，最近已成为感觉处理、学习和记忆中神经元的积极伙伴。通过促进神经元突触的发育、成熟和精细化，星形胶质细胞在塑造脑回路中发挥核心作用。在这些回路中，抑制性神经元约占脑细胞的20%，在不同区域和发育阶段存在差异。抑制作用的根本重要性通过其进化保守性得以强调，甚至在原始神经系统中也存在。值得注意的是，星形胶质细胞的发育在时间上与突触发生的高峰期以及抑制性神经元的成熟相吻合，这表明这些过程之间可能存在相互作用。从历史上看，研究主要集中在星形胶质细胞与兴奋性神经元的相互作用上；然而，人们越来越认识到星形胶质细胞 - 抑制性神经元相互作用的可能重要性，特别是在关键的发育时期。在这里，我们综述了关于星形胶质细胞和抑制性神经元发育的当前知识，强调它们相互作用的新证据，并提出假设以指导未来的研究。
广泛的研究已经确立了视听刺激多感官整合中一致性效应的关键作用。然而，对于注意力集中在一种或另一种感觉领域是否会对一致性效应的神经生理动力学产生不同影响，尤其是在频繁出现不一致的情况下，人们知之甚少。因此，本研究的目的是比较与被关注的感觉模态之间的一致性效应相关的事件相关电位（ERP）的时间和地形特征。30名健康的年轻成年人在脑电图记录期间进行了一项跨模态（视觉/听觉）注意力任务，同时呈现视听刺激（75%为不一致试验，25%为一致试验）。在行为上，观察到视觉注意力的一致性效应比听觉注意力更强。通过从每个注意力集中模态（视觉/听觉）的一致试验的ERP中减去不一致试验的ERP，提取出一致性效应ERP（ERPce）。ERPce主要由一个N1-P2-P3复合体组成，分布在左额中央，无论被关注的感觉模态如何，其振幅相似，这与行为表现相关。有趣的是，注意力集中显著影响了一致性效应的时间性，听觉注意力与视觉注意力相比，ERPce的潜伏期延迟就表明了这一点。这些结果表明，在广泛不一致的背景下，注意力集中在将同时出现的一致（尽管不相关）信号与相关信号整合方面起着重要作用。
背景：出现与膝关节骨关节炎相关的疼痛和功能受限症状的患者通常会接受膝关节置换手术。然而，仍有一部分患者对手术效果不满意，而且年轻人的手术失败风险相对更高。膝关节牵张术可能是一种可推迟这类患者进行膝关节置换手术时间的干预措施。 目的和主要结局指标：骨关节炎膝关节置换与关节牵张术研究（KARDS）的主要目的是，以膝关节损伤和骨关节炎疗效评分疼痛评分为主要结局指标，评估与膝关节置换相比，膝关节牵张术在术后12个月基于患者报告的疼痛方面的有效性。 设计和方法：KARDS是一项开放标签、双臂个体随机对照非劣效性试验，设有一个为期12个月的内部预试验阶段和过程评估，以评估招募的可行性。采用了混合专业知识设计，以考虑外科医生的专业知识以及可能缺乏的个体平衡。该试验在因2019冠状病毒病大流行而停止择期骨科手术后提前停止招募。报告了描述性统计数据。 地点：英国国家医疗服务体系信托基金。 参与者：年龄小于65岁、症状严重到经主治医生判断有必要进行膝关节置换的成年患者。 干预措施：参与者被随机分配接受膝关节牵张术（使用外固定器进行5毫米的静态牵张，持续6周）或膝关节置换术。 结果：2021年3月至2022年10月期间，24名参与者从单一中心被随机分组，术后至少有3个月的安全性随访。11名参与者被随机分配接受膝关节牵张术，13名接受膝关节置换术。17名患者为男性（71%），中位年龄60岁（47 - 65岁）。1名患者因身体不适合手术而退出，2名接受了与随机分配不同的治疗（每组各有1名交叉治疗）。膝关节牵张术组的膝关节损伤和骨关节炎疗效评分疼痛中位数从基线时的38.9（22 - 50）提高到12个月时的55.6（0 - 100），膝关节置换术组的相应评分从30.6（6 - 36）提高到75.0（50 - 100）。膝关节牵张术的不良事件更常见，针道感染是最常见的并发症（n = 4，58%）。作为过程评估的一部分，我们对二级医疗保健机构的工作人员和研究参与者进行了半结构化定性访谈。采用主题内容分析法对数据进行了分析。出现了一个总体主题：“一段意想不到的旅程”，它概括了工作人员和参与者的经历。 结论：2019冠状病毒病大流行后研究能力下降以及择期手术暂停导致了重大的招募障碍。尽管提前终止，但KARDS表明患者愿意参与一项研究新型膝关节骨关节炎治疗方法的试验，并且该试验是可行且可实施的。有限的结果表明该技术是安全的，不存在安全问题。膝关节牵张术的临床和成本效益仍不确定。KARDS嵌入式过程评估提供了有益的见解。 局限性：各研究点研究能力下降以及英国境内择期手术服务暂停给KARDS造成了重大招募障碍。研究的两个组中所有招募的患者均为白人。 未来工作：作为一项受委托开展的研究，其实施受到新冠疫情后国家医疗服务体系环境以及对国家医疗服务体系外科手术服务影响的显著影响，该研究问题仍然高度相关。此处发表的预试验数据以及所吸取的经验教训可为该领域未来的任何研究提供帮助。 资金来源：本摘要介绍了由英国国家健康与照护研究中心（NIHR）健康技术评估项目资助的独立研究，资助编号为17/122/06。
目的：光学显微镜和组织制备技术的最新创新使得复杂微血管网络的三维可视化成为可能。组织透明化技术可改善光穿透并增加成像深度。通常，基于灌注的方法用于血管标记和组织透明化。然而，在处理来自大型动物模型的组织时，基于浸泡的方法具有更高的实用性。 方法：我们展示了一种基于浸泡的心肌组织微血管标记和组织透明化方案，该方案使用番茄凝集素和CUBIC（清晰、无阻碍的脑/体成像鸡尾酒和计算分析），在高达150μm的成像深度上取得了成功。该方案针对大鼠和猪心肌组织优化了脱脂和淬灭阶段。使用信噪比（SNR）和平均z切片强度的自动分析来评估图像质量。 结果：在CUBIC试剂I孵育24小时时获得了最佳图像质量。淬灭剂TrueVIEW、甘氨酸和台盼蓝对SNR值没有显著影响。与未进行淬灭剂孵育的对照相比，TrueBlack和苏丹黑B显示出成像深度降低的趋势。总体而言，大鼠心肌组织的SNR高于猪组织样本。 结论：该方案为优化基于浸泡的心肌组织透明化方法提供了严格的基础。未来的研究将对冠状动脉微血管的解剖结构和拓扑结构进行量化，以比较疾病状态。
乳腺癌仍然是全球女性中最常被诊断出的癌症，也是癌症相关死亡的主要原因。尽管治疗取得了进展，但耐药性和毒性问题凸显了对新型、有效且更安全治疗药物的迫切需求。天然化合物因其结构多样性和生物活性，越来越多地被探索作为有前景的抗癌候选物来源。其中，多元醇，一类糖醇，据报道可通过调节氧化应激、代谢途径和细胞凋亡来影响癌细胞行为，但其确切机制和治疗潜力仍未得到充分研究。在本研究中，对一种天然存在的多元醇——卫矛醇在具有不同分子特征的乳腺癌细胞系中的抗癌潜力进行了研究。使用MTT法评估了卫矛醇对MCF-7（雌激素受体阳性）、MDA-MB-231（三阴性）和MCF-10A（非致瘤性）乳腺细胞系的细胞毒性作用。对MDA-MB-231细胞进行了包括基于流式细胞术的细胞周期分析、凋亡检测（膜联蛋白V-FITC）、线粒体膜电位评估、半胱天冬酶激活和DNA损伤分析在内的机制研究。还使用qRT-PCR评估了MMP-2和MMP-9基因的表达水平。卫矛醇在浓度≥7.5 mmol/L时对MDA-MB-231细胞表现出选择性细胞毒性，而对MCF-7和MCF-10A细胞无显著影响。在MDA-MB-231细胞中，卫矛醇诱导G0/G1期细胞周期停滞并以剂量依赖方式促进细胞凋亡。此外，观察到半胱天冬酶活性增加和线粒体去极化，表明内源性凋亡途径被激活。未检测到明显的DNA损伤；然而，MMP-2和MMP-9表达的显著下调表明其具有潜在的抗转移活性。尽管体外有效浓度相对较高，但应注意的是，在基于细胞的系统中揭示机制作用通常需要这样的水平，而且目前尚无卫矛醇的药代动力学数据。因此，本研究结果应被视为探索性和假设生成性的，强调需要进行体内药代动力学和疗效研究以评估转化可行性。总之，我们的研究结果表明，卫矛醇选择性靶向三阴性乳腺癌细胞，而不影响正常或雌激素受体阳性乳腺细胞。其诱导细胞凋亡和抑制转移基因表达的能力突出了其作为侵袭性乳腺癌亚型潜在天然治疗候选物的前景。
卵母细胞减数分裂过程中的染色体错分离会导致流产和先天性疾病。与衰老相关的过早染色体分离是错分离的主要原因。目前尚未实现有效预防过早染色体分离。在此，我们设计了基于蛋白质的人工动粒，作为诱饵来防止过早染色体分离。设计的类人工动粒诱饵是由NDC80-NUF2连接的蛋白质颗粒组成的亚微米级簇，它们可以通过与染色体动粒竞争HURP修饰的微管来建立类似双极定向的状态。这种竞争减少了施加在染色体上的过度双极微管拉力，从而有效防止老龄小鼠卵母细胞在减数分裂I和II期间过早染色体分离。这些作用抑制了卵子非整倍体。本研究提供了一种使用生物相容性人工动粒的诱饵策略，以防止与衰老相关的卵母细胞减数分裂错误。
接受放射治疗（RT）或根治性前列腺切除术（RP）作为主要治疗手段的前列腺癌患者可能会出现生化复发（BCR），这需要有效的治疗来延缓疾病进展。ARASTEP研究（NCT05794906）旨在确定与安慰剂加雄激素剥夺疗法（ADT）相比，在高危BCR患者中，将达洛鲁胺添加到ADT中是否能使用前列腺特异性膜抗原正电子发射断层扫描/计算机断层扫描（PSMA PET/CT）改善无放射学进展生存期（rPFS）。全球243个地点的约970名患者将接受每日两次600毫克达洛鲁胺或安慰剂治疗，两者均联合ADT，持续24个月或直至疾病进展、出现不可接受的毒性或撤回同意书。符合条件的患者将接受过原发性RT或RP±辅助放疗（ART）或挽救性放疗（SRT），并呈现高危BCR（前列腺特异性抗原[PSA]倍增时间<12个月，RP[±ART/SRT]后PSA≥0.2 ng/mL或仅原发性RT后PSA高于最低点≥2 ng/mL）、≥1个PSMA PET/CT阳性病变（传统成像为阴性）、血清睾酮>150 ng/dL以及东部肿瘤协作组体能状态为0/1。主要终点是使用PSMA PET/CT的rPFS，次要终点包括无转移生存期、去势抵抗性前列腺癌发生时间、总生存期、生活质量和安全性。临床试验注册：www.clinicaltrials.gov标识符为NCT05794906。
背景：尽管已经对不同人类群体和动物物种的鼻窦进行了广泛研究，但针对犬类的研究仍然相对较少。 目的：本研究旨在利用计算机断层扫描（CT）横断面成像和三维（3D）重建模型来描述犬类鼻窦的解剖和形态结构。 方法：在本研究中，分析了14只临床健康犬（7只雌性，7只雄性）的CT图像，这些犬的平均年龄为6.2±4.3岁。通过横断面成像确定鼻窦的定位和边界，以及鼻窦开口的方向和形态，而形态学特征则使用3D模型进行评估。 结果：尽管所有检查动物的形状存在差异，但双侧鼻窦均由上颌隐窝（MR）和额窦（FS）（前部、内侧和外侧）组成。在一只4岁雄性犬中，前部FS缺失。MR的体积为4cm，表面积为26cm。外侧FS最大，在两性中分别占鼻窦总体积的90%和总表面积的78%，而内侧FS最小，分别占3%和8%。MR被确定为位置最对称的鼻窦，而内侧FS的不对称程度最高。在雌性犬中，右侧外侧FS的表面积明显大于左侧。未发现年龄与鼻窦形态学之间存在相关性。 结论：尽管本研究是在特定年龄和性别的动物上进行的，未考虑品种特异性特征，但研究结果有助于更详细地了解该区域的横断面和重建解剖结构。此外，这些初步参考数据可能有助于放射科医生和临床医生诊断鼻窦疾病。
本文报道了一名50岁女性系统性硬化症患者左手慢性不愈合伤口的诊断与治疗。经过清创、封闭负压引流、臭氧治疗、植皮及指骨融合等综合治疗后，伤口成功愈合。本文强调了白细胞介素-6抑制剂在系统性硬化症合并溃疡患者治疗中可能存在的矛盾作用，并着重指出了臭氧治疗在改善组织缺氧及促进愈合方面的应用价值。
目的：分析和评估美容清创缝合联合重组人表皮生长因子（rhEGF）的临床效果。 方法：通过检索中国知网（CNKI）、万方数据、维普中文科技期刊、中国生物医学文献数据库、PubMed、Web of Science和Cochrane图书馆对文献进行系统评价。采用RevMan 5.4.1软件进行统计分析。使用Q检验（p值）评估研究间的异质性。通过漏斗图评估发表偏倚，生成森林图，并使用固定效应模型或随机效应模型计算合并比值比（OR）。 结果：联合治疗显示出良好的临床疗效[OR = 6.62，95%置信区间（95%CI）（3.14 - 13.92），p < 0.00001]，伤口愈合时间更短[平均差值（MD）= -2.69，95%CI（-3.10至-2.29），p < 0.00001]，并且在6个月时瘢痕结局改善（温哥华瘢痕量表（VSS）和患者与观察者瘢痕评估量表（POSAS）评分更低）。联合治疗组血清表皮生长因子（EGF）水平更高，而白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）水平更低（均p < 0.05）。 结论：美容清创缝合联合rhEGF在颌面部创伤治疗中具有良好的临床效果。
压力性尿失禁（SUI）是女性中常见且负担较重的疾病，对日常功能和生活质量有重大影响。在法国，不断演变的医疗法律和社会关切，尤其是围绕合成尿道中段吊带的使用，已导致诊断和治疗实践发生重大转变。在此背景下，法国泌尿外科学会（AFU）的女性泌尿学和盆底会阴学委员会（CUROPF）制定了本实践公告，以协助医疗保健专业人员对女性SUI进行诊断评估。该公告遵循国际尿控学会（ICS）和国际尿失禁咨询委员会（IUGA）的现行国际定义，将SUI与其他形式的尿失禁区分开来。该文件概述了结构化的诊断途径，包括详细的患者访谈、标准化的症状和生活质量问卷，以及重点在于咳嗽压力测试的体格检查。它确定了年龄、产次、分娩方式、肥胖和绝经状态等关键风险因素，同时也回顾了子宫切除术、放疗和便秘等更具争议性的因素。尿道活动过度和固有括约肌缺陷之间的病理生理区别被作为诊断导向和后续治疗计划的核心要素呈现。讨论了诸如排尿日记、尿垫试验和非侵入性尿动力学评估等辅助评估方法。在特定的复杂情况下会考虑侵入性尿动力学和影像学检查方法。本实践公告在国家指南未来发布之前，为处于过渡背景下面临诊断挑战的临床医生提供了实用参考。其目的是统一实践并改善SUI女性的护理途径。
Chronic respiratory diseases (CRDs) constitute a major global health burden, yet comprehensive assessments of their long-term trends, attributable risks, and future trajectories are still needed to inform public health strategies. Comprehensively analysing the global, regional, and national burden of CRDs from 1990 to 2021, evaluating the risk factors, and forecasting future trends to guide public health policies. Using the Global Burden of Diseases (GBD) 2021 data, we estimated the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) of CRDs from 1990 to 2021. The estimated annual percentage change (EAPC) was calculated to evaluate burden trends, and a Bayesian age-period-cohort model predicted the trends in age-standardized rates (ASRs). In 2021, global CRD incidence reached 55.21 million, with 4.41 million deaths. Among all CRDs, asthma exhibited the highest incidence and prevalence, whereas chronic obstructive pulmonary disease (COPD) caused the highest mortality and DALY. Regionally, High-income North America had the highest ASIR and ASPR of CRDs, while Oceania showed the highest ASMR and ASDR in 2021. In terms of age distribution, the incidences of COPD, interstitial lung disease and pulmonary sarcoidosis (ILD & PS), and pneumoconiosis (PNE) were the highest number of incident cases occurred in the 65-74 age group. Asthma, however, showed the highest incidence in the < 9 age group. Regarding risk factors, smoking caused 31.04% of all CRD-related deaths globally in 2021, while high body mass index accounted for 14.36% of asthma-related deaths. From 2022 to 2030, CRDs' ASIRs are projected to decline overall, with male ASIRs higher than female ASIRs. The findings reveal significant and uneven global CRD burden, and their mitigation warrants policy focus on tobacco control and obesity management.
心房颤动（AF）消融术已越来越多地被用作一种有效的节律控制策略，可减轻心律失常负担、改善生活质量，在某些情况下还可降低死亡率。然而，作为一种侵入性手术，它存在固有风险。严重的食管并发症，如食管穿孔或心房食管瘘，虽然罕见（发生率在0.025%至0.113%之间），但却与显著的发病率和死亡率相关。已确定了多种食管损伤的风险因素，包括与患者相关和与手术相关的特征。为了在射频（RF）消融期间降低这些风险，已采取了多种预防措施，包括使用接触力导管、高功率短持续时间能量应用，以及诸如食管温度监测、移位装置和冷却技术等保护策略。通过监测内镜检查发现的深部食管病变被认为是更严重并发症的潜在先兆，因此值得密切关注。对此类病变患者加强监测对于实现早期诊断和及时干预以防止进展为更严重并发症可能至关重要。虽然对食管和其他周围结构风险较低的脉冲场消融疗法尚未广泛应用，但实施强有力的监测策略可在RF AF消融背景下显著改善临床结果并提高患者安全性。
Late recurrence of breast cancer occurring more than two decades after curative surgery is rare, but in the era of prolonged survival, clinicians may increasingly encounter such cases. Mediastinal or hilar recurrence may radiologically mimic primary lung cancer; however, histological confirmation using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) enables accurate diagnosis with minimal invasiveness. We report the cases of two patients who developed mediastinal and hilar lymph node metastases nearly 30 years after breast cancer surgery, for whom EBUS-TBNA played a crucial diagnostic role. A 68-year-old woman with a history of right mastectomy for stage I (T1aN0M0) breast cancer 30 years earlier presented with cough and hemoptysis. Chest computed tomography revealed multiple pulmonary nodules, right hilar lymphadenopathy, and sclerotic bone lesions. Fluorodeoxyglucose positron emission tomography/computed tomography showed intense uptake in the right hilar lymph nodes and bones, whereas pulmonary nodules demonstrated only mild uptake. EBUS-TBNA of station 12R revealed adenocarcinoma positive for estrogen and progesterone receptors and negative for human epidermal growth factor receptor 2, confirming metastatic breast carcinoma. The patient was treated with abemaciclib plus fulvestrant, achieving durable disease control for 2.5 years. A 70-year-old woman who had undergone left mastectomy 27 years earlier presented with a dry cough. EBUS-TBNA of stations 4R and 7 confirmed metastatic breast carcinoma. She received nab-paclitaxel followed by trastuzumab deruxtecan, achieving disease control for 20 months. These cases demonstrate that even very late recurrences nearly three decades after surgery can achieve prolonged survival when appropriately diagnosed and optimally treated. EBUS-TBNA is a valuable and minimally invasive diagnostic tool for confirming such a late recurrence.
BACKGROUND: Rheumatoid arthritis (RA) is a complex autoimmune disease influenced by genetic and immune dysregulation. The causal roles of specific immune-related genes in RA pathogenesis remain incompletely understood. METHODS: We conducted a large-scale genome-wide association study (GWAS) meta-analysis across three RA cohorts to identify genome-wide significant risk loci. Causal genes and proteins were prioritized by integrating these results with cis-eQTL and pQTL datasets using two-sample Mendelian randomization (MR) and summary-data-based MR (SMR). Cell-type-specific expression was assessed using single-cell RNA sequencing (scRNA-seq), and gene expression in RA synovial tissue was validated via bulk RNA-seq. RESULTS: We identified 29 independent RA-associated loci, including 7 novel associations. Integrated MR and SMR analyses classified ERAP2 as a high-confidence causal gene, while SWAP70 and LTBR were deemed moderate-confidence causal genes. SWAP70 showed a protective association, whereas ERAP2 and LTBR were positively associated with RA risk. Single-cell transcriptomic analysis revealed cell-type-specific enrichment, with SWAP70 prevalent in B cells and LTBR in dendritic cells. Bulk RNA-seq confirmed the upregulation of SWAP70, RASGRP1, and RHOH in RA patients. CONCLUSION: Our integrative multi-omics framework reveals immune regulatory genes with potential causal roles in RA pathogenesis, highlighting ERAP2, SWAP70, LTBR, and other candidates as promising therapeutic targets.
肺纤维化（PF）是一种慢性、不可逆的间质性肺疾病。目前尚无能够完全治愈该疾病的有效治疗方法或药物。其发病机制仍不清楚。近年来，几位学者报告称，PF的主要原因是肺损伤后炎症反应失衡和异常修复。肺巨噬细胞作为体内的免疫细胞，在调节免疫反应和免疫耐受以及通过极化促进肺损伤修复方面发挥着重要作用。最近的研究强调了线粒体在肺纤维化中的重要性，其维护细胞内稳态和代谢作用，以及通过介导肺细胞内巨噬细胞极化影响肺纤维化进展的能力。然而，线粒体功能受损对巨噬细胞极化的调节作用在很大程度上仍不清楚。在本综述中，我们旨在总结线粒体功能障碍（包括线粒体动力学、活性氧生成增加、线粒体DNA（mtDNA）泄漏和炎性小泡激活）与驱动M1型和M2型巨噬细胞极化的关键机制之间的关联，并进一步探讨线粒体作为巨噬细胞极化关键控制中心的作用，这可能会带来针对和/或逆转疾病进展的新治疗方法。
本研究建立了一种在线固相萃取 - 超高效液相色谱 - 串联质谱法（online SPE - UPLC - MS/MS），用于快速筛查和测定原水和饮用水中的51种全氟和多氟烷基物质（PFASs）。向每个样品中添加甲酸铵和24种PFAS内标。混合后样品中甲酸铵浓度为2 mmol/L，PFAS内标含量在2.5至50 ng/L之间。每个样品通过0.22μm醋酸纤维素滤膜过滤，取5 mL等分试样注入并使用HLB在线固相萃取柱吸附，然后用2 mmol/L甲酸铵冲洗。以乙腈和2 mmol/L甲酸铵水溶液作为流动相。在BEH C色谱柱上进行梯度洗脱分离。采用电喷雾电离源负离子模式和多反应监测模式进行检测，以内标法进行定量。通过以原水和饮用水为基质测定51种PFASs的准确度和精密度对该方法进行验证。在各自范围内观察到良好的线性关系，相关系数（）>0.995。该方法的检测限（LODs，=3）和定量限（LOQs，=10）分别为0.03 - 1.5 ng/L和0.1 - 5.0 ng/L。PFASs的加标水平为1、10和50 ng/L，原水和饮用水样品的加标回收率分别为60.2% - 126.9%和60.4% - 122.6%，相应的相对标准偏差（RSDs，=6）分别为0.3% - 17.9%和0.4% - 17.7%。所建立的方法用于测定原水和饮用水中的PFAS残留，原水和饮用水中全氟烷基羧酸、全氟烷基磺酸和全氟烷基醚酸的检出率相对较高，含量分别为0.1 - 209.7 ng/L和0.1 - 63.6 ng/L。与离线固相萃取方法相比，所建立的方法所需样品量更少，从样品采集角度更方便，且内标使用量更低。它还具有分析速度快、灵敏度高和重现性好的特点。从在线富集到检测，仅需20分钟即可在ng/L水平测定51种PFASs。所建立的方法适用于原水和饮用水中各种类型PFAS的痕量测定，如全氟烷基羧酸、全氟烷基磺酸、全氟烷基醚酸、氟调聚物和氟烷基磺酰胺，从而有效提高水中全氟烷基物质的检测效率，具有重要的实际应用价值。
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related deaths worldwide. Despite advancements in antiviral therapies for hepatitis B (HBV) and hepatitis C (HCV), HCC incidence continues to rise due to metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, type 2 diabetes mellitus (T2DM), and emerging environmental and genetic risk factors. Understanding the evolving landscape of HCC pathogenesis is crucial for improved prevention and treatment strategies. OBJECTIVE: This review consolidates recent insights into established and emerging HCC risk factors, highlighting epidemiological trends, molecular mechanisms, and global disparities. It also explores novel therapeutic and preventive strategies aimed at reducing HCC burden and improving patient outcomes. METHODS: A systematic literature review was conducted, incorporating epidemiological studies, molecular research, and clinical trials on HCC risk factors. The interplay between viral hepatitis, metabolic syndrome, environmental toxins, and gut-liver axis dysregulation was analyzed to provide a comprehensive understanding of HCC development. RESULTS: While HBV and HCV remain significant drivers of HCC, metabolic risk factors-including MASLD, obesity, insulin resistance, and T2DM-are increasingly prevalent, particularly in Western populations. Environmental exposures such as aflatoxins, alcohol, smoking, and air pollution further exacerbate disease progression. Gut microbiota dysbiosis has also emerged as a key modulator of hepatic carcinogenesis. Advances in precision medicine, including tyrosine kinase inhibitors (sorafenib, lenvatinib), immune checkpoint inhibitors (nivolumab, pembrolizumab), and gut microbiota-targeted therapies, are transforming HCC management. Early detection is improving through biomarker-driven surveillance and AI-enhanced imaging techniques. CONCLUSION: The shifting epidemiology of HCC necessitates a multidisciplinary approach to prevention, early detection, and treatment. Integrating genomic profiling, biomarker-based risk stratification, and equitable healthcare access will be critical to reducing the global burden of HCC.
Long COVID affects multiple body systems, with the respiratory system being particularly vulnerable. This study aimed to analyze the lung ventilatory function and diffusion capacity of patients with severe SARS-CoV-2 pneumonia during a 24-month follow-up course. Ventilatory function and lung diffusion capacity were assessed 6, 12, 18, and 24 months after hospital discharge. Ventilatory parameters, Diffusion Lung Carbon Monoxide (DLCO), and KCO (Carbon Monoxide transfer coefficient) normalization were defined as achieving values > 80% predicted. A total of 222 patients admitted to the Intensive Care Unit (ICU) at ASST Spedali Civili di Brescia, Brescia, Italy, were enrolled. Among the 172 patients who completed the study, 140 (63%) achieved normalization of ventilatory parameters, DLCO, and KCO. The median time to recovery was 4.5 months, and the hazard ratio (HR) decreased by 2% for each year of age increase. The median time to normalize ventilatory parameters (VC, FVC, FEV, FEV1/FVC, TLC, and KCO) was 1.5 months, while the median time to alveolar volume (VA) normalization was 4.5 months. Male gender reduces the odds of normalization for FEV1/FVC and VA. The median time to DLCO normalization was 9 months, with HR reduced by 3.1% as each year of age increased and augmented by 226% in obese subjects. 24 months after severe COVID pneumonia, 14% of patients had persistent ventilatory and/or diffusive defects. Our study documented that male sex, age, and obesity impact the odds of normalization of ventilatory function and diffusive capacity. These findings underline the chronic nature of lung damage following severe COVID-19 pneumonia and the need for long-term follow-ups.
Despite substantial advances in surgical technique and immunosuppressive therapy, kidney transplantation continues to face limitations in long-term graft and patient survival. Increasingly, attention is shifting toward the exposome, the comprehensive profile of environmental, social, and biological exposures accumulated across the lifespan, as a critical yet under-investigated determinant of transplant outcomes. Evidence from diverse domains, including air pollution, heavy metal burden, dietary composition, infections, microbiome dynamics, psychosocial context, and digital health engagement, suggests that these factors exert profound effects on immune regulation, metabolic health, and graft integrity. By applying innovative approaches such as exposome-wide association studies, high-resolution biomonitoring, and multi-omics integration, researchers can begin to unravel complex exposure-disease relationships and identify previously unrecognized modifiable risks. Positioning the exposome within the kidney transplantation paradigm offers a pathway toward precision environmental medicine, enabling refined risk stratification, novel preventive strategies, and ultimately improved durability of both graft function and patient survival. However, exposome influences are highly individualized and interact in complex, non-additive ways; current evidence remains largely associative and hypothesis-generating rather than causal.
Aging trajectories are influenced by modifiable risk factors, and prior evidence has hinted that multilingualism may have protective potential. However, reliance on suboptimal health markers, small samples, inadequate confounder control and a focus on clinical cohorts led to mixed findings and limited applicability to healthy populations. Here, we developed biobehavioral age gaps, quantifying delayed or accelerated aging in 86,149 participants across 27 European countries. National surveys provided individual-level positive (functional ability, education, cognition) and adverse (cardiometabolic conditions, female sex, sensory impairments) factors, while country-level multilingualism served as an aggregate exposure. Biobehavioral factors predicted age (R = 0.24, r = 0.49, root mean squared error = 8.61), with positive factors linked to delayed aging and adverse factors to accelerated aging. Multilingualism emerged as a protective factor in cross-sectional (odds ratio = 0.46) and longitudinal (relative risk = 0.70) analyses, whereas monolingualism increased risk of accelerated aging (odds ratio = 2.11; relative risk = 1.43). Effects persisted after adjusting for linguistic, physical, social and sociopolitical exposomes. These results underscore the protective role of multilingualism and its broad applicability for global health initiatives.
The vernalization-mediated suppression of FLOWERING LOCUS C (FLC), a central flowering repressor, requires the coordinated action of non-coding RNA (COOLAIR/COLDAIR) and polycomb repressive complex 2 (PRC2)-mediated epigenetic silencing. However, the mechanistic integration of non-coding RNA transcription and PRC2 function during cold exposure remains poorly understood. In this study, we identify the R2R3-MYB transcription factor CDC5 as a critical regulator of vernalization-responsive flowering. Although the cdc5-2 mutant exhibits early flowering under normal conditions, it demonstrates delayed flowering after vernalization, along with defects in the low-temperature repression of FLC, non-coding RNA transcription, and H3K27me3 deposition. This study found that vernalization affects the binding of CDC5 to the FLC chromatin, thereby influencing the enrichment of RNA polymerase II on the FLC chromatin as well as the transcription of COOLAIR and COLDAIR. Furthermore, CDC5 physically interacts with PRC2 components, functioning as an important cofactor for H3K27me3 establishment at FLC. Our findings establish a regulatory paradigm where CDC5 coordinates non-coding RNA transcription with PRC2-mediated epigenetic silencing, thereby bridging transcriptional and epigenetic control of FLC during winter-induced flowering regulation.
INTRODUCTION: Metastatic melanoma carries a poor prognosis. Immune checkpoint inhibitors (ICIs) have improved outcomes, but responses remain variable, highlighting the need for simple prognostic biomarkers. Inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) reflect tumour burden and inflammation, though their clinical utility is unstandardised. METHODS: We retrospectively analysed 103 metastatic melanoma patients treated with anti-PD-1 monotherapy at two centres in Western Australia (2014-2020). Baseline NLR, PLR, and LDH were assessed within 30 days pre-treatment. Outcomes included clinical benefit, progression-free survival (PFS), and overall survival (OS). RESULTS: Poor ECOG performance status (PS ≥2) (RR 2.39, 95% CI 1.48-3.86) and elevated LDH (≥250 U/L) (RR 1.68, 95% CI 1.21-2.31) were associated with no clinical benefit ( < 0.001). NLR ≥5 predicted significantly worse OS (9.1 vs 28.2 months; HR 8.54, 95% CI 2.58-28.32; < 0.001). Elevated LDH predicted shorter OS (6.0 vs 50.3 months; HR 3.68, 95% CI 1.65-8.21; = 0.002) and PFS (19.0 months vs not reached; HR 2.51, 95% CI 1.37-4.72; = 0.004). CONCLUSION: ECOG PS ≥2 and elevated NLR were associated with no clinical benefit, while elevated NLR and LDH independently predicted poorer survival. These markers may serve as practical prognostic tools in metastatic melanoma treated with ICIs.
Annotating 3D LiDAR point clouds for perception tasks is fundamental for many applications e.g. autonomous driving, yet it still remains notoriously labor-intensive. Pretraining-finetuning approach can alleviate the labeling burden by fine-tuning a pre-trained backbone across various downstream datasets as well as tasks. In this paper, we propose SPOT, namely Scalable Pre-training via Occupancy prediction for learning Transferable 3D representations under such a label-efficient fine-tuning paradigm. SPOT achieves effectiveness on various public datasets with different downstream tasks, showcasing its general representation power, cross-domain robustness and data scalability which are three key factors for real-world application. Specifically, we both theoretically and empirically show, for the first time, that general representations learning can be achieved through the task of occupancy prediction. Then, to address the domain gap caused by different LiDAR sensors and annotation methods, we develop a beam re-sampling technique for point cloud augmentation combined with class-balancing strategy. Furthermore, scalable pre-training is observed, that is, the downstream performance across all the experiments gets better with more pre-training data. Additionally, such pre-training strategy also remains compatible with unlabeled data. The hope is that our findings will facilitate the understanding of LiDAR points and pave the way for future advancements in LiDAR pre-training.
BackgroundA subset of individuals with migraine are unsuitable for triptans due to intolerance, lack of efficacy, or contraindications. This phase 4 study assessed the efficacy and tolerability of a single 75-mg dose of rimegepant orally disintegrating tablet (ODT) for acute treatment of migraine in adults with documented triptan unsuitability.MethodsParticipants (aged ≥18 years with 4-14 migraine days per month) with documented history of (A) intolerance and/or lack of efficacy to ≥2 triptans or (B) contraindication to triptans were randomized (1:1) to rimegepant 75 mg ODT or placebo to treat a single migraine attack of moderate or severe pain intensity. Randomization was stratified by history of clinically relevant cardiovascular disease. The primary endpoint was the percentage of participants with migraine pain relief (no or mild pain) at 2 h post dose. Key secondary endpoints, tested using a hierarchal approach to control type 1 error, included the percentage of participants with migraine pain freedom at 2 h, rescue medication use within 24 h, return to normal function at 2 h, sustained return to normal function from 2-24 h and from 2-48 h, sustained migraine pain relief from 2-24 h and from 2-48 h, sustained migraine pain freedom from 2-24 h and from 2-48 h, and most bothersome symptom freedom at 2 h. Safety was assessed via adverse events (AEs) and laboratory tests.ResultsOverall, 585 participants (89.1% were female, mean age was 42.9 years) received study medication (rimegepant, = 295; placebo, = 290). Participants analyzed for efficacy (rimegepant, = 286; placebo, = 284) had documented failure to ≥2 triptans with ≥1 reason due to prior intolerance (30.5%) and/or ≥1 reason due to lack of efficacy (84.9%); 9.1% had a contraindication. Rimegepant demonstrated superiority over placebo for the primary endpoint of migraine pain relief at 2 h (55.9% vs 32.7%; difference [95% CI]: 23.2% [15.3-31.1%]; < 0.0001) and all 10 alpha-protected key secondary endpoints including pain freedom at 2 h (all ≤ 0.0005). AE rates were similar across treatments (12.5% vs 12.1%), with no severe AEs, serious AEs, or clinically significant laboratory test abnormalities reported in the rimegepant group.ConclusionsA single 75-mg dose of rimegepant ODT was efficacious and well tolerated for acute treatment of migraine in adults unsuitable for triptans. This first prospective trial of a gepant in this population supports calcitonin gene-related peptide antagonism as a valuable option when triptans are unsuitable.Trial RegistrationClinicaltrials.gov NCT05509400.
细胞间通讯对于胚胎的健康发育至关重要，然而细胞外空间在母胎对话中的作用和动态变化仍不清楚。此外，对于早期子宫内膜准备阶段以及胚胎进入子宫腔后母体和胚胎的代谢状态，我们了解甚少。利用人类体外共培养模型和细胞外囊泡（EV）特异性工具，我们在细胞间通讯的早期阶段动态追踪了胚胎细胞和子宫内膜细胞之间EV的分泌、摄取和加工过程。激素刺激改变了子宫内膜的分泌产物，产生了不同的EV群体。刺激后的EV（St-EV）在大小、分泌动态、摄取效率和代谢货物方面与未刺激的EV（NSt-EV）不同，它们选择性地包装与能量相关的代谢物和芳烃受体（AhR）配体。AhR抑制增加了球体附着，表明AhR信号通过调节子宫内膜环境来调控着床。此外，受子宫内膜和胚胎来源的EV影响的脂滴（LD）被胚胎细胞主动分泌和摄取，突出了它们在着床中的作用。EV不仅在胚胎和子宫内膜之间交换，还迅速被内化，影响线粒体活性、脂质代谢和细胞外基质重塑。EV衍生的mRNA在摄取后1小时内发生翻译，驱动细胞变化并增强胚胎附着。这些发现表明，在子宫内膜和胚胎之间调动的EV、细胞外代谢物和LD相互协作，促进胚胎附着和着床。这项研究增进了我们对胚胎-母体EV介导通讯的理解，并为研究其他生物学背景下EV介导的细胞间同时双向串扰提供了一个有价值的模型。
Micronutrients, though required in relatively small quantities by the human body, are essential for maintaining normal physiological functions and play a crucial role in the prevention and management of various diseases. Atherosclerosis (AS) is a common chronic inflammatory condition that often presents without obvious symptoms in its early stages but can lead to severe health issues such as acute myocardial infarction and stroke. The involvement of micronutrients in the early prevention and treatment of AS is critical, yet the efficacy of micronutrient supplementation for AS remains a subject of debate, and the specific mechanisms by which micronutrients influence AS are not fully understood. This study systematically summarises the mechanisms of micronutrients in AS and proposes that their roles in AS prevention and treatment should be properly understood and utilised. We further point out the limitations of current research and propose the future direction of systemic interventions based on the nutritional network, providing novel strategies for the prevention and treatment of AS.
BACKGROUND: Emerging evidence indicates that baseline use of certain concomitant drugs may affect the efficacy of immune checkpoint inhibitors (ICIs), including PD-1, PD-L1, and CTLA-4 inhibitors, in patients with cancer. However, most previous studies have evaluated individual drug classes in isolation, without considering potential interactions among multiple drugs. AIMS: This study aimed to evaluate the individual and combined effects of commonly prescribed concomitant drugs on the efficacy and safety of ICI-based therapy in patients with non-small cell lung cancer (NSCLC). METHODS: We conducted a retrospective analysis of 124 patients with advanced or recurrent NSCLC who received first-line ICI-based treatments at a single institution. Drug exposure at treatment initiation was assessed for proton pump inhibitors (PPIs), low-dose aspirin, non-steroidal anti-inflammatory drugs, statins, biguanides, antibiotics, and probiotics. Associations with progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) were analyzed using multivariate Cox regression models. RESULTS: PPI use was independently associated with shorter PFS (HR: 2.44, p < 0.001) and OS (HR: 2.04, p = 0.01). In contrast, low-dose aspirin use was independently associated with longer PFS (HR: 0.31, p = 0.01). Patients receiving both PPIs and aspirin had longer PFS and OS compared to those receiving PPIs alone, although the differences were not statistically significant. No consistent associations were observed for other drugs. The incidence of irAEs was not significantly affected by concomitant drug use. CONCLUSION: PPI use at baseline may be associated with reduced efficacy of ICI therapy in NSCLC patients. In contrast, low-dose aspirin use was independently associated with improved PFS, and may potentially mitigate the negative effects of PPIs. These findings underscore the importance of considering concomitant drug use when initiating ICI treatment. Prospective studies are needed to validate these observations and clarify underlying mechanisms.
背景/目的：光化性角化病（AK）是一种常见的皮肤疾病，与长期日晒和年龄增长有关。作为鳞状细胞癌的前驱病变，它作为预防目标具有临床相关性。虽然流行病学研究提出了各种风险因素，但因果推断往往受到混杂因素的限制。孟德尔随机化（MR）利用基因变异作为暴露因素的替代指标，有助于解决这一问题。本综述旨在概述已发表的将AK作为暴露因素或结局进行研究的MR研究。 材料与方法：我们对MEDLINE和Embase数据库从建库至2025年8月进行了系统的文献检索。符合条件的研究是采用MR研究AK与任何健康相关特征之间关联的原创性人体研究。 结果：纳入了8项研究，所有研究均使用汇总水平的全基因组关联数据进行两样本MR分析，主要来自欧洲人群。这些研究探讨了多种暴露因素，包括代谢特征、免疫细胞特征、皮肤病状况和日光敏感性。一项研究将AK作为暴露因素来评估其与皮肤癌的关联。大多数分析都是探索性的，没有任何暴露-结局对在一篇以上的论文中进行研究，这限制了结论的得出并排除了荟萃分析。 结论：关于AK的MR研究数量有限，但方法多样。尽管目前的证据基础较小，但本综述强调了MR如何应用于AK，并可能为未来的研究方向提供参考。
引言：调节性T细胞（Tregs）是免疫系统的关键调节因子，具有双重作用。Tregs在预防自身免疫方面具有保护作用，但也可表现出免疫抑制能力，使肿瘤能够逃避免疫识别和破坏，从而促进肿瘤进展。靶向Tregs以降低其免疫抑制能力为增强抗肿瘤免疫力和改善癌症治疗效果提供了一种有前景的策略。 涵盖领域：本综述探讨了Tregs在免疫系统中的作用，深入研究了它们对癌症和肿瘤进展的贡献，并重点介绍了靶向Tregs的治疗策略以及创新的递送系统。 专家观点：靶向肿瘤浸润调节性T细胞（Tregs）在癌症免疫治疗中是一种有前景但复杂的方法。然而，其成功受到自身免疫风险、肿瘤内递送效率低下以及患者免疫异质性的限制。整合生物标志物引导分层、单细胞和空间分析的精准策略可以提高选择性和治疗效果。识别肿瘤特异性Treg标志物以及区分稳定的、具有抑制作用的Tregs与更具可塑性或“脆弱”的亚群对于推进靶向免疫治疗至关重要。对肿瘤驻留Tregs进行部分功能重编程，而不是完全耗竭它们，提供了一种在保留外周免疫调节的同时削弱其抑制能力的策略，从而在不破坏耐受性的情况下促进局部抗肿瘤反应。
一名17岁的前精英级网球运动员因在长时间比赛中出现呼吸困难、疲劳和过度嗜睡而前来就诊。在网球比赛的局间休息时，他会变得嗜睡，以至于在比赛中有几次几乎昏厥。他白天并不过度嗜睡（爱泼沃斯嗜睡量表评分为6分），也没有报告任何非运动性昏厥或猝倒发作。他的病史因10岁时发生的一起严重道路交通事故而引人注目，当时需要进行气管插管并长时间通气14天。他的恢复过程因声门下狭窄而复杂化，后来通过喉气管重建手术进行了修复。13岁时，他接受了声门下球囊扩张术以及左侧杓状软骨切除术和杓间瘢痕带分离术。该患者被转介到专门的呼吸困难诊疗机构进行进一步评估。
Analytical chemistry experiments are essential foundational courses for first- and second-year undergraduates in chemistry， chemical engineering， materials science， and pharmacy. These courses provide students with principles and operational skills of analytical instruments， alongside training in qualitative and quantitative analysis. However， current teaching practices face three main challenges： （1） insufficient focus on instrumental analysis； （2） outdated experimental content misaligned with modern scientific advancements； and （3） limited experimental hours due to curriculum constraints. To systematically address these issues， we proposed educational objectives， competency goals， and course objectives based on outcome-based education （OBE） philosophy. Building upon this backdrop， a comprehensive experiment utilizing electrospray ionization mass spectrometry （ESI-MS） was designed to investigate non-covalent interactions between double-stranded deoxyribonucleic acid （DNA） and naringin， a flavonoid natural drug. The experiment is offered to third-year undergraduate students as an elective. In the implementation process， a blended teaching model combining online and offline methods is adopted. The experimental teaching process is structured into three stages： pre-class preparation， in-class practice， and post-class review. Pre-class tasks include literature reviews， artificial intelligence （AI）-assisted summaries， pre-lab report writing and group discussions. This part is mainly conducted online without occupying class hours. During in-class practice， students synthesized double-stranded DNA by annealing single-stranded DNA （heated at 90 ℃ for 15 min， followed by slowly cooling to （25±1） ℃ overnight and stored at -20 ℃）. The resulting DNA was incubated with naringin at a 1∶4 concentration ratio in ammonium acetate for 15 min. The mixture was then analyzed by ESI-MS on a linear ion trap mass spectrometer. Both negative and positive ion modes were employed with optimized parameters encompassing spray voltage， capillary voltage， tube lens offset， heated capillary temperature， nitrogen sheath and auxiliary gas flows. Data acquisition involved 150 averaged scans using Xcalibur software. ESI-MS under negative ion mode was used to detect the non-covalent complexes. Secondary mass spectrometry （MS/MS） of 5-charged complex ions showed guanine base loss and minimal drug dissociation， indicating strong non-covalent interactions. In positive ion mode， MS yielded lower complex abundance， likely due to charge redistribution during ionization. The results reveal that naringin binds DNA predominantly via stacking and hydrogen bonding， with a 1∶1 stoichiometry （relative abundance 60.91%） and a relative binding affinity of 39.20%. Post-class， students were required to process data， write formal lab reports， create presentations for defense， and design a feasible extension experiment. At the same time， a grading system was established for these three phases. The evaluation system emphasizes formative assessment， focusing on aspects such as compliance with experimental procedures， workflow efficiency， safety measures， teamwork， problem-solving skills， and experimental data handling. This multidimensional approach ensures equitable grading and pedagogical validity. This curriculum bridges research and education by introducing MS-based non-covalent interaction analysis into undergraduate curricula. The extended experimental design permits curricular expansion of the course. Some students designed structure-activity relationship （SAR） investigations of flavonoids （e.g.， naringenin vs. naringin）， revealing the role of glycosylation in DNA binding affinity. In addition， students designed a fluorescence quenching spectroscopy experiment， demonstrating interdisciplinary problem-solving skills. It closely aligns with the OBE philosophy， a student-centered framework that fosters innovation. Feedback indicates that 96% of undergraduates perceived significant improvements in their research capabilities and interdisciplinary integration skills. However， some challenges were noted， including students' initial hesitancy with advanced instrumentation and limited instruments and drugs. We plan to improve teaching in these areas in the future. In conclusion， this OBE-driven experiment successfully modernized analytical chemistry education in mass spectrometry applications by integrating theoretical knowledge with cutting-edge research skills. The project establishes a comprehensive teaching platform and constructs a holistic teaching system， featuring operational safety and accessibility while offering strong demonstrative value in fostering interest， extensibility and innovation. The experiment not only enriches the content of analytical chemistry courses， inspires students' research interests， and hones their critical thinking abilities， but also enhances their safety awareness and lays a solid foundation for future research endeavors， thus achieving the comprehensive educational goals of experimental teaching.
背景：脉冲射频（PRF）是一种神经调节技术，已广泛应用于疼痛管理，最近作为传统射频消融（RFA）的非破坏性替代方法受到关注，尤其是在外周神经性疼痛方面。在过去十年中，PRF因其在各种慢性疼痛病症中的潜在益处而受到越来越多的研究。 目的：本综述旨在总结PRF在慢性疼痛管理中的基本原理、作用机制、现有证据及临床应用。 研究设计：叙述性综述。 方法：使用PubMed、Scopus和谷歌学术对截至2024年发表的关于PRF的研究进行全面文献检索。关键词包括“脉冲射频”“脉冲式射频”“脉冲RF”和“脉冲RF”。纳入了相关的病例报告、病例系列、观察性研究、随机对照试验（RCT）、荟萃分析、系统评价和综述文章。 结果：PRF在管理各种神经性疼痛病症方面显示出有前景的结果，尤其是神经根性疼痛和带状疱疹后神经痛。临床证据也支持其在三叉神经痛、枕神经痛、颈源性头痛、慢性偏头痛、股外侧皮神经痛、阴部神经痛和尾骨痛以及肌肉骨骼病症如膝关节骨关节炎和肩部疼痛方面的有效性。包括关节内和经皮PRF在内的新兴应用已显示出潜在益处。调整PRF设置，如高压PRF、延长持续时间PRF和脉冲剂量射频，可能会进一步提高治疗效果，不过还需要更多验证。 局限性：本综述本质上是叙述性的，而非系统分析。纳入的研究质量各异，从病例报告到系统评价不等，这取决于每种病症的研究可得性。此外，PRF方法、治疗参数和结局测量存在显著异质性，缺乏标准化方案导致临床结局存在变异性。 结论：PRF是一种通过电场调节疼痛的安全、非消融性技术。它在神经性疼痛，尤其是神经根性疼痛和带状疱疹后神经痛方面已显示出有效性。PRF能以最小风险提供长期疼痛缓解，不过还需要进一步研究来优化其参数并扩大其在慢性疼痛管理中的应用。
背景：膝关节骨关节炎（KOA）是一种常见的退行性疾病，会导致老年人出现严重残疾。超声引导下脉冲射频（UG-PRF）已被证明是一种非药物、侵入性较小的替代治疗方法，可减轻严重的慢性关节疼痛。 目的：确定使用UG-PRF治疗KOA疼痛是否能改善该疾病患者的短期和长期临床结局。 研究设计：系统评价和荟萃分析。 方法：在PubMed、MEDLINE、Embase和Cochrane图书馆中，对从这些数据库建立到2024年7月11日发表的相关研究进行了全面检索。根据预先定义的纳入标准选择评估UG-PRF在KOA患者中有效性的研究，该标准要求仅使用超声引导进行PRF治疗。数据提取和合成采用随机效应模型分析与疼痛减轻和身体功能改善相关的结局。我们使用推荐分级评估、制定和评价（GRADE）框架来评估证据的稳健性。 结果：共识别出658条记录，8项研究涉及688例患者纳入荟萃分析。UG-PRF与治疗后1个月（MD = -14.40；95%CI [-19.61, -9.19]；P < 0.01；GRADE：高）、3个月（MD = -7.83；95%CI [-10.38, -5.27]；P < 0.01；GRADE：高）、6个月（MD = -5.64；95%CI [-7.62, -3.66]；P < 0.01；GRADE：高）和12个月时视觉模拟量表（VAS）评分的显著降低相关（MD = -1.08；95%CI [-1.94, -0.23]；P < 0.01；GRADE：中等），且所有这些结果均表现出高度异质性（I²>90%；P < 0.01）。同样，次要结局与治疗后1个月（MD = -20.71；95%CI [-27.43, -13.99]；P < 0.01；GRADE：高）和3个月时WOMAC评分的显著改善相关（MD = -22.09；95%CI [-31.33, -12.84]；P < 0.01；GRADE：高），异质性较高（1个月时I² = 77%，3个月时I² = 89%；P < 0.01）。敏感性分析证实了结果的稳健性，但12个月时的VAS评分除外。亚组分析表明不同治疗靶点之间无显著差异（P > 0.05）。1个月和6个月时VAS结局提示存在发表偏倚，但失效安全分析（使12个月效应无效需要N = 86）和修剪填充法维持了研究结果的显著性。 局限性：WOMAC评分报告不完整限制了研究结论的稳健性，尤其是在长期疗效方面。此外，目前关于脉冲射频消融（RFA）后神经再生机制的数据有限，限制了对导致12个月时疼痛复发因素的全面理解。 结论：UG-PRF可有效减轻KOA疼痛并在短期内改善功能，治疗后6个月内观察到显著益处。然而，镇痛效果在12个月时减弱，突出了对该技术长期疗效和潜在机制进行进一步研究的必要性。荟萃分析支持将UG-PRF作为一种安全、微创的选择应用于≥40岁（平均62.1±9.4岁）成人KOA疼痛的管理，尽管持续缓解疼痛可能需要额外的干预措施。
BACKGROUND: The safety, effectiveness and cost-effectiveness of mitral valve repair via thoracoscopically guided minithoracotomy compared with conventional median sternotomy (Sternotomy) in patients with degenerative mitral valve regurgitation is uncertain and widely debated. OBJECTIVES: To determine if Mini was more effective than Sternotomy in terms of physical functioning and associated return to usual activities and was cost-effective compared with Sternotomy. DESIGN: A pragmatic, multicentre, expertise-based, superiority, randomised trial. PARTICIPANTS: Adults with degenerative mitral valve regurgitation undergoing mitral valve repair surgery. SETTING: Ten tertiary care institutions in the United Kingdom. INTERVENTION: Mini or Sternotomy mitral valve repair performed by an expert surgeon. BLINDING: Primary outcome measure [Short Form 36-item Health Survey, version 2 (SF-36v2) physical functioning score] was measured by an independent assessor, blinded to allocation. Echocardiographic findings were measured in a core laboratory, blinded to allocation. OUTCOME MEASURES: Primary outcomes were physical functioning and associated return to usual activities measured by change from baseline in SF-36v2 physical function domain at 12 weeks following index surgery. The primary economic measure was incremental cost per quality-adjusted life-year over the year following surgery. Secondary outcomes included recurrent mitral regurgitation grade, physical activity and quality of life measured at time points to 1 year. Safety outcomes included death, repeat mitral valve surgery or heart failure hospitalisation up to 1 year. RESULTS: Between November 2016 and January 2021, 330 participants were randomised; 166 to Mini and 164 to Sternotomy. Of these, 309 underwent surgery and 294 reported the primary outcome. Thirty per cent were female. At 12 weeks, mean difference between groups in the change in SF-36v2 physical function -scores was 0.68 (95% confidence interval -1.89 to 3.26). Valve repair rates (96%) were similar in both groups. Echocardiography demonstrated mitral regurgitation severity as none or mild for 92% of participants at 1 year in both groups. The composite safety outcome occurred in 5.4% (9/166) of Mini and 6.1% (10/163) of Sternotomy participants at 1 year. On average, Mini was more costly £29,424 (95% confidence interval 26,909 to 31,940) versus £27,397 (95% confidence interval 25,172 to 29,620) and more effective 0.81 quality-adjusted life-years (95% confidence interval 0.78 to 0.84) versus 0.78 (95% confidence interval 0.75 to 0.81) than Sternotomy. The adjusted incremental cost-effectiveness ratio was £74,863 per quality-adjusted life-year for the comparison between Mini and Sternotomy. Mini has a probability of < 50% of being cost-effective at the range of willingness-to-pay values considered. LIMITATIONS: To minimise bias, SF-36v2 and all echocardiographic measures were independently assessed by personnel blinded to allocation. Expertise-based randomisation was important to address the limitations of previous studies; however, it is possible that it may have introduced potential confounders. CONCLUSIONS: Mini is not superior to Sternotomy in recovery of physical function at 12 weeks. Mini achieves high rates and quality of valve repair and has similar safety outcomes at 1 year to Sternotomy. The balance of probabilities favoured Sternotomy as the preferred surgical procedure in the base-case analysis over the range of willingness-to-pay values society might consider worthwhile for a quality-adjusted life-year. . Results provide high-quality evidence to inform shared decision-making and treatment guidelines. FUTURE WORK: Work is ongoing to disseminate findings and influence guidelines; patients have consented to longer-term follow-up. From an economics perspective, the currently available evidence shows that further research into patient preferences is important to inform the choice of surgical procedure. TRIAL REGISTRATION: This trial is registered as ISRCTN 13930454. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/192/110) and is published in full in ; Vol. 29, No. 55. See the NIHR Funding and Awards website for further award information.
BACKGROUND: Pharmacists often identify symptoms during medication reviews that may or may not be adverse medicine events (AMEs), but these have not yet been quantified. This study aimed to quantify the extent of these symptoms representing AMEs by comparing them with a known set of AMEs and symptoms listed in existing medicine-related symptom assessment tools. METHOD: A secondary analysis of data from the Reducing Medicine-Induced Deterioration and Adverse Reactions (ReMInDAR) trial was conducted. Adverse events or symptoms were extracted from pharmacists' progress notes, and their frequency and Medicine Likeliness Ratio (probability of being medicine-related) were determined. Pharmacist-recorded adverse events were compared to a subset of AMEs identified by a clinical panel, and agreement was assessed using Cohen's κ. Pharmacist-recorded adverse events or symptoms were also compared with those in the PHArmacotherapeutical Symptom Evaluation-20 questions (PHASE-20), and the Patient Reported Outcome Measure, Inquiry into Side Effects (PROMISE). RESULT: Pharmacists recorded 3.1 symptoms per person; 68.8% of the symptoms had a medicine-likeness ratio ≥ 40.0%. The most prevalent medicine-related events recorded by pharmacists included falls (13.6%), swelling (7.1%), constipation (5.4%), nocturia (4.2%), shortness of breath (4.0%), bleeding (4.0%), nausea and vomiting (3.1%), dizziness (2.8%), drowsiness (2.3%), and rash (2.0%). Of the subset of 273 AMEs identified by the panel, 14.7% corresponded to adverse events recorded by pharmacists. The agreement between pharmacist-recorded and panel-identified AMEs was significant but low (κ = 0.074, p = 0.008). The majority of frequently detected medicine-related symptoms were in PROMISE (56.4% of recorded AMEs) and PHASE-20 (81.3% of recorded AMEs). CONCLUSION: While pharmacists recorded a notable number and variety of adverse events or symptoms, underreporting and discrepancies were still observed. As items in the PHASE-20 aligned with most recorded events, further research is warranted to determine if it can help pharmacists in improving the detection and monitoring of AMEs. PLAIN LANGUAGE SUMMARY: Pharmacists often notice symptoms during medication reviews that may or may not be caused by the medicines. This study aimed to measure how often the symptoms reported by pharmacists were side effects of the medicines in use. We looked at data from a previous trial in aged care homes and reviewed the notes pharmacists wrote about possible symptoms or side effects. We then compared these to a list of known medicine-related problems identified by medical experts. On average, pharmacists recorded about three symptoms per person, and more than two-thirds of these were likely to be related to medicines. The most common side effects or symptoms included falling, swelling, difficulty passing stools, needing to urinate at night, feeling short of breath, bleeding, feeling nausea or vomiting, feeling dizzy, feeling sleepy, and skin rashes. However, only a small number of the problems recorded by pharmacists matched the expert-reviewed list. Most of the symptoms reported by pharmacists were also included in PHASE-20 symptom checklists, which is designed to help identify medicine-related symptoms. This suggests that this tool might support pharmacists to detect and track medicine-related problems. Further research is needed to explore how best to use this tool in practice.
P3是视觉识别的一种心理生理指标，与目标检测、记忆编码和动作选择有关。然而，对于诸如面孔等刺激而言，计算呈现的刺激与所表征目标的相似度是一项定义不明确的任务，因为潜在相关特征众多。我们之前提出，当前的神经网络可以在客观的物理层面和主观的认知层面定义刺激，从而计算相似度。在面孔身份识别任务中，这种相似度——或者说感知/表征距离倒数——线性地预测了P3波幅。然而，这并未明确距离与P3的关系反映的是自上而下的任务相关识别，还是自下而上的家族相似性重复效应。因此，我们重新审视了该范式，但纳入了与陪衬物精确匹配的呈现：在与目标匹配的距离上采样并呈现的任务无关图像。结果表明，在N170潜伏期出现了目标与其他图像之间的早期二元区分，而对于P3，发现了明显的距离效应：距离越大，P3越小。目标相关性的效应与感知陪衬物的效应明显可分离，感知陪衬物根本不影响N170，对P3仅表现出微小的二元效应，与特定距离无关。综上所述，我们认为在视觉工作记忆中保持目标涉及一种早期的自上而下机制，该机制评估做出感知决策的证据。在此机制之后不久，会有一个更被动的自下而上过程，该过程会更新刺激身份的概率和表征。
Menopause leads to loss of cardiovascular and renal protection, and while hormone therapy offers benefits, its efficacy may depend on health status at menopause onset. We hypothesized that preexisting hypertension blunts the renal, cardiac, and vascular effects of Estradiol (E2). Female Long-Evans rats were ovariectomized (OVX) at 46 weeks to model menopause and received either E2 or vehicle, and some were infused with angiotensin II (ANG; 700 ng/kg/min) 4 weeks before OVX. Blood pressure (BP) was measured by tail cuff, renal function by urine collection, collagen deposition by histology, and mRNA expression in aorta and kidney by droplet digital PCR. ANG increased BP and proteinuria (p = 0.02), water intake (p < 0.001), urinary output, heart weight, and aortic NOX4 (p < 0.01), confirming hypertension and oxidative stress. E2 reduced body weight (p = 0.02), increased bone mineral content (p = 0.01), and prevented uterine atrophy (p < 0.001), confirming E2 treatment. While E2 attenuated cardiac hypertrophy (p = 0.004), it exacerbated proteinuria, decreased GFR (p < 0.05), and failed to reduce aortic NOX4. ANG did not affect tissue estrogen receptor expression, while E2 showed tissue-specific regulation of GPER and ERα. In this hypertensive OVX model, E2 failed to protect renal and vascular damage, emphasizing the importance of cardiovascular health at menopause when considering hormone therapy.
背景：帕妥珠单抗德曲妥珠单抗（HER3-DXd）是一种新型的靶向HER3的抗体药物偶联物，HER3在转移性乳腺癌的中枢神经系统转移灶中过表达。我们旨在评估HER3-DXd在新诊断或局部治疗后进展的转移性乳腺癌和脑转移患者中的活性和安全性。 方法：TUXEDO-3试验是一项多队列、多中心、开放标签、单臂2期试验，在西班牙和奥地利的6个地点进行。在该队列（3个队列中的第1个）中，我们纳入了年龄≥18岁、组织学确诊为乳腺癌且有影像学记录的转移性疾病、新诊断的脑转移或局部治疗后进展的脑转移、至少有一个≥10mm的可测量脑病灶且东部肿瘤协作组体能状态为0-2的成年患者。患者每3周静脉注射一次HER3-DXd 5.6mg/kg。根据神经肿瘤脑转移反应评估标准，主要终点的阈值是至少15%的患者有颅内反应。在全分析人群（即所有接受至少一剂HER3-DXd的参与者）中进行活性和安全性分析。该试验（ClinicalTrials.gov标识符：NCT05865990和欧盟临床试验注册号：2023-503251-10-00）正在进行，不再招募患者。 结果：在2023年12月12日至2024年7月8日期间，招募了21名可评估的女性患者（5名激素受体阳性乳腺癌患者、9名HER2阳性乳腺癌患者和7名三阴性乳腺癌患者）。15名（71%）为白人；其余6名患者未报告种族。晚期疾病既往治疗线数的中位数为4（四分位间距2-4）。中位治疗持续时间为3.0个月（四分位间距0.7-7.7），中位随访时间为4.9个月（四分位间距3.6-8.5）。21名患者中有5名（24%）达到主要终点，有颅内反应，无论乳腺癌亚型如何（总缓解率23.8%，95%CI 8.2-47.1）。最常见的3级或更严重的治疗中出现的不良事件是3名（14%）患者出现中性粒细胞减少，2名（10%）患者出现腹泻，各有1名（5%）患者出现乏力和呕吐。6名（29%）患者发生严重不良事件，1名（5%）患者出现与研究治疗相关的2级肺炎。未报告与治疗相关的死亡。 解读：HER3-DXd在转移性乳腺癌和活动性脑转移患者中显示出有前景的临床活性，并可为这种情况下提供一种新的治疗选择。 资助：第一三共株式会社和默克夏普&多姆公司。
新生儿惊厥是重要的神经学事件，需要尽早识别和处理以预防不良影响。队列比较和基于规则的模型无法考虑脑电图（EEG）信号的细微差别，并且需要大量时间来分析和解释原始的新生儿EEG信号。基于人工智能的方法的最新进展表明了完成此类任务的可能性，但它们仍然存在一些缺点，例如需要大量带标签的数据集、计算过程效率低下以及对噪声敏感，这些都阻碍了其临床应用。在这方面，为了克服这些限制，引入了名为基于自适应原型的细微瞬态模式感知变压器（APSTPT）的新多组件框架，用于新生儿惊厥检测、分类及其严重程度量化。预处理是第一阶段，在该阶段去除噪声和伪迹，仅放大相关的脑信号。接下来是特征提取，其中使用功率谱密度和锁相值组件来识别重要的频谱和相位同步特征。通过跨通道协方差注意力对这些方面进行微调，以处理通道间的依赖性。使用原型学习对原型进行实时自适应调整，使得惊厥类型的分类更好且更具动态性，因为能够捕捉到信号更细微的细节。此外，多尺度熵分析测量不同时间尺度上的信号复杂性，并分别将惊厥的严重程度准确地区分为轻度、中度和重度病例。这种结构化方法能够在时间序列上准确分离惊厥事件，并且根据不同数据集的特征具有灵活性。使用TUH EEG语料库和Zenodo数据集进行的实验证明了所提出框架的有效性，分类准确率为99.74%，严重程度评估准确率为98.87%，高于先前的方法。因此，APSTPT框架无论窗口长度和不同数据集的条件如何，都表现出稳定的性能，显示出其在临床环境中实时实施的灵活性。
