2025年 · 第138卷第13期

脓毒症是一种威胁生命的疾病，主要由感染引发，如果不及时干预，可迅速进展为多器官功能障碍综合征（MODS）。长期以来，肠道被认为是脓毒症和MODS发病机制的关键驱动因素。^[1]在严重脓毒症和脓毒性休克中，肠道通常是最先受损和最后恢复的器官，使患者易患肠道生态失调和功能障碍，这进一步加速了脓毒性MODS。^[2]越来越多的证据强调了肠道微生物群在脓毒症病理生理学中的关键作用，因为脓毒症诱导的微生物组成破坏可能导致器官衰竭。^[1]这种相互作用表明肠道微生物群失调和脓毒症进展之间存在潜在的恶性循环。^[3]在这篇社论中，我们探讨了肠道微生物群在脓毒症中的作用和潜在的治疗干预。

急性呼吸窘迫综合征（ARDS）的治疗已经取得了实质性进展，从其首次描述到其定义和管理指南的最新更新。^[1,2]然而，关于最佳治疗策略仍然存在很大的不确定性。这些差距凸显了重新评估临床实践和启动创新研究以应对已解决的挑战的必要性。

脓毒症是显著的全球健康负担，具有显著的发病率和死亡率。宿主对感染的免疫反应在脓毒性并发症的发展中似乎是一把双刃剑。尽管适当的免疫应答对于病原体清除至关重要，但过度或失调的应答可导致免疫失调和随后的器官损伤。免疫应答可以根据个体患者特征、病原体类型、感染部位和共存因素而变化。这种异质性对免疫状态的临床评估提出了实质性的挑战。

心力衰竭是一种日益严重的流行病，因为它影响着全球约6400万人，^[1]它每年的发病率为200万例，其中三分之一在中国。^[2,3]其中，10%进展为终末期疾病，心脏移植仍然是唯一的治疗方法。尽管有这一迫切需求，但巨大的差异仍然存在：全世界每年仅进行6000例心脏移植，<500例儿科病例，从而导致1:10 0的惊人供需缺口（国际心肺移植学会，2023年注册）。^[2]这种严重的差异导致每年超过30%的等待名单上的患者死亡<1%接受移植——需要在供体优化和受体特异性治疗策略方面进行紧急创新。

副空化子宫畸形（ACUM）是一种罕见的梗阻性子宫异常，目前仍知之甚少，给临床治疗带来了挑战。其发病机制假设涉及通常在圆韧带附件附近的导管苗勒管组织的复制和持续存在，可能与gubernaculum功能障碍有关。ACUM由Acién的系统专门分类，尽管罕见的变体需要持续的国际研究来完善分类框架。该共识旨在为ACUM的病理生理学、术语、临床表现、诊断和治疗制定良好的临床实践建议。一个由中国和欧洲专家组成的工作组在获得欧洲妇科内镜学会批准后，根据现有的最佳证据和专家意见制定了建议。ACUM患者表现为典型症状，如痛经和性交困难，以及非典型症状，包括胃肠道和全身性骨盆疼痛。诊断标准包括圆韧带附近的前外侧子宫肌层中孤立的空化病变，内衬子宫内膜组织并充满出血性液体，被子宫肌层纤维同心取向的子宫肌层外套膜包围，通常与正常子宫腔相关。通过超声波和磁共振成像进行诊断是最准确的。ACUM的手术切除被认为是提供接近完全症状解决的决定性治疗，在可能的情况下，应首选微创方法。手术的时间和尝试怀孕前的间隔时间仍不清楚。术后分娩方式根据子宫肌层受累程度个体化。目前的共识总结了ACUM的现有证据，为其管理提供了良好的临床实践建议。在ACUMs的理解和管理方面存在的差距，突出了进一步研究以指导临床决策的必要性。

Colorectal cancer (CRC), a major global health concern, necessitates innovative treatments. Chimeric antigen receptor (CAR) T cells have shown promises, yet they grapple with challenges. The spotlight pivots to the rising heroes: CAR natural killer (NK) cells, offering advantages such as higher safety profiles, cost-effectiveness, and efficacy against solid tumors. Nevertheless, the specific mechanisms underlying CAR NK cell trafficking and their interplay within the complex tumor microenvironment require further in-depth exploration. Herein, we provide insights into the design and engineering of CAR NK cells, antigen targets in CRC, and success in overcoming resistance mechanisms with an emphasis on the potential for clinical trials.

In recent years, growing evidence indicates that the nervous system plays an indispensable role in tumor development and metastasis. Elucidating crosstalk between the nervous system and tumor progression has thrived as a hot topic and a new direction for understanding cancer pathogenesis. Notably, many novel discoveries have suggested that neurotransmitter receptors (NRs) are not only widely expressed in cancer cells, but also play key roles in regulating cancer initiation and progression by diverse approaches. In this review, we summarized the latest advance in cancer neuroscience, especially emphasizing the important roles of different NRs in cancer development and prevention. The exemplary studies presented herein illustrate the emerging view that NRs are profoundly influential, manifested in tumor growth, apoptosis, angiogenesis, metastasis, resistance to drugs, and participate in the formation of neural–cancer interactions. In addition, NRs also regulate cellular metabolic processes and tumor microenvironment (TME) remodeling. More importantly, numerous basic and clinical studies have suggested that NRs may be potential targets for cancer treatments, and corresponding agonists or antagonists have been identified effectively in controlling tumor growth and metastasis. In conclusion, NRs are emerging as novel targets for anti-cancer drug exploration and clinical cancer treatments, while trying to uncover deeper mechanisms and connections between NRs and cancer is of high clinical significance and translational value.

Definitive treatment of lung cancer with radiotherapy is challenging, as respiratory motion and anatomical changes can increase the risk of severe off-target effects during radiotherapy. Online adaptive radiotherapy (ART) is an evolving approach that enables timely modification of a treatment plan during the interfraction of radiotherapy, in response to physiologic or anatomic variations, aiming to improve the dose distribution for precise targeting and delivery in lung cancer patients. The effectiveness of online ART depends on the seamless integration of multiple components: sufficient quality of linear accelerator-integrated imaging guidance, deformable image registration, automatic recontouring, and efficient quality assurance and workflow. This review summarizes the present status of online ART for lung cancer, including key technologies, as well as the challenges and areas of active research in this field.

The choice of unicompartmental knee arthroplasty (UKA) vs. total knee arthroplasty (TKA) in the surgical treatment of knee osteoarthritis (KOA) remains controversial. This study aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the clinical results of UKA and TKA for treating unicompartmental KOA.

PubMed, Embase, and the Cochrane Library were systematically searched for articles published up to January 2, 2023. The literature was rigorously screened to include only RCTs comparing UKA and TKA for unicompartmental KOA. A systematic review and meta-analysis were performed to calculate the mean difference (MD), relative risk (RR), and 95% confidence interval (CI) according to the Cochrane standards.

Thirteen publications involving 683 UKAs and 683 TKAs were analyzed. Except for one study with a follow-up period of 15 years, all outcome measures reported were within 5 years of follow-up. Meta-analysis showed better knee recovery (MD: 1.23; 95% CI: 1.01–1.45; P <0.001), greater knee function (MD: 1.78; 95% CI: 0.34–3.22; P = 0.020), less pain (MD: 0.75; 95% CI: 0.43–1.06; P <0.001), and better health status (MD: 3.75; 95% CI: 0.81–6.69; P = 0.010) after UKA than TKA. However, considering the minimal clinically important difference values for these variables, the findings were not clinically relevant. Moreover, UKA patients had fewer complications (RR: 0.59; 95% CI: 0.45–0.78; P <0.001) and shorter hospital stays (MD: –0.89; 95% CI: –1.57 to –0.22; P = 0.009) than did TKA patients. There were no statistically significant differences in terms of postoperative range of movement, revision, failure, operation time, and patient satisfaction.

In terms of clinical efficacy, there was no obvious advantage of UKA over TKA in the surgical treatment of knee OA when considering the minimal clinically important difference. The main advantage of UKA over TKA is that it leads to fewer complications and a shorter length of hospital stay. It is ideal to perform prospective studies with longer follow-up periods to fully evaluate the long-term efficacy and safety of the two procedures in the future.

Severe stroke has high rates of mortality and morbidity. This study aimed to investigate the clinical course, causes of worsening, and outcomes of severe ischemic stroke.

This prospective, multicenter cohort study enrolled adult patients admitted ≤30 days after ischemic stroke from nine hospitals in China between September 2017 and December 2019. Severe stroke was defined as a score of ≥15 on the National Institutes of Health Stroke Scale (NIHSS). Clinical worsening was defined as an increase of 4 in the NIHSS score from baseline. Unfavorable functional outcome was defined as a modified Rankin scale score ≥3 at 3 months and 1 year after stroke onset, respectively. We performed Logistic regression to explore baseline features and reperfusion therapies associated with clinical worsening and functional outcomes.

Among 4201 patients enrolled, 854 patients (20.33%) had severe stroke on admission. Of 3347 patients without severe stroke on admission, 142 (4.24%) patients developed severe stroke in hospital. Of 854 patients with severe stroke on admission, 33.95% (290/854) experienced clinical worsening (median time from stroke onset: 43 h, Q1–Q3: 20–88 h), with brain edema (54.83% [159/290]) as the leading cause; 24.59% (210/854) of these patients died by 30 days, and 81.47% (677/831) and 78.44% (633/807) had unfavorable functional outcomes at 3 months and 1 year respectively. Reperfusion reduced the risk of worsening (adjusted odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.12–0.49, P <0.01), 30-day death (adjusted OR: 0.22, 95% CI: 0.11–0.41, P <0.01), and unfavorable functional outcomes at 3 months (adjusted OR: 0.24, 95% CI: 0.08–0.68, P <0.01) and 1 year (adjusted OR: 0.17, 95% CI: 0.06–0.50, P <0.01).

Approximately one-fifth of patients with ischemic stroke had severe neurological deficits on admission. Clinical worsening mainly occurred in the first 3 to 4 days after stroke onset, with brain edema as the leading cause of worsening. Reperfusion reduced the risk of clinical worsening and improved functional outcomes.

Epidemiological data on chronic diarrhea in the Chinese population are lacking, and the association between obesity and chronic diarrhea in East Asian populations remains inconclusive. This study aimed to investigate the prevalence of chronic diarrhea and its association with obesity in a representative community-dwelling Chinese population.

This cross-sectional study was based on a multistage, randomized cluster sampling involving 3503 residents aged 20–69 years from representative urban and rural communities in Beijing. Chronic diarrhea was assessed using the Bristol Stool Form Scale (BSFS), and obesity was determined based on body mass index (BMI). Logistic regression analysis and restricted cubic splines were used to evaluate the relationship between obesity and chronic diarrhea.

The standardized prevalence of chronic diarrhea in the study population was 12.88%. The average BMI was 24.67 kg/m². Of all the participants, 35.17% (1232/3503) of participants were classified as overweight and 16.13% (565/3503) as obese. After adjustment for potential confounders, individuals with obesity had an increased risk of chronic diarrhea as compared to normal weight individuals (odds ratio = 1.58, 95% confidence interval: 1.20–2.06). A nonlinear association between BMI and the risk of chronic diarrhea was observed in community residents of males and the overall participant group (P = 0.026 and 0.017, respectively).

This study presents initial findings on the prevalence of chronic diarrhea among residents of Chinese communities while offering substantiated evidence regarding the significant association between obesity and chronic diarrhea. These findings offer a novel perspective on gastrointestinal health management.

Regulatory dendritic cell (DCreg) subset exhibits a unique capacity for inducing immune tolerance among the variety subsets of dendritic cells (DCs) within gut-associated lymphoid tissues (GALTs). Fms-like tyrosine kinase 3 ligand (FLT3L) is involved in the differentiation of DCregs and the subsequent expansion of regulatory T-cells (Tregs) mediated by DCregs, though the precise mechanism remains poorly understood. This study aimed to explore the expansion mechanism of Treg induced by DCreg and the role of FLT3L in this process.

DCregs were distinguished from other DC subsets isolated from GALTs of BALB/c mice through a mixed lymphocyte reaction assay. The functions and mechanisms by which FLT3L promoted Treg expansion via DCregs were investigated in vitro through co-culture experiments involving DCregs and either CD4⁺CD25^- T-cells or CD4⁺CD25⁺ T-cells. Additionally, an in vivo experiment was conducted using a dextran sulfate sodium (DSS)-induced colitis model in mice.

CD103⁺CD11b⁺ DC exhibited DCreg-like functionality and was identified as DCreg for subsequent investigation. Analysis of Foxp3⁺Treg percentages within a co-culture system of CD4⁺CD25^- T-cells and DCregs, with or without FLT3L, demonstrated the involvement of the FLT3/FLT3L axis in driving the differentiation of precursor T-cells into Foxp3⁺ Tregs induced by DCregs. Cell migration and co-culture assays revealed that the FLT3/FLT3L axis enhanced DCreg migration toward Tregs via the Rho pathway. Additionally, it was observed that DCregs could promote Treg proliferation through the Notch pathway, as inhibition of Notch signaling by DAPT (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester) suppressed Treg expansion within the co-culture system of DCregs and CD4⁺ T-cells or CD4⁺CD25⁺ T-cells. Furthermore, the FLT3/FLT3L axis influenced JAG1 expression in DCregs, indirectly modulating Treg expansion. In vivo experiments further established that FLT3L promoted DCreg expansion and restored Treg balance in DSS-induced colitis models, thereby ameliorating colitis symptoms in mice.

The FLT3/FLT3L axis is integral to the maintenance of DCreg function in Treg expansion.

Immunosuppression is closely related to the pathogenesis of sepsis, but the underlying mechanisms have not yet been fully elucidated. In this study, we aimed to examine the role of the Sterile Alpha Motif, Src Homology 3 domain and nuclear localization signal 1 (SAMSN1) in sepsis and elucidate its potential molecular mechanism in sepsis induced immunosuppression.

RNA sequencing databases were used to validate SAMSN1 expression in sepsis. The impact of SAMSN1 on sepsis was verified using gene knockout mice. Flow cytometry was employed to delineate how SAMSN1 affects immunity in sepsis, focusing on immune cell types and T cell functions. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated gene editing in RAW264.7 macrophages enabled interrogation of SAMSN1’s regulatory effects on essential macrophage functions, including cell proliferation and phagocytic capacity. The mechanism of SAMSN1 in the interaction between macrophages and T cells was investigated using the RAW264.7 cell line and primary cell lines.

SAMSN1 expression was significantly increased in patients with sepsis and was positively correlated with sepsis mortality. Genetic deletion of Samsn1 in murine sepsis model improved T cell survival, elevated T cell cytolytic activity, and activated T cell signaling transduction. Concurrently, Samsn1 knockout augmented macrophage proliferation capacity and phagocytic efficiency. In macrophage, SAMSN1 binds to Kelch-like epichlorohydrin-associated protein 1 (KEAP1), causing nuclear factor erythroid 2-related factor 2 (NRF2) to dissociate from the KEAP1–NRF2 complex and translocate into the nucleus. This promotes the transcription of the coinhibitory molecules CD48/CD86/carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), which bind to their corresponding receptors natural killer cell receptor 2B4/CD152/T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) on the surface of T cells, inducing T-cell exhaustion.

SAMSN1 deletion augmented adaptive T cell immunity and macrophage phagocytic-proliferative dual function. Furthermore, it mediates the KEAP1–NRF2 axis, which affects the expression of coinhibitory molecules on macrophages, leading to T-cell exhaustion. This novel immunosuppression mechanism potentially provides a candidate molecular target for sepsis immunotherapy.

致编辑：缺血性心脏病（IHD）仍然是全球死亡率的主要原因，急性心肌梗死（AMI）构成了重大的公共卫生问题。尽管大多数AMI病例涉及阻塞性冠状动脉疾病（MI-CAD），但约5-10%的患者出现非阻塞性冠状动脉心肌梗死（MINOCA）。^[1]虽然经皮冠状动脉介入治疗对MI-CAD有效，但MINOCA患者尽管主要冠状动脉血管没有明显狭窄，但由于治疗方法不充分，其结果通常与MI-CAD患者一样差或更差。

致编辑：子宫内膜癌（EC）是中国第二大常见妇科恶性肿瘤，发病率呈上升趋势。^[1,2]在中国，EC患者的5年生存率从2003-2005年的55.1%提高到2012-2015年的72.8%。然而，由于社会人口统计学、临床病理学和治疗相关因素，这仍然低于美国的81%。^[3,4]EC是一种复杂的疾病，具有多种危险因素、不同的组织学亚型和多种可用的治疗方案。然而，我们对中国EC的真实特征和治疗模式知之甚少。^[5]因此，这项大规模、多中心研究旨在调查中国新诊断EC患者的人口统计学、组织病理学和分子特征，并为当前的治疗模式提供见解。

致编辑：包括关节软骨（AC）层和软骨下骨的软骨-软骨下骨（SB）单元承受膝关节最严重的冲击力。软骨的机械完整性及其对损伤的抵抗力不仅取决于其细胞外基质的生化组成，还取决于其与潜在SB的相互作用。两种结构协同工作，具有互补的机械功能，前者作为承重，后者作为结构梁和减震器。^[1]SB吸收关节传递的大部分机械刺激。^[1]SB包括两个不同的解剖实体：软骨下骨板（SP）和软骨下小梁（ST）骨，它们在组成和机械性能上有很大不同。骨是一种纳米复合材料，其中坚硬的无机（羟基磷灰石微晶）和有机（胶原原纤维）组分在纳米尺度上分级排列。^[2]骨质量取决于骨成分（矿物质、胶原蛋白和水）的形状、大小和组成的空间分布。^[3,4]先前的研究表明，SB弹性模量的初始降低发生在骨关节炎（OA）病理过程中。^[5]AC变性可能直接受到SB变化引起的机械环境变化的影响。^[5]然而，据我们所知，对骨软骨区域纳米级机械性能的理解是有限的，这限制了理解疾病进展和设计替代材料的能力。很少有研究调查纳米级表面形貌的变化与SB和AC的机械性能之间的关系。因此，我们研究的一个目的是评估Dunkin Hartley（DH）豚鼠膝关节AC的形貌和机械性能相对于OA阶段的变化，特别关注表面粗糙度——组织润滑的关键决定因素。另一个目的是将观察到的AC表面形貌和机械性能的变化与SB的变化相关联，这对于理解OA发病机制中软骨-软骨下骨单位内的功能相互作用至关重要。我们假设AC表面粗糙度以及ST和SP的压痕模量随着OA的进展而增加，并且在OA发病机制中比它们的骨基质地形图特征起着更重要的作用。

致编辑：环状脓疱型银屑病（APP）是全身性脓疱型银屑病（GPP）的一种罕见变体，表现为复发性环状红斑病变，伴有小的无菌脓疱，遵循亚急性轨迹。APP的复发性大大降低了患者的生活质量。由于其罕见，统一的治疗方案仍然难以捉摸。我们的研究分析了来自4个原始病例以及来自现有文献的41个病例的数据，包括人口统计学数据、遗传谱、临床表现和对治疗的反应。此外，我们进行了全基因组测序（WGS）来检测APP的遗传特征。本研究获得香港大学深圳医院机构审查委员会批准（No.[2024]151）。获得了所有患者的书面知情同意书。

致编辑：Upadacitinib是一种口服janus激酶（JAK）抑制剂，与JAK2、JAK3或酪氨酸激酶2相比，对JAK1表现出更高的抑制效力，使其成为治疗特应性皮炎（AD）的有前途的候选药物。全球试验Measure Up 1、Measure Up 2和AD Up已经证明了中重度AD的疗效和安全性数据，无论是作为单一疗法还是与局部皮质类固醇（TC）联合使用。^[1,2]更新的52周结果初步报告了52周内的持续临床获益，^[3,4]但是关于中国患者长期结果的数据仍然有限。AD病理生理学的种族差异，包括免疫特征的差异，强调了对地区特异性证据的需求。^[5]这个事后对Measure Up 1和AD Up试验的分析评估了upadacitinib在中国患者中的140周疗效和安全性。