2024年 · 第137卷第11期

镇静和镇痛治疗在神经重症监护中至关重要，但围绕评估、给药和停药仍存在争议。随着神经危重症医学的进步，循证医学的更新，考虑到知识和实践的可变性，国家神经疾病医疗质量管理中心和中国重症医学学会组织神经危重症专家组成工作组[补充文件1，http://links.lww.com/CM9/B958]更新了《重型脑损伤患者镇静镇痛专家共识（2013）》。^[1]本次更新旨在回顾和总结2013年以来发表的关于神经危重症患者镇静和镇痛不同方面的文献，并已在http://www.guidelines-registry.org注册（编号：PREPARE-2023CN332）。本共识的范围仅限于因原发性和/或继发性脑损伤而入住神经重症监护病房的成年患者。应用修改后的德尔菲法，通过三轮德尔菲问卷和一轮面对面会议收集、反馈和讨论专家意见，本次更新涉及5个领域18个问题，并制定了31项建议。本共识旨在供参与护理神经危重症患者的医疗保健专业人员使用。^[2]在每项建议之后，我们会显示同意的百分比水平，然后是投票赞成的参与者占投票参与者总数的比例。

2018-2019年中国慢性肾脏病（CKD）患病率为8.2%。^[1]CKD可能进展为终末期肾病(ESKD)，需要肾脏替代治疗，如透析或肾移植，^[2]这给家庭和社会都带来了巨大的负担。此外，CKD患者具有包括心血管疾病在内的合并症的高风险。^[3]死亡风险随着估计肾小球滤过率（eGFR）的下降而上升。^[3]相当一部分CKD患者在达到需要透析的阶段之前死亡，主要死于心血管事件。^[3]因此，延迟CKD的进展和减少心血管事件是患者护理的关键要素。近年来，在CKD患者的心肾保护方面取得了重要进展。具体而言，钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂的问世为CKD的治疗提供了新的重要途径。

为了提高胶质瘤多学科团队（MDT）管理在不同地区和不同级别医院的一致性，我们基于目前可用的证据更新了中国胶质瘤MDT的专家共识。该版本修订和更新了胶质瘤MDT的过程管理规则和质量控制标准，为相关临床学科和医师提供参考和指导。共识专家组的所有成员、摘要、背景和前景见补充文件http://links.lww.com/CM9/B999。

In humans, the liver is a central metabolic organ with a complex and unique histological microenvironment. Hepatocellular carcinoma (HCC), which is a highly aggressive disease with a poor prognosis, accounts for most cases of primary liver cancer. As an emerging hallmark of cancers, metabolic reprogramming acts as a runaway mechanism that disrupts homeostasis of the affected organs, including the liver. Specifically, rewiring of the liver metabolic microenvironment, including lipid metabolism, is driven by HCC cells, propelling the phenotypes of HCC cells, including dissemination, invasion, and even metastasis in return. The resulting formation of this vicious loop facilitates various malignant behaviors of HCC further. However, few articles have comprehensively summarized lipid reprogramming in HCC metastasis. Here, we have reviewed the general situation of the liver microenvironment and the physiological lipid metabolism in the liver, and highlighted the effects of different aspects of lipid metabolism on HCC metastasis to explore the underlying mechanisms. In addition, we have recapitulated promising therapeutic strategies targeting lipid metabolism and the effects of lipid metabolic reprogramming on the efficacy of HCC systematical therapy, aiming to offer new perspectives for targeted therapy.

The advent of chimeric antigen receptor (CAR)-T cell immunotherapies has led to breakthroughs in the treatment of hematological malignancies. However, their success in treating solid tumors has been limited. CAR-natural killer (NK) cells have several advantages over CAR-T cells because NK cells can be made from pre-existing cell lines or allogeneic NK cells with a mismatched major histocompatibility complex (MHC), which means they are more likely to become an "off-the-shelf" product. Moreover, they can kill cancer cells via CAR-dependent/independent pathways and have limited toxicity. Macrophages are the most malleable immune cells in the body. These cells can efficiently infiltrate into tumors and are present in large numbers in tumor microenvironments (TMEs). Importantly, CAR-macrophages (CAR-Ms) have recently yielded exciting preclinical results in several solid tumors. Nevertheless, CAR-T, CAR-NK, and CAR-M all have their own advantages and limitations. In this review, we systematically discuss the current status, progress, and the major hurdles of CAR-T cells, CAR-NK cells, and CAR-M as they relate to five aspects: CAR structure, therapeutic mechanisms, the latest research progress, current challenges and solutions, and comparison according to the existing research in order to provide a reasonable option for treating solid tumors in the future.

Aging is accompanied by significant inhibition of hematopoietic and immune system function and disruption of bone marrow structure. Aging-related alterations in the inflammatory response, immunity, and stem cell niches are at the root of hematopoietic aging. Understanding the molecular mechanisms underlying hematopoietic and bone marrow aging can aid the clinical treatment of aging-related diseases. In particular, it is unknown how the niche reprograms hematopoietic stem cells (HSCs) in an age-dependent manner to maintain normal hematopoiesis in elderly individuals. Recently, specific inhibitors and blood exchange methods have been shown to reshape the hematopoietic niche and reverse hematopoietic aging. Here, we present the latest scientific discoveries related to hematopoietic aging and hematopoietic system rejuvenation, discuss the relationships between hematopoietic niche aging and HSC aging, and describe related studies on stem cell-mediated regulation of hematopoietic aging, aiming to provide new ideas for further study.

经常观察到新出现的传染病。由于病原体的不可预测性、发生时间和地点的复杂性以及传播的特点，传染病的发生具有很强的不确定性。及早发现并在合理时间内立即实施有效干预措施是预防大流行病的关键。^[1]然而，由于传统的监测和预警严重依赖医疗机构被动报告的不足，^[2]预警时间滞后于聚集性病例关口传染病的危险因素识别、辨证分型（不明原因肺炎）、疑似病例确诊。本文旨在面对上述挑战，提出一个通用的疫情情报模型，以建立一个基于监测检测、风险评估和预警三位一体的新型传染病监测和预警系统。

Histological healing is closely associated with improved long-term clinical outcomes and lowered relapses in patients with ulcerative colitis (UC). Here, we developed a novel diagnostic criterion for assessing histological healing in UC patients.

We conducted a retrospective cohort study in UC patients, whose treatment was iteratively optimized to achieve mucosal healing at Shanghai Tenth People’s Hospital of Tongji University from January 2017 to May 2022. We identified an inflammatory cell enumeration index (ICEI) for assessing histological healing based on the proportions of eosinophils, CD177⁺ neutrophils, and CD40L⁺ T cells in the colonic lamina propria under high power field (HPF), and the outcomes (risks of symptomatic relapses) of achieving histological remission vs. persistent histological inflammation using Kaplan-Meier curves. Intrareader reliability and inter-reader reliability were evaluated by each reader. The relationships to the changes in the Nancy index and the Geboes score were also assessed for responsiveness. The ICEI was further validated in a new cohort of UC patients from other nine university hospitals.

We developed an ICEI for clinical diagnosis of histological healing, i.e., Y = 1.701X₁ + 0.758X₂ + 1.347X₃ - 7.745 (X₁, X₂, and X₃ represent the proportions of CD177⁺ neutrophils, eosinophils, and CD40L⁺ T cells, respectively, in the colonic lamina propria under HPF). The receiver operating characteristics curve (ROC) analysis revealed that Y <-0.391 was the cutoff value for the diagnosis of histological healing and that an area under the curve (AUC) was 0.942 (95% confidence interval [CI]: 0.905-0.979) with a sensitivity of 92.5% and a specificity of 83.6% (P <0.001). The intraclass correlation coefficient (ICC) for the intrareader reliability was 0.855 (95% CI: 0.781-0.909), and ICEI had good inter-reader reliability of 0.832 (95% CI: 0.748-0.894). During an 18-month follow-up, patients with histological healing had a substantially better outcome compared with those with unachieved histological healing (P <0.001) using ICEI. During a 12-month follow-up from other nine hospitals, patients with histological healing also had a lower risk of relapse than patients with unachieved histological healing.

ICEI can be used to predict histological healing and identify patients with a risk of relapse 12 months and 18 months after clinical therapy. Therefore, ICEI provides a promising, simplified approach to monitor histological healing and to predict the prognosis of UC.

Chinese Clinical Trial Registry, No. ChiCTR2300077792.

Cardiovascular disease (CVD) has emerged as the leading cause of death from prostate cancer (PCa) in recent decades, bringing a great disease burden worldwide. Men with preexisting CVD have an increased risk for major adverse cardiovascular events when treated with androgen deprivation therapy (ADT). The present study aimed to explore the prevalence and risk evaluation of CVD among people with newly diagnosed PCa in China.

Clinical data of newly diagnosed PCa patients were retrospectively collected from 34 centers in China from 2010 to 2022 through convenience sampling. CVD was defined as myocardial infarction, arrhythmia, heart failure, stroke, ischemic heart disease, and others. CVD risk was estimated by calculating Framingham risk scores (FRS). Patients were accordingly divided into low-, medium-, and high-risk groups. χ² or Fisher’s exact test was used for comparison of categorical variables.

A total of 4253 patients were enrolled in the present study. A total of 27.0% (1147/4253) of patients had comorbid PCa and CVD, and 7.2% (307/4253) had two or more CVDs. The enrolled population was distributed in six regions of China, and approximately 71.0% (3019/4253) of patients lived in urban areas. With imaging and pathological evaluation, most PCa patients were diagnosed at an advanced stage, with 20.5% (871/4253) locally progressing and 20.5% (871/4253) showing metastasis. Most of them initiated prostatectomy (46.6%, 1983/4253) or regimens involving ADT therapy (45.7%, 1944/4253) for prostate cancer. In the present PCa cohort, 43.1% (1832/4253) of patients had hypertension, and half of them had poorly controlled blood pressure. With FRS stratification, as expected, a higher risk of CVD was related to aging and metabolic disturbance. However, we also found that patients with treatment involving ADT presented an originally higher risk of CVD than those without ADT. This was in accordance with clinical practice, i.e., aged patients or patients at advanced oncological stages were inclined to accept systematic integrative therapy instead of surgery. Among patients who underwent medical castration, only 4.0% (45/1118) received gonadotropin releasing hormone antagonists, in stark contrast to the grim situation of CVD prevalence and risk.

PCa patients in China are diagnosed at an advanced stage. A heavy CVD burden was present at the initiation of treatment. Patients who accepted ADT-related therapy showed an original higher risk of CVD, but the awareness of cardiovascular protection was far from sufficient.

To address the need for immunotherapy in patients with advanced primary hepatocellular carcinoma (HCC), combination with radiotherapy (RT) has emerged as a promising strategy. In preclinical studies, irradiated tumors released tumor antigens to synergistically increase the antitumor effect of immunotherapy. Hence, we investigated whether RT enhances the efficacy of anti-programmed death receptor-1 (PD-1) inhibitors in advanced HCC in real-world practice.

Between August 2018 and June 2021, 172 patients with advanced primary HCC were enrolled in the tertiary center (Zhongshan Hospital of Fudan University); 95 were treated with a combination of RT and the inhibitor of PD-1 (RT-PD1 cohort), and 77 were administered anti-PD-1 therapy (PD1 cohort). The first cycle of PD-1 inhibitors was administered within 60 days or concurrently with RT. Propensity score matching for bias reduction was used to evaluate the clinical outcomes.

Among 71 propensity-matched pairs, median progression-free survival was 5.7 months in the RT-PD1 cohort vs. 2.9 months in the PD1 cohort (P <0.001). Median overall survival was 20.9 months in the RT-PD1 cohort vs. 11.2 months in the PD1 cohort (P = 0.018). Compared with patients in the PD1 cohort, patients in the RT-PD1 cohort had significantly higher objective response rates (40.8%, 29/71 vs. 19.7%, 14/71, P = 0.006) and disease control rates (62.0%, 44/71 vs. 31.0%, 22/71, P <0.001). The incidences of toxic effects were not significantly different between the two cohorts.

RT plus anti-PD-1 therapy is well tolerated. RT enhances the efficacy of anti-PD-1 therapy in patients with advanced primary HCC by improving survival outcomes without increased toxic effects.

Evidence indicates that low muscle strength is associated with an increased cardiovascular diseases (CVDs) risk. However, the association between muscle strength changes based on repeated measurements and CVD incidence remains unclear.

The study used data from the China Health and Retirement Longitudinal Study in 2011 (Wave 1), 2013 (Wave 2), 2015 (Wave 3), and 2018 (Wave 4). Low muscle strength was defined as handgrip strength <28 kg for men or <18 kg for women, or chair-rising time ≥12 s. Based on changes in muscle strength from Waves 1 to 2, participants were categorized into four groups of Normal-Normal, Low-Normal, Normal-Low, and Low-Low. CVD events, including heart disease and stroke, were recorded using a self-reported questionnaire during Waves 3 and 4 visits. Cox proportional hazards models were used to investigate the association between muscle strength changes and CVD incidence after multivariable adjustments. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated with the Normal-Normal group as the reference.

A total of 1164 CVD cases were identified among 6608 participants. Compared to participants with sustained normal muscle strength, the CVD risks increased progressively across groups of the Low-Normal (HR = 1.20, 95% CI: 1.01-1.43), the Normal-Low (HR = 1.35, 95% CI: 1.14-1.60), and the Low-Low (HR = 1.76, 95% CI: 1.49-2.07). Similar patterns were observed for the significant associations between muscle strength status and the incidence risks of heart disease and stroke. Subgroup analyses showed that the significant associations between CVD and muscle strength changes were consistent across age, sex, and body mass index (BMI) categories.

The study found that muscle strength changes were associated with CVD risk. This suggests that continuous tracking of muscle status may be helpful in screening cardiovascular risk.

The ability to generate functional hepatocytes without relying on donor liver organs holds significant therapeutic promise in the fields of regenerative medicine and potential liver disease treatments. Clustered regularly interspaced short palindromic repeats (CRISPR) activator (CRISPRa) is a powerful tool that can conveniently and efficiently activate the expression of multiple endogenous genes simultaneously, providing a new strategy for cell fate determination. The main purpose of this study is to explore the feasibility of applying CRISPRa for hepatocyte reprogramming and its application in the treatment of mouse liver fibrosis.

The differentiation of mouse embryonic fibroblasts (MEFs) into functional induced hepatocyte-like cells (iHeps) was achieved by utilizing the CRISPRa synergistic activation mediator (SAM) system, which drove the combined expression of three endogenous transcription factors—Gata4, Foxa3, and Hnf1a—or alternatively, the expression of two transcription factors, Gata4 and Foxa3. In vivo, we injected adeno-associated virus serotype 6 (AAV6) carrying the CRISPRa SAM system into liver fibrotic Col1a1-Cre^ER; Cas9^fl/fl mice, effectively activating the expression of endogenous Gata4 and Foxa3 in fibroblasts. The endogenous transcriptional activation of genes was confirmed using real-time quantitative polymerase chain reaction (RT-qPCR) and RNA-seq, and the morphology and characteristics of the induced hepatocytes were observed through microscopy. The level of hepatocyte reprogramming in vivo is detected by immunofluorescence staining, while the improvement of liver fibrosis is evaluated through Sirius red staining, alpha-smooth muscle actin (α-SMA) immunofluorescence staining, and blood alanine aminotransferase (ALT) examination.

Activation of only two factors, Gata4 and Foxa3, via CRISPRa was sufficient to successfully induce the transformation of MEFs into iHeps. These iHeps could be expanded in vitro and displayed functional characteristics similar to those of mature hepatocytes, such as drug metabolism and glycogen storage. Additionally, AAV6-based delivery of the CRISPRa SAM system effectively induced the hepatic reprogramming from fibroblasts in mice with live fibrosis. After 8 weeks of induction, the reprogrammed hepatocytes comprised 0.87% of the total hepatocyte population in the mice, significantly reducing liver fibrosis.

CRISPRa-induced hepatocyte reprogramming may be a promising strategy for generating functional hepatocytes and treating liver fibrosis caused by hepatic diseases.

结节性痒疹（PN）作为慢性痒疹（CPG）的一种亚型，以结节性病变和严重瘙痒为特征，显著影响患者的生活质量。^[1]据观察，PN患者经常有合并症，包括身体和精神疾病。^[2]然而，缺乏关于中国PN患者合并症的信息。本研究旨在通过使用具有代表性的患者人群来填补这一空白，以提供中国PN患者合并症的全面数据。

致编辑：强烈推荐内镜逆行胰胆管造影（ERCP）用于胆总管结石取石。但仍有并发症的风险，如ERCP后胆管炎（PEC）和ERCP后胰腺炎（PEP）。胆道引流包括内镜鼻胆管引流（ENBD）和胆道支架被认为可以减少PEC和PEP的发生。但ENBD管会引起患者不适，部分患者可能自行拔管。此外，在插入常规胆道支架用于短期胆道引流后需要额外的内窥镜支架移除，增加了医疗成本。

致编辑：由于机器人手术具有精确、稳定和易于控制的优点，机器人系统在手术中的使用正在增加。尽管取得了这一进展，机器人技术在整形和重建手术中的采用比许多其他专业要慢。最近的研究显示了在整形外科、重建外科和显微外科中使用机器人辅助的前景。

致编辑：在过去的十年中，新辅助化疗（NAC）已经成为乳腺癌的一种被广泛接受的治疗选择，尽管在中国还没有关于NAC的详细描述的报道。^[1]先前的一项研究发现，在临床淋巴结阴性（cN0）乳腺癌患者中，97.7%（432/442）的乳腺病理学完全缓解（bpCR）为ypN0（腋窝淋巴结无转移）；71.6%（882/1232）无bpCR达到ypN0（P<0.001).至于达到bpCR的人表皮生长因子受体2（HER2）阳性或三阴性乳腺癌（TNBC），淋巴结转移的概率小于2%。本研究旨在利用2010年至2020年中国乳腺外科学会（CSBrS）研究的数据调查中国NAC的状况。它试图回答以下问题：目前NAC利用的趋势是什么，以及在中国乳腺和腋窝淋巴结的影响是什么。

致编辑：遗传性严重胰岛素抵抗综合征（H-SIRS）表现出广泛且可变的临床谱，并导致内分泌和心血管系统的严重并发症。建议采用多种治疗方法控制H-SIRS的高血糖，包括饮食干预、胰岛素治疗、胰岛素增敏和重组人胰岛素样生长因子-1（rhIGF-1）给药。^[1]然而，H-SIRS的异质性病因导致不同突变患者血糖控制不佳，需要多种抗高血糖药物治疗。本研究描述了2例确诊为H-SIRS的病例以及多药治疗和钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）单药治疗的治疗效果。

致编辑：残疾权重（DWs）是量化与估计残疾调整生命年（DALYs）的非致命结果相关的健康损失的基本因素。虽然最近在中国大陆出版了国家和次国家的DWs集，^[1]仅来自4925名回答了用于锚定0-1 DWs量表的人口健康等效性（PHE）问题的参与者的数据不包括来自福建省的参与者。此外，生活在不同城市的人们是否共享相同的DWs仍然是未知的。这项研究提供了一种替代方法，使用非参数回归来定位欧洲调查中使用的DWs量表，^[2]旨在测量福建省省级和副省级的DWs。

致编辑：铜是体内至关重要的微量元素，在新陈代谢和生物功能中起着关键作用。铜离子有两种形式，Cu¹+和铜²⁺，其中铜¹⁺是存储在单元格中的主要形式。大量研究表明，细胞内铜积累可引起氧化应激并破坏细胞功能。^[1]与细胞凋亡、自噬、焦下垂、铁下垂不同，铜下垂是2022年新发现的细胞死亡类型。^[2]它由线粒体中铁氧还蛋白1（FDX1）的蛋白质脂酰化介导。成人肾癌最常见的病理类型是透明细胞肾细胞癌（ccRCC），占所有肾细胞癌（RCC）病例的70-80%。^[3]目前，手术切除是RCC的首选治疗方法，因为放疗、化疗和免疫治疗在治疗ccRCC中显示出有限的有效性。然而，铜突诱导可能为ccRCC的治疗提供一种新的方法。

致编辑：恶性胸腔积液（Malignant pleural effusion，MPE）是主要来源于恶性肿瘤患者胸膜转移的胸膜腔内大量渗出液的集合。MPE的形成与血管生成、血管通透性增加、淋巴阻塞、免疫反应和肿瘤转移微环境有关，但目前仍缺乏基于分子的MPE诊断和下一代治疗策略。外泌体是具有双层脂质膜结构的囊泡，广泛分布于体液中，几乎所有细胞均可产生。越来越多的证据表明，外来体与MPE的发展有关，并且与靶向治疗或免疫治疗的功效和对其的反应相关。虽然外泌体是MPE的主要成分之一，但外泌体在MPE中的来源和功能作用仍不清楚。

致编辑：由于先天性心脏病相关肺动脉高压（CHD-PH）疾病的异质性和儿童患者肺血管系统的发育，儿童CHD-PH的治疗与成人有显著差异。^[1]CHD-PH的早期识别和干预对于CHD儿童的疾病管理具有重要意义，迫切需要无创、准确的临床工具来预测CHD儿童的PH风险。然而，目前的风险评分系统对儿科CHD-PH的适用性仍不清楚。此外，目前没有用户友好的、非侵入性的在线工具可用于预测CHD-PH，并且在亚洲人群中缺乏相关研究。本研究旨在开发和验证用于估计先天性心脏病儿童肺动脉高压和临床恶化风险的预测工具。