2024年 · 第137卷第11期

Sedation and analgesia therapy are essential in neurocritical care, but there are ongoing controversies surrounding assessment, administration, and withdrawal. With advances in neurocritical care medicine, updated evidence-based medicine, considering the variability in knowledge and practice, the National Center for Healthcare Quality Management in Neurological Diseases and the Chinese Society of Critical Care Medicine organized experts in neurocritical care to form a working group [Supplementary File 1, http://links.lww.com/CM9/B958] to update the "Expert Consensus on Sedation and Analgesia for Patients with Severe Brain Injury (2013)" .^[1]This update aimed to review and summarize the literature published since 2013 across different aspects of sedation and analgesia in neurocritical care patients and has been registered on http://www.guidelines-registry.org (No. PREPARE-2023CN332). The scope of this consensus is limited to adult patients admitted to neurocritical care units because of primary and/or secondary brain injuries. Applying the modified Delphi method to collect, feedback and discuss expert opinions through three rounds of Delphi questionnaires and one round of face-to-face meeting, this update addressed 5 domains with 18 questions and formulated 31 recommendations. This consensus is intended for use by healthcare professionals involved in caring for neurocritical care patients.^[2]Following each recommendation, we present the percentage level of agreement followed by the rate of participants voting in favor to the total number of participants casting their vote.

The prevalence of chronic kidney disease (CKD) in China was 8.2% in 2018-2019.^[1]CKD may progress to end-stage kidney disease (ESKD), necessitating kidney replacement treatment such as dialysis or kidney transplantation,^[2]which imposes a substantial burden on both family and society. Moreover, patients with CKD have a high risk of comorbidities including cardiovascular diseases.^[3]The risk of death rises as the estimated glomerular filtration rate (eGFR) declines.^[3]A substantial portion of CKD patients die, primarily from cardiovascular events, before reaching the stage requiring dialysis.^[3]As such, delaying the progression of CKD and reducing cardiovascular events are key elements in patient care. In recent years, important progress has been made in the cardiorenal protection of patients with CKD. Specifically, the advent of sodium-glucose cotransporter 2 (SGLT2) inhibitors has provided a new and important approach for the treatment of CKD.

To increase the consistency of glioma multidisciplinary team (MDT) management across different regions and hospitals at varying levels, we have updated the Expert Consensus on MDT of Glioma in China based on the currently available evidence. This version has revised and updated the process-management rules and quality-control standards for a glioma MDT, providing reference and guidance for relevant clinical disciplines and physicians. All members of the Consensus Expert Group, abstract, background, and prospects can be seen in supplementary file, 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.

Emerging infectious diseases have been frequently observed. The occurrence of infectious diseases is highly uncertain because of the unpredictability of pathogen, the complexity of occurrence time and site, and the characteristics of transmission. Early detection and immediate implementation of effective interventions within a reasonable time are the keys to preventing pandemics.^[1]However, due to the insufficiency of the traditional surveillance and early warning, which relied heavily on passive reporting by healthcare institutions,^[2]the early warning time lags behind the risk factor identification, syndrome differentiation (pneumonia of unknown cause), and suspected case confirmation of the infectious disease at the gateway of clustered cases. This paper aimed to face the challenges mentioned above and propose a universal epidemic intelligence model to establish a novel infectious disease surveillance and early warning system based on the trinity of surveillance and detection, risk assessment, and early warning.

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.

Prurigo nodularis (PN), as a subtype of chronic prurigo (CPG), is characterized by nodular lesions and severe pruritus, which significantly affect patients’ quality of life.^[1]It has been observed that patients with PN often have comorbidities, including physical and mental diseases.^[2]However, information on comorbidities in Chinese PN patients is lacking. This study aims to fill this gap by using a representative patient population to provide comprehensive data on comorbidities in Chinese patients with PN.

To the Editor:Endoscopic retrograde cholangiopancreatography (ERCP) is strongly recommended for stone removal of choledocholithiasis. But there is still risk of complications such as post-ERCP cholangitis (PEC) and post-ERCP pancreatitis (PEP). Biliary drainage including endoscopic nasobiliary drainage (ENBD) and biliary stent is considered to reduce the occurrence of PEC and PEP. However, the ENBD tube will cause patient discomfort, and some patients may extract the tube by themselves. Furthermore, additional endoscopic stent removal is required after insertion of conventional biliary stent for short-term biliary drainage, increasing medical costs.

To the Editor:Owing to the fact that robotic surgery has the advantages of being accurate, stable, and easy to control, the use of robotic systems in surgery is increasing. Despite this progress, the adoption of robotic technology in plastic and reconstructive surgery has been slower than many other specialties. Recent research has shown promise for the use of robotic assistance in plastic surgery, reconstructive surgery, and microsurgery.

To the Editor: In the last decade, neoadjuvant chemotherapy (NAC) has become a well-accepted treatment option for breast cancer, although few detailed description of NAC in China has yet been reported.^[1]A previous study found that among patients with clinically node-negative (cN0) breast cancer, 97.7% (432/442) with breast pathologic complete response (bpCR) had ypN0 (absence of metastases in the axillary lymph nodes); and 71.6% (882/1232) without bpCR achieved ypN0 (P<0.001). As for human epidermal growth factor receptor 2 (HER2) positive or triple-negative breast cancer (TNBC) that achieved bpCR, the probability of lymph node metastasis was less than 2%. This research aimed to investigate NAC status in China using data obtained from the Chinese Society of Breast Surgery (CSBrS) study from 2010 to 2020. It seeks to answer the following questions: what the current trend in NAC utilization is and what the effects of breast and axillary lymph node are in China.

To the Editor:Hereditary severe insulin resistance syndrome (H-SIRS) shows a wide and variable clinical spectrum and results in severe complications in the endocrinological and cardiovascular systems. Multiple treatments are recommended to control hyperglycemia in H-SIRS, including dietary intervention, insulin therapy, insulin sensitization, and recombinant human insulin-like growth factor-1 (rhIGF-1) administration.^[1]However, the heterogeneous etiology of H-SIRS leads to poor glycemic control in patients with different mutations, requiring multiple antihyperglycemic medications. This study described two cases diagnosed with H-SIRS and the treatment effect of multi-drug therapy and sodium-glucose cotransporter 2 inhibitor (SGLT2i) monotherapy.

To the Editor:Disability weights (DWs) are essential factors to quantify health losses relating to non-fatal outcomes for estimates of disability-adjusted life years (DALYs). Although national and subnational sets of DWs were published recently in the Chinese mainland,^[1]data from only 4925 participants who responded to population health equivalence (PHE) questions used to anchor the 0-1 DWs scale did not include participants from Fujian province. Moreover, it remains unknown whether people living in different cities share the same DWs. This study provided an alternative approach using non-parametric regression to locate the DWs scale, as used in European surveys,^[2]aimed at measuring DWs at the provincial and subprovincial levels in Fujian.

To the Editor: Copper is a crucial trace element in the body that plays a key role in metabolism and biological functions. Copper ions are found in two forms, Cu¹+ and Cu²⁺, of which Cu¹⁺is the main form stored in cells. Numerous studies have shown that intracellular copper accumulation can cause oxidative stress and disrupt cellular function.^[1]Different from apoptosis, autophagy, pyroptosis, and ferroptosis, cuproptosis is a newly discovered type of cell death in 2022.^[2]It is mediated by protein lipoylation with ferredoxin 1 (FDX1) in mitochondria. The most common pathological type of kidney cancer in adults is clear cell renal cell carcinoma (ccRCC), which accounts for 70-80% of all cases of renal cell carcinoma (RCC).^[3]Currently, surgical resection is the preferred treatment for RCC, as radiotherapy, chemotherapy, and immunotherapy have shown limited effectiveness in treating ccRCC. However, cuproptosis induction may offer a new approach for ccRCC treatment.

To the Editor:Malignant pleural effusion (MPE) is a collection of a large amount of exudative fluid in the pleural cavity that mainly originates from pleural metastases in patients with malignant tumors. The formation of MPE is related to angiogenesis, increased vascular permeability, lymphatic obstruction, immune reactions, and the tumor metastasis microenvironment, but molecular-based diagnostic and next-generation therapeutic strategies for MPE are still lacking. Exosomes are vesicles with a double-layered lipid membrane structure that are widely distributed in body fluids and can be produced by almost all cells. Increased evidence has shown that exosomes are related to the development of MPE and are correlated with the efficacy of and response to targeted therapy or immunotherapy. Although exosomes are one of the main components of MPE, the source and functional role of exosomes in MPE are still unclear.

To the Editor:Owing to the heterogeneity of congenital heart disease-associated pulmonary hypertension (CHD-PH) disease and the development of the pulmonary vascular system in pediatric patients, the management of CHD-PH in children is significantly different from that in adults.^[1]Early identification and intervention of CHD-PH are of great significance for disease management in children with CHD, and non-invasive, accurate clinical tools are urgently needed to predict PH risk in children with CHD. However, the applicability of the current risk-scoring system to pediatric CHD-PH remains unclear. Furthermore, there are presently no user-friendly, non-invasive online tools available for predicting CHD-PH, and there is a scarcity of related studies in Asian populations. This study aimed to develop and validate the prediction tools for estimating the risk of pulmonary hypertension and clinical deterioration in children with congenital heart disease.