2024年 · 第137卷第05期

Hirschsprung disease (HSCR) is a congenital anomaly of the intestine caused by the developmental absence of the enteric nervous system, which results in variable lengths of intestinal dysfunction and requires surgical intervention.^[1]Due to the complex etiology, multiple surgical procedures and postoperative complications, the diagnosis and treatment strategies of HSCR have always been the focus of pediatric surgeons around the world. Seventy pediatric surgical experts with rich clinical experience from almost all national and provincial children’s medical centers in China constituted the Chinese Research Group of Hirschsprung disease (CRGHSCR). All members discussed and compiled the disagreements concerning the diagnosis, treatment [Supplementary File, http://links. lww.com/CM9/B890], and perioperative management of HSCR based on existing evidence from previous articles, in combination with the latest high-quality evidence. The current consensus statement is aimed at standardizing the diagnostic and surgical strategies, and emphasizing postoperative rehabilitation training, to systematically improve postoperative recovery and to improve the quality of life in long-term follow-up.

The brain is a complex organ that requires precise mapping to understand its structure and function. Brain atlases provide a powerful tool for studying brain circuits, discovering biological markers for early diagnosis, and developing personalized treatments for neuropsychiatric disorders. Neuromodulation techniques, such as transcranial magnetic stimulation and deep brain stimulation, have revolutionized clinical therapies for neuropsychiatric disorders. However, the lack of fine-scale brain atlases limits the precision and effectiveness of these techniques. Advances in neuroimaging and machine learning techniques have led to the emergence of stereotactic-assisted neurosurgery and navigation systems. Still, the individual variability among patients and the diversity of brain diseases make it necessary to develop personalized solutions. The article provides an overview of recent advances in individualized brain mapping and navigated neuromodulation and discusses the methodological profiles, advantages, disadvantages, and future trends of these techniques. The article concludes by posing open questions about the future development of individualized brain mapping and navigated neuromodulation.

Biliary tract cancers (BTC), a heterogeneous disease with poor prognosis, including gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC). Although surgery is currently the primary regimen to treat BTC, most BTC patients are diagnosed at an advanced stage and miss the opportunity of surgical eradication. As a result, non-surgical therapy serves as the main intervention for advanced BTC. In recent years, immunotherapy has emerged as one of the most promising therapies in a number of solid cancers, and it includes immune checkpoint inhibitors (ICIs) monotherapy or combined therapy, tumor vaccines, oncolytic virus immunotherapy, adoptive cell therapy (ACT), and cytokine therapy. However, these therapies have been practiced in limited clinical settings in patients with BTC. In this review, we focus on the discussion of latest advances of immunotherapy in BTC and update the progress of multiple current clinical trials with different immunotherapies.

Lung cancer remains the most common cause of cancer death. Given the continued research into new drugs and combination therapies, outcomes in lung cancer have been improved, and clinical benefits have been expanded to a broader patient population. However, the overall cure and survival rates for lung cancer patients remain low, especially in metastatic cases. Among the available lung cancer treatment options, such as surgery, radiation therapy, chemotherapy, targeted therapies, and alternative therapies, immunotherapy has shown to be the most promising. The exponential progress in immuno-oncology research and recent advancements made in the field of immunotherapy will further increase the survival and quality of life for lung cancer patients. Substantial progress has been made in targeted therapies using tyrosine kinase inhibitors and monoclonal antibody immune checkpoint inhibitors with many US Food And Drug Administration (FDA)-approved drugs targeting the programmed cell death ligand-1 protein (e.g., durvalumab, atezolizumab), the programmed cell death-1 receptor (e.g., nivolumab, pembrolizumab), and cytotoxic T-lymphocyte-associated antigen 4 (e.g., tremelimumab, ipilimumab). Cytokines, cancer vaccines, adoptive T cell therapies, and Natural killer cell mono- and combinational therapies are rapidly being studied, yet to date, there are currently none that are FDA-approved for the treatment of lung cancer. In this review, we discuss the current lung cancer therapies with an emphasis on immunotherapy, including the challenges for future research and clinical applications.

Differentiated thyroid cancer (DTC) is commonly diagnosed in women of child-bearing age, but whether pregnancy influences the prognosis of DTC remains controversial. This study aimed to summarize existing evidence regarding the association of pregnancy with recurrence risk in patients previously treated for DTC.

We searched PubMed, Embase, Web of Science, Cochrane, and Scopus based on the prespecified protocol registered at PROSPERO (CRD42022367896). After study selection, two researchers independently extracted data from the included studies. For quantitative data synthesis, we used random-effects meta-analysis models to pool the proportion of recurrence (for pregnant women only) and odds ratio (OR; comparing the risk of recurrence between the pregnancy group and the nonpregnancy group), respectively. Then we conducted subgroup analyses to explore whether risk of recurrence differed by response to therapy status or duration of follow-up time. We also assessed quality of the included studies.

A total of ten studies were included. The sample size ranged from 8 to 235, with participants’ age at pregnancy or delivery ranging from 28 to 35 years. The follow-up time varied from 0.1 to 36.0 years. The pooled proportion of recurrence in all pregnant patients was 0.13 (95% confidence intervals [CI]: 0.06-0.25; I²: 0.58). Among six included studies reporting response to therapy status before pregnancy, we observed a trend for increasingly higher risk of recurrence from excellent, indeterminate, and biochemically incomplete to structurally incomplete response to therapy (P_trend <0.05). The pooled risk of recurrence in the pregnancy group showed no evidence of a significant difference from that in the nonpregnancy group (OR: 0.75; 95% CI: 0.45-1.23; I²: 0). The difference in follow-up time (below/above five years) was not associated with either the proportion of recurrence in all pregnant patients (P >0.05) or the OR of recurrence in studies with a comparison group (P >0.05). Two included studies that focused on patients with distant metastasis also did not show a significant difference in disease recurrence between pregnancy and nonpregnancy groups (OR: 0.51 [95% CI: 0.14-1.87; I²: 59%]).

In general, pregnancy appears to have a minimal association with the disease recurrence of DTC with initial treatment. Clinicians should pay more attention to progression of DTC among pregnant women with biochemical and/or structural persistence.

PROSPERO, https://www.crd.york.ac.uk/PROSPERO/; No. CRD42022367896.

With the advent of small-molecule drugs, treatment of inflammatory bowel disease (IBD) has reached a new stage. In contrast to biologics, small-molecule drugs can be made into oral dosage forms with a short half-life and are suitable for administration 1-2 times a day. Small-molecule drugs work by inhibiting the transmission of key intracellular signaling pathways in the pathogenesis of ulcerative colitis (UC) and Crohn’s disease (CD) [Figure 1]. They do not induce anti-drug antibodies in patients or lead to loss of response after treatment.

Tuberculosis (TB) is an infectious disease caused byMycobacterium tuberculosis. Although the diagnostic technology of pulmonary tuberculosis (PTB) has advanced, accurate and differential diagnoses of PTB are still challenging. In recent years, the rapid development of artificial intelligence (AI) and its wide application in the medical field have provided new opportunities for diagnosing and treating TB and PTB. The machine learning model of AI has not only helped physicians improve diagnostic accuracy, but also enabled them to make early preventive diagnoses for individuals at increased risk of infection. Furthermore, AI can guide physicians to formulate targeted treatment strategies for PTB patients with different conditions.

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease over decades, which, however, remains the leading cause of morbidity and mortality in preterm infants.^[1]Although multiple factors, including gastrointestinal tract bacterial colonization, immaturity, and formula feeding, are reported to be involved in the pathogenesis of NEC, the precise mechanisms are not well understood. Owing to the advances in metagenomic sequencing, ample evidences have illustrated the presence of gut dysbacteriosis in infants with NEC, which is characterized by an elevated abundance of Proteobacteria, reduced abundance of Firmicutes phyla, and an overall decrease in bacterial diversity, providing novel insights into NEC progression.^[1,2]Additionally, the bacterial replication rates, particularly those of Enterobacteriaceae, rapidly increase two days prior to NEC diagnosis.^[2]Moreover, aberrant changes of the gut bacteriome are associated with NEC severity. During NEC, the occurrence of pneumatosis intestinalis and the presence of air in the gastrointestinal wall suggest impaired mucosal regeneration and bacterial invasion.^[3]From this point of view, invading bacteria or their toxins can induce the secretion of a cascade of inflammatory mediator, which is postulated to facilitate the onset of NEC. However, it has to be mentioned that although the specific bacterial signatures precede NEC onset, the causal relationship between gut dysbacteriosis and NEC onset needs to be investigated, and further questions of to what extent the aberrant gut bacteriome is attributable to the progression of NEC should be the area of further investigation.

Hyperglycemia frequently induces apoptosis in endothelial cells and ultimately contributes to microvascular dysfunction in patients with diabetes mellitus (DM). Previous research reported that the expression of integrins as well as their ligands was elevated in the diseased vessels of DM patients. However, the association between integrins and hyperglycemia-induced cell death is still unclear. This research was designed to investigate the role played by integrin subunit β5 (ITGB5) in hyperglycemia-induced endothelial cell apoptosis.

We used leptin receptor knockout (Lepr-KO) (db/db) mice as spontaneous diabetes animal model. Selective deletion of ITGB5 in endothelial cell was achieved by injecting vascular targeted adeno-associated virus via tail vein. Besides, we also applied small interfering RNA in vitro to study the mechanism of ITGB5 in regulating high glucose-induced cell apoptosis.

ITGB5 and its ligand, fibronectin, were both upregulated after exposure to high glucose in vivo and in vitro. ITGB5 knockdown alleviated hyperglycemia-induced vascular endothelial cell apoptosis and microvascular rarefaction in vivo. In vitro analysis revealed that knockdown of either ITGB5 or fibronectin ameliorated high glucose-induced apoptosis in human umbilical vascular endothelial cells (HUVECs). In addition, knockdown of ITGB5 inhibited fibronectin-induced HUVEC apoptosis, which indicated that the fibronectin-ITGB5 interaction participated in high glucose-induced endothelial cell apoptosis. By using RNA-sequencing technology and bioinformatic analysis, we identified Forkhead Box Protein O1 (FoxO1) as an important downstream target regulated by ITGB5. Moreover, we demonstrated that the excessive macroautophagy induced by high glucose can contribute to HUVEC apoptosis, which was regulated by the ITGB5-FoxO1 axis.

The study revealed that high glucose-induced endothelial cell apoptosis was positively regulated by ITGB5, which suggested that ITGB5 could potentially be used to predict and treat DM-related vascular complications.

While type 2 diabetes mellitus (T2DM) is considered a putative causal risk factor for coronary artery disease (CAD), the intrinsic link underlying T2DM and CAD is not fully understood. We aimed to highlight the importance of integrated care targeting both diseases by investigating the phenotypic and genetic relationships between T2DM and CAD.

We evaluated phenotypic associations using data from the United Kingdom Biobank (N = 472,050). We investigated genetic relationships by leveraging genomic data conducted in European ancestry for T2DM, with and without adjustment for body mass index (BMI) (T2DM: N_case/N_control = 74,124/824,006; T2DM adjusted for BMI [T2DM_adjBMI]: N_case/N_control = 50,409/523,897) and for CAD (N_case/N_control = 181,522/984,168). We performed additional analyses using genomic data conducted in multiancestry individuals for T2DM (N_case/N_control = 180,834/1,159,055).

Observational analysis suggested a bidirectional relationship between T2DM and CAD (T2DM→CAD: hazard ratio [HR] = 2.12, 95% confidence interval [CI]: 2.01–2.24; CAD→T2DM: HR = 1.72, 95% CI: 1.63–1.81). A positive overall genetic correlation between T2DM and CAD was observed (r_g = 0.39, P = 1.43 × 10^-75), which was largely independent of BMI (T2DM_adjBMI–CAD: r_g = 0.31, P = 1.20 × 10^–36). This was corroborated by six local signals, among which 9p21.3 showed the strongest genetic correlation. Cross-trait meta-analysis replicated 101 previously reported loci and discovered six novel pleiotropic loci. Mendelian randomization analysis supported a bidirectional causal relationship (T2DM→CAD: odds ratio [OR] = 1.13, 95% CI: 1.11-1.16; CAD→T2DM: OR = 1.12, 95% CI: 1.07-1.18), which was confirmed in multiancestry individuals (T2DM→CAD: OR = 1.13, 95% CI: 1.10-1.16; CAD→T2DM: OR = 1.08, 95% CI: 1.04-1.13). This bidirectional relationship was significantly mediated by systolic blood pressure and intake of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, with mediation proportions of 54.1% (95% CI: 24.9-83.4%) and 90.4% (95% CI: 29.3-151.5%), respectively.

Our observational and genetic analyses demonstrated an intrinsic bidirectional relationship between T2DM and CAD and clarified the biological mechanisms underlying this relationship.

Cerebrovascular disease (CVD) ranks among the foremost factors responsible for mortality on a global scale. The mortality patterns of CVDs and temporal trends in China need to be well-illustrated and updated.

We collected mortality data on patients with CVD from Chinese Center for Disease Control and Prevention’s Disease Surveillance Points (CDC-DSP) system. The mortality of CVD in 2020 was described by age, sex, residence, and region. The temporal trend from 2013 to 2019 was evaluated using joinpoint regression, and estimated rates of decline were extrapolated until 2030 using time series models.

In 2019, the age-standardized mortality in China (ASMRC) per 100,000 individuals was 113.2. The ASMRC for males (137.7/10⁵) and rural areas (123.0/10⁵) were both higher when stratified by gender and urban/rural residence. The central region had the highest mortality (126.5/10⁵), the western region had a slightly lower mortality (123.5/10⁵), and the eastern region had the lowest mortality (97.3/10⁵). The age-specific mortality showed an accelerated upward trend from aged 55-59 years, with maximum mortality observed in individuals over 85 years of age. The age-standardized mortality of CVD decreased by 2.43% (95% confidence interval, 1.02-3.81%) annually from 2013 to 2019. Notably, the age-specific mortality of CVD increased from 2013 to 2019 for the age group of over 85 years. In 2020, both the absolute number of CVD cases and the crude mortality of CVD have increased compared to their values in 2019. The estimated total deaths due to CVD were estimated to reach 2.3 million in 2025 and 2.4 million in 2030.

The heightened focus on the burden of CVD among males, rural areas, the central and western of China, and individuals aged 75 years and above has emerged as a pivotal determinant in further decreasing mortalities, consequently presenting novel challenges to strategies for disease prevention and control.

Copper and zinc are involved in the development of multiple malignancies; yet, epidemiological evidence on hepatocellular carcinoma (HCC) is limited. This study aimed to investigate the association between dietary intake and serum levels of copper and zinc with the risk of HCC.

A total of 434 case-control pairs matched for sex and age (±1 year) were included in this study. Cases with newly diagnosed HCC were from the Guangdong Liver Cancer Cohort (GLCC) study, and healthy controls were from the Guangzhou Nutrition and Health Study (GNHS). A semi-quantitative 79-item food frequency questionnaire (FFQ) was used to assess habitual dietary intakes of copper and zinc. Serum levels of copper and zinc were measured by using inductively coupled plasma mass spectrometry. The copper (Cu)/ zinc (Zn) ratio was computed by dividing copper levels by zinc levels. Conditional logistic regression models were performed to calculate the odds ratio (OR) and 95% confidence intervals (CI) for per 1 standard deviation increase (per-SD increase) in copper and zinc levels.

Higher dietary intake (OR_{per-SD increase} = 0.65, 95% CI: 0.44, 0.96, P_trend = 0.029) and serum levels of zinc (OR_{per-SD increase} = 0.11, 95% CI: 0.04, 0.30, P_trend <0.001) were both associated with a lower risk of HCC. Subgroup analyses showed that the inverse association was only pronounced in men but not in women (P_interaction = 0.041 for dietary zinc intake and 0.010 for serum zinc levels). Serum copper levels (OR_{per-SD increase} = 2.05, 95% CI: 1.39, 3.03, P_trend = 0.020) and serum Cu/Zn ratio (OR_{per-SD increase} = 6.53, 95% CI: 2.52, 16.92, P_trend <0.001) were positively associated with HCC risk, while dietary copper intake and dietary Cu/Zn ratio were not associated with HCC risk.

Zinc may be a protective factor for HCC, especially among men, but the effects of copper on HCC risk are not clear.

Polycystic ovarian syndrome (PCOS) is a heterogeneous and complex reproductive endocrinological disease that could lead to infertility. There were many attempts to classify PCOS but it remains unclear whether there is a specific subgroup of PCOS that is associated with the best or worst reproductive outcomes of assisted reproductive techniques (ART).

Infertile PCOS patients who underwent their first cycle of in vitro fertilization (IVF) in West China Second University Hospital, Sichuan University from January 2019 to December 2021 were included. Basic clinical and laboratory information of each individual were extracted. Unsupervised cluster analysis was performed. Controlled ovarian stimulation parameters and reproductive outcomes were collected and compared between the different clusters of PCOS.

Our analysis clustered women with PCOS into "reproductive", "metabolic", and "balanced" clusters based on nine traits. Reproductive group was characterized by high levels of testosterone (T), sex hormone-binding globulin (SHBG), follicular stimulation hormone (FSH), luteinizing hormone (LH), and anti-Müllerian hormone (AMH). Metabolic group was characterized by high levels of body mass index (BMI), fasting insulin, and fasting glucose. Balanced group was characterized by low levels of the aforementioned reproductive and metabolic parameters, except for SHBG. Compared with PCOS patients in reproductive and balanced clusters, those in metabolic cluster had lower rates of good quality day 3 embryo and blastocyst formation. Moreover, PCOS patients in the reproductive cluster had greater fresh embryo transfer (ET) cancelation rate and clinical pregnancy rate after fresh ET than metabolic cluster (odds ratio [OR] = 3.37, 95% confidence interval [CI]: 1.77-6.44, and OR = 6.19, 95% CI: 1.58-24.24, respectively). And compared with PCOS of metabolic cluster, PCOS of balanced cluster also had higher chance for fresh ET cancelation (OR = 2.83, 95% CI: 1.26-6.35).

Our study suggested that PCOS patients in metabolic cluster may be associated with adverse reproductive outcomes and might need individualized treatment and careful monitoring before and during ART.

To the Editor: Tricuspid regurgitation (TR) associated with valve disease is a general medical issue with growing prevalence and socioeconomic burden. TR, especially moderate or severe TR, has been reported to be associated with an increased risk of heart failure and mortality.^[1]Studies have shown that blood calcium levels and blood phosphorus levels have a great influence on the human body, especially on the cardiovascular system. Elevated serum calcium levels were reported to be a risk factor for cardiovascular disease.^[2]A meta-analysis reported that moderate dietary calcium intake protects against cardiovascular and all-cause mortality and that calcium supplementation reduces mortality in women.^[3]

To the Editor: The nomenclature for steatotic liver disease has been a topic of debate since 2020. The conventional expression, non-alcoholic fatty liver disease (NAFLD), was introduced in 1980 to describe the occurrence of steatosis in the absence of other hepatic diseases. However, in recent years, there has been a growing movement to phase out and retire this term. In 2020, Eslamet al^[1]proposed a new definition — metabolic (dysfunction) associated fatty liver disease (MAFLD) — redefining the disease to include hepatic steatosis along with other factors such as diabetes, obesity, overweight, or meeting the criteria for metabolic dysfunction. The transition from NAFLD to MAFLD was deemed necessary for several reasons, including the inability of NAFLD to clearly explain the disease’s pathophysiology, the possibility of patient stigma due to the term "alcoholic," potential miscommunication between patient and physician, and a preference for defining the disease by positive diagnostic criteria rather than through exclusion.^[1]Although MAFLD and NAFLD did not correspond to the identical population, there was a high consistency between NAFLD and MAFLD.^[2]The shift in terminology without comprehensive understanding of its implications has also been met with resistance, mainly due to the potential confusion it could cause. In an effort to conclude the ongoing debate, a team of 236 experts from 56 different countries endeavored to pinpoint a new, more appropriate name to supersede the term NAFLD. The consensus reached was to rename the condition as metabolic dysfunction-associated steatotic liver disease (MASLD). The definition of MASLD includes the presence of steatosis paired with a minimum of one of five predetermined cardiometabolic criteria. The existence of cardiometabolic factors in conjunction with secondary etiologies has been categorized separately from MASLD.^[3]

To the Editor: Severe acute pancreatitis (SAP) is a common critical disease in gastroenterology, and 69.3% of patients have acute kidney injury (AKI).^[1]Early diagnosis and treatment are very important in improving the prognosis of these patients.

To the Editor:Major depressive disorder (MDD) is a mood disorder characterized by complex patterns of emotional, cognitive, and behavioral symptomology and deficits in daily functioning. Genital symptoms, including a reduction in libido and menstrual disturbances, have been considered to be a classic symptom of MDD for many decades. Previous evidence has reached a broad consensus that the incidence of genital symptoms is higher in patients with MDD than in the general population. A systematic review and meta-analysis found a bidirectional association between MDD and genital symptoms, with patients with MDD showing a 50-70% increased risk of developing genital symptoms, while individuals with genital symptoms had a 130-210% increased risk of developing MDD.^[1]As previously reported, 50-70% of people with MDD experience sexual dysfunction.^[2]To date, few studies have focused on the comparison of clinical features between patients with MDD with and without genital symptoms, and the longitudinal prognosis.

To the Editor:Pulmonary nodules are defined as localized opacities of up to 30 mm in diameter, surrounded by pulmonary parenchyma or located adjacent to the pleura.^[1]The ideal management for pulmonary nodules is to diagnose and treat malignant nodules as early as possible and minimize radiation exposures, based on the general guidance. Clinical practice guidelines (CPGs) always provide efficient recommendations based on systematic reviews of high-quality evidence and reporting to optimize patient care.^[2]Accumulating evidence shows that adherence to the guidelines improves patient outcomes.^[3]However, the reporting quality of CPGs seems poor.^[4]Several instruments have been generated to evaluate the quality of CPGs. The International Reporting Items for Practice Guidelines in Healthcare (RIGHT) checklist is widely used to evaluate the reporting quality of CPGs and provides a systematic reporting framework to inform the creation, reporting, and assessment of CPGs.^[5]The RIGHT checklist with an explanation and elaboration statement can assist developers in reporting guidelines, support journal editors and peer reviewers when considering guideline reports, and help healthcare practitioners understand and implement a guideline. In this study, we evaluated the reporting quality of the CPGs for pulmonary nodules published from 2012 to 2022 with the RIGHT checklist to support more transparent, clear, and explicit guideline reporting in future.

To the Editor: Hypertension is one of the leading risk factors for cardiovascular disease and affects approximately 30% of the adult population.^[1,2]Environmental heavy metal pollution is an important public health concern. Toxic metals may increase the risk of hypertension or other cardiovascular diseases, even beyond the influence of conventional behavioral risk factors.^[3]Meanwhile certain essential trace elements, such as selenium, zinc, and iron, are involved in various enzyme reactions directly related to blood pressure regulation and are beneficial to the human body within a specific range.^[4]The analysis of health outcomes specific to metal mixtures is challenging by nonlinear relationships and interactions between toxic metals and essential trace elements.^[5]The development of innovative statistical methods for analyzing mixtures has greatly facilitated the exploration of the health effects of multiple pollutant exposures, such as Bayesian kernel machine regression (BKMR) and quantile g-computation (QG-C). BKMR can be used to estimate the exposure-response function, including nonlinear exposure-response curves, linear functions with main effects and their interaction, as well as nonlinear functions incorporating a synergistic interaction between them. The QG-C model considers the nonlinearity and nonadditivity of individual exposures effects and the overall mixture, enabling valid inference on the individual contributions to that metal mixture by calculating the weight of each element in each direction.