2023年 · 第136卷第08期

In 2001, the draft sequence of the first human genome was reported, followed by a near-complete sequence published in 2004. One promise of the trove of genomes was to allow scientists to uncover the genetic basis of human diseases, and thereby to facilitate the design of rational diagnostics and therapeutics. Two decades later, more than 420,000 loci have been associated with hundreds of phenotypes by genome-wide association studies (GWASs),^[1]a comprehensive, unbiased, and hypothesis-free approach. For any given phenotype, there were a large number of underlying genetic loci, each exhibiting only small effect, but in combination, they could explain a significant proportion of the variance of phenotypes in the general population. Thus, by aggregating the effects of relevant genetic loci into a single indicator, polygenic scores (PGSs) (also referred to polygenic risk scores [PRSs], or genetic or genomic risk scores [GRSs] for diseases) have emerged as a quantitative measure to predict an individual’s genetic predisposition to a phenotype. Although different methods have been proposed to construct PGSs, some common principles and reporting standards have been described to a less extent in recent reviews.^[2,3]

Ferroptosis is an iron-dependent cell death pathway that is different from apoptosis, pyroptosis, and necrosis. The main characteristics of ferroptosis are the Fenton reaction mediated by intracellular free divalent iron ions, lipid peroxidation of cell membrane lipids, and inhibition of the anti-lipid peroxidation activity of intracellular glutathione peroxidase 4 (GPX4). Recent studies have shown that ferroptosis can be involved in the pathological processes of many disorders, such as ischemia– reperfusion injury, nervous system diseases, and blood diseases. However, the specific mechanisms by which ferroptosis participates in the occurrence and development of acute leukemia still need to be more fully and deeply studied. This article reviews the characteristics of ferroptosis and the regulatory mechanisms promoting or inhibiting ferroptosis. More importantly, it further discusses the role of ferroptosis in acute leukemia and predicts a change in treatment strategy brought about by increased knowledge of the role of ferroptosis in acute leukemia.

Eosinophilic gastroenteritis (EGE) is a gastrointestinal disorder of unclear etiology that is characterized by eosinophilic infiltration of the stomach and small intestine, and consists of mucosal, muscular, and serosal subtypes. Eosinophilic infiltration of the gastrointestinal tract is a fundamental histopathological characteristic of EGE and is driven by several T-helper type 2 (Th2)-dependent cytokines and induced by food allergy. Due to the lack of a diagnostic gold standard, EGE has a high rate of delayed diagnosis or misdiagnosis. However, several new diagnostic strategies have been developed, such as novel genetic biomarkers and imaging tests. Although dietary therapy and corticosteroids remain the common choices for EGE treatment, recent decades have seen the emergence of novel treatment alternatives, such as biologics that target particular molecules involved in the pathogenic process. Preliminary investigations and clinical trials have demonstrated the efficacy of biologics and provided additional insights for the era of refractory or corticosteroid-dependent EGE biologics.

The prevalence of obesity has increased worldwide in recent decades. Genetic factors are now known to play a substantial role in the predisposition to obesity and may contribute up to 70% of the risk for obesity. Technological advancements during the last decades have allowed the identification of many hundreds of genetic markers associated with obesity. However, the transformation of current genetic variant-obesity associations into biological knowledge has been proven challenging. Genomics and proteomics are complementary fields, as proteomics extends functional analyses. Integrating genomic and proteomic data can help to bridge a gap in knowledge regarding genetic variant–obesity associations and to identify new drug targets for the treatment of obesity. We provide an overview of the published papers on the integrated analysis of proteomic and genomic data in obesity and summarize four mainstream strategies: overlap, colocalization, Mendelian randomization, and proteome-wide association studies. The integrated analyses identified many obesity-associated proteins, such as leptin, follistatin, and adenylate cyclase 3. Despite great progress, integrative studies focusing on obesity are still limited. There is an increased demand for large prospective cohort studies to identify and validate findings, and further apply these findings to the prevention, intervention, and treatment of obesity. In addition, we also discuss several other potential integration methods.

Pancreatic β-cells elevate insulin production and secretion through a compensatory mechanism to override insulin resistance under metabolic stress conditions. Deficits in β-cell compensatory capacity result in hyperglycemia and type 2 diabetes (T2D). However, the mechanism in the regulation of β-cell compensative capacity remains elusive. Nuclear factor-Y (NF-Y) is critical for pancreatic islets’ homeostasis under physiological conditions, but its role in β-cell compensatory response to insulin resistance in obesity is unclear.

In this study, using obese (ob/ob) mice with an absence of NF-Y subunit A (NF-YA) in β-cells (ob, Nf-ya βKO) as well as rat insulinoma cell line (INS1)-based models, we determined whether NF-Y-mediated apoptosis makes an essential contribution to β-cell compensation upon metabolic stress.

Obese animals had markedly augmented NF-Y expression in pancreatic islets. Deletion of β-cell Nf-ya in obese mice worsened glucose intolerance and resulted in β-cell dysfunction, which was attributable to augmented β-cell apoptosis and reactive oxygen species (ROS). Furthermore, primary pancreatic islets from Nf-ya βKO mice were sensitive to palmitate-induced β-cell apoptosis due to mitochondrial impairment and the attenuated antioxidant response, which resulted in the aggravation of phosphorylated c-Jun N-terminal kinase (JNK) and cleaved caspase-3. These detrimental effects were completely relieved by ROS scavenger. Ultimately, forced overexpression of NF-Y in INS1 β-cell line could rescue palmitate-induced β-cell apoptosis, dysfunction, and mitochondrial impairment.

Pancreatic NF-Y might be an essential regulator of β-cell compensation under metabolic stress.

Given the general unavailability, common adverse effects, and complicated administration of tetracycline, the clinical application of classic bismuth quadruple therapy (BQT) is greatly limited. Whether minocycline can replace tetracycline for Helicobacter pylori (H. pylori) eradication is unknown. We aimed to compare the eradication rate, safety, and compliance between minocycline- and tetracycline-containing BQT as first-line regimens.

This randomized controlled trial was conducted on 434 naïve patients with H. pylori infection. The participants were randomly assigned to 14-day minocycline-containing BQT group (bismuth potassium citrate 110 mg q.i.d., esomeprazole 20 mg b.i.d., metronidazole 400 mg q.i.d., and minocycline 100 mg b.i.d.) and tetracycline-containing BQT group (bismuth potassium citrate/esomeprazole/metronidazole with doses same as above and tetracycline 500 mg q.i.d.). Safety and compliance were assessed within 3 days after eradication. Urea breath test was performed at 4–8 weeks after eradication to evaluate outcome. We used a noninferiority test to compare the eradication rates of the two groups. The intergroup differences were evaluated using Pearson chi-squared or Fisher’s exact test for categorical variables and Student’s t-test for continuous variables.

As for the eradication rates of minocycline- and tetracycline-containing BQT, the results of both intention-to-treat (ITT) and per-protocol (PP) analyses showed that the difference rate of lower limit of 95% confidence interval (CI) was >−10.0% (ITT analysis: 181/217 [83.4%] vs. 180/217 [82.9%], with a rate difference of 0.5% [−6.9% to 7.9%]; PP analysis: 177/193 [91.7%] vs. 176/191 [92.1%], with a rate difference of −0.4% [−5.6% to 6.4%]). Except for dizziness more common (35/215 [16.3%] vs. 13/214 [6.1%], P = 0.001) in minocycline-containing therapy groups, the incidences of adverse events (75/215 [34.9%] vs. 88/214 [41.1%]) and compliance (195/215 [90.7%] vs. 192/214 [89.7%]) were similar between the two groups.

The eradication efficacy of minocycline-containing BQT was noninferior to tetracycline-containing BQT as first-line regimen for H. pylori eradication with similar safety and compliance.

ClinicalTrials.gov, ChiCTR 1900023646.

Although intensively studied in patients with cardiovascular diseases (CVDs), the prognostic value of diastolic blood pressure (DBP) has little been elucidated in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). This study aimed to reveal the prognostic value of DBP in AECOPD patients.

Inpatients with AECOPD were prospectively enrolled from 10 medical centers in China between September 2017 and July 2021. DBP was measured on admission. The primary outcome was all-cause in-hospital mortality; invasive mechanical ventilation and intensive care unit (ICU) admission were secondary outcomes. Least absolute shrinkage and selection operator (LASSO) and multivariable Cox regressions were used to identify independent prognostic factors and calculate the hazard ratio (HR) and 95% confidence interval (CI) for adverse outcomes.

Among 13,633 included patients with AECOPD, 197 (1.45%) died during their hospital stay. Multivariable Cox regression analysis showed that low DBP on admission (<70 mmHg) was associated with increased risk of in-hospital mortality (HR = 2.16, 95% CI: 1.53–3.05, Z = 4.37, P <0.01), invasive mechanical ventilation (HR = 1.65, 95% CI: 1.32–2.05, Z = 19.67, P < 0.01), and ICU admission (HR = 1.45, 95% CI: 1.24–1.69, Z = 22.08, P <0.01) in the overall cohort. Similar findings were observed in subgroups with or without CVDs, except for invasive mechanical ventilation in the subgroup with CVDs. When DBP was further categorized in 5-mmHg increments from <50 mmHg to ≥100 mmHg, and 75 to <80 mmHg was taken as reference, HRs for in-hospital mortality increased almost linearly with decreased DBP in the overall cohort and subgroups of patients with CVDs; higher DBP was not associated with the risk of in-hospital mortality.

Low on-admission DBP, particularly <70 mmHg, was associated with an increased risk of adverse outcomes among inpatients with AECOPD, with or without CVDs, which may serve as a convenient predictor of poor prognosis in these patients.

Chinese Clinical Trail Registry, No. ChiCTR2100044625.

The clinical features of enthesitis in patients with psoriatic arthritis (PsA) have been reported in some Western countries, but data in China are very limited. This study aimed to describe the characteristics of enthesitis in Chinese patients with PsA and compared them with those in other cohorts.

Patients with PsA enrolled in the Chinese Registry of Psoriatic Arthritis (CREPAR) (December 2018 to June 2021) were included. Data including demographics, clinical characteristics, disease activity measures, and treatment were collected at enrollment. Enthesitis was assessed by the Spondyloarthritis Research Consortium of Canada (SPARCC), Maastricht ankylosing spondylitis enthesitis score (MASES), and Leeds enthesitis index (LEI) indices. A multivariable logistic model was used to identify factors related to enthesitis. We also compared our results with those of other cohorts.

In total, 1074 PsA patients were included, 308 (28.7%) of whom had enthesitis. The average number of enthesitis was 3.3 ± 2.8 (range: 1.0–18.0). More than half of the patients (165, 53.6%) had one or two tender entheseal sites. Patients with enthesitis had an earlier age of onset for both psoriasis and arthritis, reported a higher proportion of PsA duration over 5 years, and had a higher percentage of axial involvement and greater disease activity. Multivariable logistic regression showed that axial involvement (odds ratio [OR] 2.21, 95% confidence interval [CI], 1.59–3.08; P <0.001), psoriasis area and severity index (PASI) (OR: 1.03, 95% CI: 1.01–1.04; P = 0.002), and disease activity score 28-C reactive protein (DAS28-CRP) (OR: 1.25, 95% CI: 1.01–1.55; P = 0.037) were associated with enthesitis. Compared with the results of other studies, Chinese patients with enthesitis had a younger age, lower body mass index (BMI), a higher rate of positive human leukocyte antigen (HLA)-B27, more frequent dactylitis, and a higher proportion of conventional synthetic disease-modifying antirheumatic drugs’ (csDMARDs) use.

Enthesitis is a common condition among Chinese patients with PsA. It is important to evaluate entheses in both peripheral and axial sites.

Limited data are available on the comparison of clinical outcomes of complete vs. incomplete percutaneous coronary intervention (PCI) for patients with chronic total occlusion (CTO) and multi-vessel disease (MVD). The study aimed to compare their clinical outcomes.

A total of 558 patients with CTO and MVD were divided into the optimal medical treatment (OMT) group (n = 86), incomplete PCI group (n = 327), and complete PCI group (n = 145). Propensity score matching (PSM) was performed between the complete and incomplete PCI groups as sensitivity analysis. The primary outcome was defined as the occurrence of major adverse cardiovascular events (MACEs), and unstable angina was defined as the secondary outcome.

At a median follow-up of 21 months, there were statistical differences among the OMT, incomplete PCI, and complete PCI groups in the rates of MACEs (43.0% [37/86] vs. 30.6% [100/327] vs. 20.0% [29/145], respectively, P = 0.016) and unstable angina (24.4% [21/86] vs. 19.3% [63/327] vs. 10.3% [15/145], respectively, P = 0.010). Complete PCI was associated with lower MACE compared with OMT (adjusted hazard ratio [HR] = 2.00; 95% confidence interval [CI] = 1.23 – 3.27; P = 0.005) or incomplete PCI (adjusted HR = 1.58; 95% CI = 1.04–2.39; P = 0.031). Sensitivity analysis of PSM showed similar results to the above on the rates of MACEs between complete PCI and incomplete PCI groups (20.5% [25/122] vs. 32.6% [62/190], respectively; adjusted HR = 0.55; 95% CI = 0.32–0.96; P = 0.035) and unstable angina (10.7% [13/122] vs. 20.5% [39/190], respectively; adjusted HR = 0.48; 95% CI = 0.24–0.99; P = 0.046).

For treatment of CTO and MVD, complete PCI reduced the long-term risk of MACEs and unstable angina, as compared with incomplete PCI and OMT. Complete PCI in both CTO and non-CTO lesions can potentially improve the prognosis of patients with CTO and MVD.

Sarcopenia is an age-related progressive skeletal muscle disorder involving the loss of muscle mass or strength and physiological function. Efficient and precise AI algorithms may play a significant role in the diagnosis of sarcopenia. In this study, we aimed to develop a machine learning model for sarcopenia diagnosis using clinical characteristics and laboratory indicators of aging cohorts.

We developed models of sarcopenia using the baseline data from the West China Health and Aging Trend (WCHAT) study. For external validation, we used the Xiamen Aging Trend (XMAT) cohort. We compared the support vector machine (SVM), random forest (RF), eXtreme Gradient Boosting (XGB), and Wide and Deep (W&D) models. The area under the receiver operating curve (AUC) and accuracy (ACC) were used to evaluate the diagnostic efficiency of the models.

The WCHAT cohort, which included a total of 4057 participants for the training and testing datasets, and the XMAT cohort, which consisted of 553 participants for the external validation dataset, were enrolled in this study. Among the four models, W&D had the best performance (AUC = 0.916 ± 0.006, ACC = 0.882 ± 0.006), followed by SVM (AUC = 0.907 ± 0.004, ACC = 0.877 ± 0.006), XGB (AUC = 0.877 ± 0.005, ACC = 0.868 ± 0.005), and RF (AUC = 0.843 ± 0.031, ACC = 0.836 ± 0.024) in the training dataset. Meanwhile, in the testing dataset, the diagnostic efficiency of the models from large to small was W&D (AUC = 0.881, ACC = 0.862), XGB (AUC = 0.858, ACC = 0.861), RF (AUC = 0.843, ACC = 0.836), and SVM (AUC = 0.829, ACC = 0.857). In the external validation dataset, the performance of W&D (AUC = 0.970, ACC = 0.911) was the best among the four models, followed by RF (AUC = 0.830, ACC = 0.769), SVM (AUC = 0.766, ACC = 0.738), and XGB (AUC = 0.722, ACC = 0.749).

The W&D model not only had excellent diagnostic performance for sarcopenia but also showed good economic efficiency and timeliness. It could be widely used in primary health care institutions or developing areas with an aging population.

Chictr.org, ChiCTR 1800018895.

Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia. In addition to systemic immune/inflammatory effects in response to tumor progression, tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss. However, the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood.

The yki-gut tumors were induced in fruit flies. Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3 (IGFBP-3) treated cells. Immunoblotting was used to display phenotypes of tumor cells and adipocytes. Quantitative polymerase chain reaction (qPCR) analysis was carried out to examine the gene expression levels such as Acc1, Acly, and Fasn et al.

In this study, it was revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes. IGFBP-3, which is highly expressed in cachectic tumor cells, antagonized insulin/IGF-like signaling (IIS) and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes. Conditioned medium from cachectic tumor cells, such as Capan-1 and C26 cells, contained excessive IGFBP-3 that potently induced lipolysis in adipocytes. Notably, neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes. Furthermore, cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS, ensuring their escape from IGFBP-3-associated growth suppression. Finally, cachectic tumor-derived ImpL2, the IGFBP-3 homolog, also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila. Most importantly, IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients, especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients.

Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.

To the Editor: Esophageal cancer (EC) ranks ninth and fifth among the leading cause of global cancer-related morbidity and mortality, respectively.^[1]Esophageal squamous cell carcinoma (ESCC) is the predominant histologic subtype of EC in China. Population screening effectively decreases the morbidity and mortality of ESCC, highlighting the necessity of early detection and early diagnosis.^[2]However, it is hard to generalize the endoscopy screening from high-risk populations in high-risk areas to the natural populations in larger areas. With the development of high-throughput sequencing technologies, the microbiota is an emerging field to provide new clues about the primary screening of ESCC. Consequently, this study summarized indicative genera associated with ESCC progression in paired esophageal biopsy and swab specimens, and developed risk stratification models of high-risk populations based on microbial factors, epidemiological factors, and actual detection requirements.

To the Editor: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are recognized as one of the essential drugs for the treatment of heart failure (HF). Recent randomized controlled trials (RCTs) have shown that the SGLT-2 inhibitors significantly reduced the occurrence of HF hospitalizations or cardiovascular mortality in HF patients.^[1,2,3]In addition, a comprehensive meta-analysis confirmed that SGLT-2 inhibitors improve the prognosis of patients with HF regardless of left ventricular ejection fraction.^[4]However, the analysis by race is not highlighted in this meta-analysis. Since some studies have suggested a poorer prognosis for HF patients in Asia compared to those in Western countries,^[5,6,7]we hypothesized that SGLT-2 inhibitors would have different efficacy in Asians compared to Western HF patients. Therefore, we performed a meta-analysis to elucidate the effectiveness of SGLT-2 inhibitors for Asian HF patients.

To the Editor: Ureterostenosis is one of the most common complications after kidney transplantation, with an incidence rate of 1.0–8.3% according to a relevant report.^[1,2]This complication may cause postrenal obstruction, affecting the function of the transplanted kidney and increasing the risk of kidney loss. As for laparoscopic surgery, open surgery, or interventional treatment, the location and separation of the ureter may be inaccurate, even the ureter damage, the length of the ureter may be not enough, or the ureter may fail to pass through the segment of stenosis for unclear anatomical level, serious tissue adhesion, and special location for operation, thus causing failure of the operation. Therefore, treatment with efficacy and feasibility will be necessary to treat ureterostenosis after kidney transplantation. Magnetic compression anastomosis (MCA) is a recanalization method utilizing the attraction between anastomotic devices made of magnetic materials to compress the parietal layer or tissue of the viscera, thus causing local ischemia or necrosis.^[3]MCA has been applied in the biliary tract, gastrointestinal tract, and vascular anastomosis preliminarily, with remarkable efficacy.^[3,4]MCA was performed in the treatment of ureterostenosis after kidney transplantation based on these advantages that were reported previously.

To the Editor:Human immunodeficiency virus (HIV) type 1 infection remains a serious and intractable public health problem worldwide. In 2020, there were 37.7 million surviving individuals with HIV infection worldwide and 680,000 HIV-related deaths reported by the Joint United Nations Programme on HIV/acquired immune deficiency syndrome (AIDS) (UNAIDS).^[1]To combat the complex HIV epidemic, countries are exploring appropriate antiretroviral therapy (ART) strategies in accordance with actual conditions, striving to ensure that more patients can receive therapy. The initiation time of ART has been constantly adjusted throughout the past decade. The World Health Organization (WHO) proposed the concept of rapid initiation of ART in 2017, explicitly suggesting that HIV-positive individuals start ART within 7 days of diagnosis.^[2]Studies have shown that rapid initiation can increase viral suppression and medication adherence^[3]and reduce HIV transmission and fatality^[4]; thus, it is more advantageous than the conventional therapeutic strategy and contributes to promote HIV prevention and treatment. We collected clinical and cost data to construct decision tree models for cost-effectiveness evaluation of different ART strategies. Our findings will support the rapid initiation of ART in China from the perspective of health economics and serve as a reference for the optimization of medical resource allocation.

To the Editor:Community-acquired pneumonia (CAP) in adults refers to inflammation of the lung parenchyma involving the alveolar wall. It occurs in the community environment (outside the hospital), including pneumonia caused by pathogens with definite latency after admission. CAP is still the main burden of medical and health resources. With the use of broad-spectrum antimicrobial agents, the aging population, and the emergence of new pathogens, the pathogen spectrum of CAP has changed. In addition to the traditional methods of microbiological cultivation and immunology detection, nucleic acid testing is playing more and more important roles in pathogen detection, which has greatly expanded the detection scope of pathogen. Presently, there is no epidemiological survey of the pathogenic changes in Fujian province. Thus, we carried out retrospective epidemiological studies on CAP pathogens in four centers in different regions of Fujian, and analyzed the effects of age and season on the distribution of pathogens, in order to provide a theoretical basis for regional CAP diagnosis and treatment. This study enrolled the data from 2012 to 2018 except those in 2019–2022 because coronavirus disease 2019 (COVID-19) epidemic may pose certain impact on the distribution of pathogens of CAP.

To the Editor: Phase III clinical trials have been used to provide evidence in support of the approval of most new agents in the treatment of cancer.^[1]The selection of the primary endpoint is critical to the outcome of phase III clinical trials and the launch of the cancer drug. In the present study, we performed a cross-sectional study to describe the endpoint information and analyze the trends over time in the research and development of cancer drugs tested in phase III clinical trials in China.

To the Editor:Placenta accreta spectrum (PAS) disorders refer to a spectrum of abnormal placentation. PAS subtypes include placenta accreta (creta or adherenta, PA), placenta increta (PI), and placenta percreta (PP). The incidence of PAS has dramatically increased over the past four decades. A study using a nationally representative sample in the United States showed that the prevalence of PAS was 0.29% among women who underwent cesarean delivery with live birth.^[1]Women with PAS are at a considerably higher risk of concurrent hemorrhage, bladder and urinary tract injury, and hysterectomy during delivery.^[1]

To the Editor: Due to the highly complex nature of intensity-modulated radiotherapy (IMRT) planning and delivery, patient specific quality assurance (PSQA) should be implemented to assure the reliability of treatment delivery and improve the treatment efficacy. A pre-treatment PSQA program is a routine procedure in IMRT and, to some extent, can avoid serious errors in dose delivery. However, there is no guarantee that the dose delivered to the patient is the same as planned, due to the patient’s anatomical change, setup uncertainty, and organ motion during treatments. Therefore,in vivodosimetry (IVD) has been recommended as part of routine IMRT to monitor the actual dose delivered to the patient, detect the source of errors, and assist in adaptive therapy.

The authors declare that in the article "Fecal transplantation can alleviate tic severity in a Tourette syndrome mouse model by modulating intestinal flora and promoting serotonin secretion" which was published in vol. 135, issue 6, page 707–713 of theChinese Medical Journal,^[1]the affiliation of the first author should be corrected as "Department of Gastroenterology, Jinan Children’s Hospital, Jinan, Shandong 250022, China." The authors deeply apologize for any inconvenience caused.