2024年 · 第137卷第03期

Hong Kong Medical Journal(HKMJ) is the flagship general medical journal in the Hong Kong Special Administrative Region, China, with an international outlook. We are committed to publishing and promoting high-quality research. Led by our Editor-in-Chief, Professor Martin CS Wong, our Editorial Board is pleased to collaborate with Dr. Chen Wang, the Editor-in-Chief of theChinese Medical Journal(CMJ), as well as the editors of CMJ to enhance the visibility of our respective journals and foster a collaborate environment that brings forth ideas and knowledge to our readers.

Indeterminate biliary stricture (IBS) refers to biliary stricture with an uncertain histological diagnosis^[1]and can be classified as non-neoplastic stricture or neoplastic stricture. The former is mainly caused by various inflammatory biliopancreatic diseases, congenital malformations, or postoperative bile duct injury, while the latter exists in neoplastic lesions such as cholangiocarcinoma, invasion from pancreatic cancer, and adenomas in the bile duct. Most non-neoplastic strictures can be relieved by endoscopic or conservative medical treatment, and only a few require surgical intervention. Nevertheless, radical surgery or palliative biliary drainage should be applied for neoplastic strictures according to the progression of the disease. Therefore, it is essential to obtain an accurate diagnosis for IBS in clinical work.

Aortic dissection is a life-threatening condition for which diagnosis mainly relies on imaging examinations, while reliable biomarkers to detect or monitor are still under investigation. Recent advances in technologies provide an unprecedented opportunity to yield the identification of clinically valuable biomarkers, including proteins, ribonucleic acids (RNAs), and deoxyribonucleic acids (DNAs), for early detection of pathological changes in susceptible patients, rapid diagnosis at the bedside after onset, and a superior therapeutic regimen primarily within the concept of personalized and tailored endovascular therapy for aortic dissection.

According to the Global Burden of Disease Study 2017, there are 132 million patients with chronic kidney disease (CKD) in China,^[1]and the prevalence of hypertension in Chinese patients with CKD (67.3%) is significantly higher than that in the general population (23.2%).^[2,3]CKD is both a cause and a consequence of hypertension, and these two conditions form a vicious cycle that leads to the high prevalence rate of hypertension in patients with CKD. Uncontrolled hypertension accelerates the deterioration of renal function, which significantly increases the risk of developing end-stage renal disease (ESRD), as well as cardiovascular and cerebrovascular diseases, leading to poor patient outcomes.

Asthma imposes a large healthcare burden in China and the United States (US). However, the trends of asthma mortality and the relative risk factors have not been comparatively analyzed between the countries. The aim of this study was to compare the mortality and risk factors between China and the US.

The deaths, and mortality rates of asthma in China and the US during 1990–2019 were obtained from the Global Burden of Disease Study 2019. The age–period–cohort model was used to estimate these mortality rates based on a log-linear scale with additive age, period, and cohort effects. The population attributable fractions of risk factors for asthma were estimated.

In 1990–2019, the asthma mortality rate was higher in China than in the US. The crude and age-standardized asthma mortality rates trended downward in both China and the US from 1990 to 2019. The decline in mortality was more obvious in China. Mortality gap between the two countries was narrowing. A sex difference in asthma mortality was observed with higher mortality in males in China and females in the US. The age effects showed that mortality increased with age in adults older than 20 years, particularly in the elderly. Downward trends were generally observed in the period and cohort rate ratios in both countries, with China experiencing a more obvious decrease. Smoking and high body mass index (BMI) were the leading risk factors for asthma mortality in China and the US, respectively. Mortality attributable to occupational asthmagens and smoking decreased the most in China and the US, respectively.

In 1990–2019, the asthma mortality rate was higher in China than in the US; however, the mortality gap has narrowed. Mortality increased with age in adults. The improvements in asthma death risk with period and birth cohort were more obvious in China than in the US. Smoking, high BMI, and aging are major health problems associated with asthma control. The role of occupational asthmagens in asthma mortality underscores the importance of management and prevention of occupational asthma.

The conversion of adenosine (A) to inosine (I) through deamination is the prevailing form of RNA editing, impacting numerous nuclear and cytoplasmic transcripts across various eukaryotic species. Millions of high-confidence RNA editing sites have been identified and integrated into various RNA databases, providing a convenient platform for the rapid identification of key drivers of cancer and potential therapeutic targets. However, the available database for integration of RNA editing in hematopoietic cells and hematopoietic malignancies is still lacking.

We downloaded RNA sequencing (RNA-seq) data of 29 leukemia patients and 19 healthy donors from National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database, and RNA-seq data of 12 mouse hematopoietic cell populations obtained from our previous research were also used. We performed sequence alignment, identified RNA editing sites, and obtained characteristic editing sites related to normal hematopoietic development and abnormal editing sites associated with hematologic diseases.

We established a new database, "REDH", represents RNA editome in hematopoietic differentiation and malignancy. REDH is a curated database of associations between RNA editome and hematopoiesis. REDH integrates 30,796 editing sites from 12 murine adult hematopoietic cell populations and systematically characterizes more than 400,000 edited events in malignant hematopoietic samples from 48 cohorts (human). Through the Differentiation, Disease, Enrichment, and knowledge modules, each A-to-I editing site is systematically integrated, including its distribution throughout the genome, its clinical information (human sample), and functional editing sites under physiological and pathological conditions. Furthermore, REDH compares the similarities and differences of editing sites between different hematologic malignancies and healthy control.

REDH is accessible at http://www.redhdatabase.com/. This user-friendly database would aid in understanding the mechanisms of RNA editing in hematopoietic differentiation and malignancies. It provides a set of data related to the maintenance of hematopoietic homeostasis and identifying potential therapeutic targets in malignancies.

The disease burdens for endometrial cancer (EC) vary across different countries and geographical regions and change every year. Herein, we reported the updated results of the Global Burden of Disease Study 2019 on EC with respect to age-standardized incidence and mortality from 1990 to 2019.

The annual percentage change (APC) of incidence and mortality was evaluated using joinpoint regression analysis to examine the temporal trends during the same timeframe in terms of the global landscape, different sociodemographic indices (SDI), and geographic regions. The relationship between Human Development Index (HDI) and incidence and mortality was additionally explored.

The age-standardized incidence rates (ASIRs) revealed a significant average global elevation by 0.5% per year (95% confidence interval [CI], 0.3–0.7; P <0.001). The age-standardized mortality rates (ASMRs), in contrast, fell by an average of 0.8% per year (95% CI, −1.0 to −0.7; P <0.001) worldwide. The ASIRs and ASMRs for EC varied across different SDIs and geographical regions. We noted four temporal trends and a significant reduction by 0.5% per year since 2010 in the ASIR, whereas we detected six consecutively decreasing temporal trends in ASMR during the entire period. Notably, the estimated APCs were significantly positively correlated with HDIs (ρ = 0.22; 95% CI, 0.07–0.35; P = 0.003) with regard to incident cases in 2019.

Incidence rates for EC reflected a significant increase overall (although we observed a decline since 2010), and the death rates declined consecutively from 1990 to 2019. We posit that more precise strategies can be tailored and then implemented based on the distinct age-standardized incidence and mortality burden in different geographical areas.

Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized immune-mediated disorder that can affect almost any organ in the human body. IgG4-RD can be categorized into proliferative and fibrotic subtypes based on patients’ clinicopathological characteristics. This study aimed to compare the clinical manifestations, laboratory findings, and treatment outcomes of IgG4-RD among different subtypes.

We prospectively enrolled 622 patients with newly diagnosed IgG4-RD at Peking Union Medical College Hospital from March 2011 to August 2021. The patients were divided into three groups according to their clinicopathological characteristics: proliferative, fibrotic, and mixed subtypes. We compared demographic features, clinical manifestations, organ involvement, laboratory tests, and treatment agents across three subtypes. We then assessed the differences in treatment outcomes among 448 patients receiving glucocorticoids alone or in combination with immunosuppressants. Moreover, risk factors of relapse were revealed by applying the univariate and multivariate Cox regression analysis.

We classified the 622 patients into three groups consisting of 470 proliferative patients, 55 fibrotic patients, and 97 mixed patients, respectively. We found that gender distribution, age, disease duration, and frequency of allergy history were significantly different among subgroups. In terms of organ involvement, submandibular and lacrimal glands were frequently involved in the proliferative subtype, while retroperitoneum was the most commonly involved site in both fibrotic subtype and mixed subtype. The comparison of laboratory tests revealed that eosinophils (P = 0.010), total IgE (P = 0.006), high-sensitivity C-reactive protein (P <0.001), erythrocyte sedimentation rate (P <0.001), complement C4 (P <0.001), IgG (P = 0.001), IgG1 (P <0.001), IgG4 (P <0.001), and IgA (P <0.001), at baseline were significantly different among three subtypes. Compared with proliferative and mixed subtypes, the fibrotic subtype showed the lowest rate of relapse (log-rank P = 0.014).

Our study revealed the differences in demographic characteristics, clinical manifestations, organ involvement, laboratory tests, treatment agents, and outcomes across proliferative, fibrotic, and mixed subtypes in the retrospective cohort study. Given significant differences in relapse-free survival among the three subtypes, treatment regimens, and follow-up frequency should be considered separately according to different subtypes.

ClinicalTrials. gov, NCT01670695.

A phase II trial on recombinant human tenecteplase tissue-type plasminogen activator (rhTNK-tPA) has previously shown its preliminary efficacy in ST elevation myocardial infarction (STEMI) patients. This study was designed as a pivotal postmarketing trial to compare its efficacy and safety with rrecombinant human tissue-type plasminogen activator alteplase (rt-PA) in Chinese patients with STEMI.

In this multicenter, randomized, open-label, non-inferiority trial, patients with acute STEMI were randomly assigned (1:1) to receive an intravenous bolus of 16 mg rhTNK-tPA or an intravenous bolus of 8 mg rt-PA followed by an infusion of 42 mg in 90 min. The primary endpoint was recanalization defined by thrombolysis in myocardial infarction (TIMI) flow grade 2 or 3. The secondary endpoint was clinically justified recanalization. Other endpoints included 30-day major adverse cardiovascular and cerebrovascular events (MACCEs) and safety endpoints.

From July 2016 to September 2019, 767 eligible patients were randomly assigned to receive rhTNK-tPA (n = 384) or rt-PA (n = 383). Among them, 369 patients had coronary angiography data on TIMI flow, and 711 patients had data on clinically justified recanalization. Both used a –15% difference as the non-inferiority efficacy margin. In comparison to rt-PA, both the proportion of patients with TIMI grade 2 or 3 flow (78.3% [148/189] vs. 81.7% [147/180]; differences: –3.4%; 95% confidence interval [CI]: –11.5%, 4.8%) and clinically justified recanalization (85.4% [305/357] vs. 85.9% [304/354]; difference: –0.5%; 95% CI: –5.6%, 4.7%) in the rhTNK-tPA group were non-inferior. The occurrence of 30-day MACCEs (10.2% [39/384] vs. 11.0% [42/383]; hazard ratio: 0.96; 95% CI: 0.61, 1.50) did not differ significantly between groups. No safety outcomes significantly differed between groups.

rhTNK-tPA was non-inferior to rt-PA in the effect of improving recanalization of the infarct-related artery, a validated surrogate of clinical outcomes, among Chinese patients with acute STEMI.

www.ClinicalTrials.gov (No. NCT02835534).

The effect of bariatric surgery on type 2 diabetes mellitus (T2DM) control can be assessed based on predictive models of T2DM remission. Various models have been externally verified internationally. However, long-term validated results after laparoscopic sleeve gastrectomy (LSG) surgery are lacking. The best model for the Chinese population is also unknown.

We retrospectively analyzed Chinese population data 5 years after LSG at Beijing Shijitan Hospital in China between March 2009 and December 2016. The independent t-test, Mann–Whitney U test, and chi-squared test were used to compare characteristics between T2DM remission and non-remission groups. We evaluated the predictive efficacy of each model for longterm T2DM remission after LSG by calculating the area under the curve (AUC), sensitivity, specificity, Youden index, positive predictive value (PPV), negative predictive value (NPV), and predicted-to-observed ratio, and performed calibration using Hosmer–Lemeshow test for 11 prediction models.

We enrolled 108 patients, including 44 (40.7%) men, with a mean age of 35.5 years. The mean body mass index was 40.3 ± 9.1 kg/m², the percentage of excess weight loss (%EWL) was (75.9 ± 30.4)%, and the percentage of total weight loss (% TWL) was (29.1 ± 10.6)%. The mean glycated hemoglobin A1c (HbA1c) level was (7.3 ± 1.8)% preoperatively and decreased to (5.9 ± 1.0)% 5 years after LSG. The 5-year postoperative complete and partial remission rates of T2DM were 50.9% [55/108] and 27.8% [30/108], respectively. Six models, i.e., "ABCD", individualized metabolic surgery (IMS), advanced-DiaRem, DiaBetter, Dixon et al’s regression model, and Panunzi et al’s regression model, showed a good discrimination ability (all AUC >0.8). The "ABCD" (sensitivity, 74%; specificity, 80%; AUC, 0.82 [95% confidence interval [CI]: 0.74–0.89]), IMS (sensitivity, 78%; specificity, 84%; AUC, 0.82 [95% CI: 0.73–0.89]), and Panunzi et al’s regression models (sensitivity, 78%; specificity, 91%; AUC, 0.86 [95% CI: 0.78–0.92]) showed good discernibility. In the Hosmer–Lemeshow goodness-of-fit test, except for DiaRem (P <0.01), DiaBetter (P <0.01), Hayes et al (P = 0.03), Park et al (P = 0.02), and Ramos-Levi et al’s (P <0.01) models, all models had a satifactory fit results (P >0.05). The P values of calibration results of the "ABCD" and IMS were 0.07 and 0.14, respectively. The predicted-to-observed ratios of the "ABCD" and IMS were 0.87 and 0.89, respectively.

The prediction model IMS was recommended for clinical use because of excellent predictive performance, good statistical test results, and simple and practical design features.

Pathological scars are a disorder that can lead to various cosmetic, psychological, and functional problems, and no effective assessment methods are currently available. Assessment and treatment of pathological scars are based on cutaneous manifestations. A two-photon microscope (TPM) with the potential for real-time non-invasive assessment may help determine the under-surface pathophysiological conditions in vivo. This study used a portable handheld TPM to image epidermal cells and dermal collagen structures in pathological scars and normal skin in vivo to evaluate the effectiveness of treatment in scar patients.

Fifteen patients with pathological scars and three healthy controls were recruited. Imaging was performed using a portable handheld TPM. Five indexes were extracted from two dimensional (2D) and three dimensional (3D) perspectives, including collagen depth, dermo-epidermal junction (DEJ) contour ratio, thickness, orientation, and occupation (proportion of collagen fibers in the field of view) of collagen. Two depth-dependent indexes were computed through the 3D second harmonic generation image and three morphology-related indexes from the 2D images. We assessed index differences between scar and normal skin and changes before and after treatment.

Pathological scars and normal skin differed markedly regarding the epidermal morphological structure and the spectral characteristics of collagen fibers. Five indexes were employed to distinguish between normal skin and scar tissue. Statistically significant differences were found in average depth (t = 9.917, P <0.001), thickness (t = 4.037, P <0.001), occupation (t= 2.169, P <0.050), orientation of collagen (t = 3.669, P <0.001), and the DEJ contour ratio (t = 5.105, P <0.001).

Use of portable handheld TPM can distinguish collagen from skin tissues; thus, it is more suitable for scar imaging than reflectance confocal microscopy. Thus, a TPM may be an auxiliary tool for scar treatment selection and assessing treatment efficacy.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer associated with poor prognosis and limited treatment options. The androgen receptor (AR) has emerged as a potential therapeutic target for luminal androgen receptor (LAR) TNBC. However, multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits. This study aimed to investigate the role of AR in TNBC and its detailed mechanism.

Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4 (NECTIN4) expression in TNBC tissues. Then, in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta (ERβ) in TNBC. Chromatin immunoprecipitation sequencing (ChIP-seq), co-immunoprecipitation (co-IP), molecular docking method, and luciferase reporter assay were performed to identify key molecules that affect the function of AR.

Based on the TNBC tissue array analysis, we revealed that ERβ and AR were positive in 21.92% (32/146) and 24.66% (36/146) of 146 TNBC samples, respectively, and about 13.70% (20/146) of TNBC patients were ERβ positive and AR positive. We further demonstrated the pro-tumoral effects of AR on TNBC cells, however, the oncogenic biology was significantly suppressed when ERβ transfection in LAR TNBC cell lines but not in AR-negative TNBC. Mechanistically, we identified that NECTIN4 promoter –42 bp to –28 bp was an AR response element, and that ERβ interacted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial–mesenchymal transition in tumor progression.

This study suggests that ERβ functions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation. Therefore, our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.

To the Editor:Esophageal cancer, one of the most common cancer types in China, with an estimated 346,633 new cases and 323,600 deaths in 2022, is becoming an increasingly serious clinical and public health problem.^[1]The successful promotion of the self-management strategy has indicated that lifestyle modifications can be valuable in the primary prevention of cancer development. Adopting a healthy lifestyle has become a novel strategy for primary prevention and risk reduction in high-risk areas. Previous epidemiological studies have identified several lifestyle-related risk factors for esophageal cancer, including smoking and diet.^[2]Each factor can typically explain a modest proportion of cancer risk. However, when combined, these known risk factors may substantially affect the risk of esophageal cancer. Nevertheless, some risk factors for esophageal cancer are non-modifiable, including age, low socioeconomic status, and family history. Whether and how these non-modifiable risk factors affect primary cancer prevention by intervening with modifiable risk factors remain unclear.

To the Editor:While 20–60% of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have comorbid asthma (known as refractory asthma), asthma is undiagnosed in 25–48% of CRSwNP patients with comorbid asthma.^[1]Moreover, the prevalence of persistent airflow limitation (PAL) is high in CRSwNP patients with comorbid asthma. However, the factors indicating comorbid asthma in patients with CRSwNP and reflecting PAL in those with comorbid asthma have not been fully elucidated. Small airway dysfunction (SAD) has been found in CRSwNP patients, even in the absence of asthma; and the severity of SAD in patients with comorbid asthma is correlated with the duration of asthma history.^[2]This study therefore aimed to evaluate the clinical characteristics, especially small airway parameters as indicators of comorbid asthma in patients with CRSwNP and of PAL in CRSwNP patients with comorbid asthma. Besides, in order to identify the characteristics of CRSwNP patients with asthma, we also compared the prevalence of SAD and PAL between asthma patients with or without CRSwNP.

To the Editor: Chronic obstructive pulmonary disease (COPD) is a condition that severely endangers human health. In 2018, Wanget al^[1]reported that there are approximately 100 million patients with COPD in China, with a 13.7% prevalence in people aged over 40 years. The disease severity, frequency of exacerbations, and comorbidities, which are commonly (30–57%) observed in patients with COPD, are the three most crucial elements affecting the economic and societal consequences of COPD.^[2]Hospitalizations for exacerbations are the main contributors to health care expenses. To reduce the clinical and financial burden of COPD, interventions are needed to slow the disease course, avoid exacerbations, and reduce comorbidities, such as approaches for improving the prognosis and treatment efficacy in COPD. Advances in high-throughput omics technology have revolutionized disease research. We gathered data regarding omics methods in the field of COPD research. Genomics, transcriptomics, single-cell transcriptome analysis, proteomics, metabolomics, microbiomics, radiomics, and pharmacogenomics studies were obtained from the PubMed database. Our findings revealed the factors related to COPD prognosis and treatment efficacy by using omics data with predictive potential [Supplementary Figure 1, http://links.lww.com/CM9/B913]. Omics may constitute a powerful tool for monitoring COPD prognosis, providing hope for future individualized treatment.

To the Editor:Significant hyperfibrinolysis is always accompanied by surgical trauma and tourniquet use in total knee arthroplasty (TKA), leading to considerable hidden blood loss, inflammation, and pain, thereby impeding the recovery process. Enhanced recovery after surgery (ERAS) has promoted the development of patient blood management in recent decades. And numerous methods of blood conservation, including tranexamic acid (TXA), a lysine analog competitive inhibitor of plasmin and plasminogen, have been studied.^[1,2,3]However, some issues remain controversial, such as the optimal TXA regimen in TKA. On the other hand, the use of TXA in arthroplasty is considered off-label, although the current guideline or consensus suggests its routine use in arthroplasty. Furthermore, the maximum daily dose of TXA specified in the specification is 2 g. Our preceding single-center study demonstrated that a high initial dose (60 mg/kg) plus three postoperative doses (3 h, 12 h, and 24 h for 1 g) should provide the ceiling effect on blood-sparing in TKA when compared with the regimen of 60 mg/kg plus five postoperative doses.^[4]These results were encouraging, but it is unclear if the total dose (approximately 6 g) is superior to the legal dose (2 g).

To the Editor: Norepinephrine (NE), which belongs to the catecholamine family, is increasingly produced by the sympathetic nervous system and adrenal medulla when the host is under stress. It has been demonstrated that NE has a significant anti-inflammatory effect. In addition, increasing evidence has indicated that stress hormones are directly involved in the interaction between bacteria and the host. A variety of bacteria can exhibit changes in growth, virulence, and biofilm by high concentrations of NE. Therefore, this article aimed to summarize the main research developments regarding the effects of NE on host immunity and bacterial infection, as well as the attendant molecular mechanisms [Figure 1].

To the Editor: Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy characterized by extracellular deposition of misfolded insoluble amyloid fibrils.^[1]Electrocardiography (ECG) is an essential diagnostic test characterized by low QRS voltages in CA, observed in 20–74% of patients.^[2]Ciprianiet al^[3]reported that low QRS voltages could independently predict cardiovascular death. But the mechanisms underlying low QRS voltages in CA remain unclear.

To the Editor: Breast cancer is a prevalent malignant tumor and ranks as the second leading cause of cancer-related deaths globally.^[1]The breast is the target organ of some endocrine hormones, which regulate its growth and development. Aside from estrogen and progesterone, the relationship among prolactin, androgen, and breast cancer has recently garnered increasing attention.

To the Editor: Varicocele (VC) is a vascular disease and considered as the main cause of male infertility.^[1]The incidence of VC in the common male population was 4.4–22.6%, of which the incidence of primary infertility was 35–40%, while the incidence of secondary infertility was as high as 80%.^[2]The exact pathophysiological mechanism of male infertility caused by VC and regulative molecules are still unclear. Clear and definite molecular markers of VC disease are helpful for early prevention and timely treatment. This study aimed to screen candidate regulative molecules playing a role in male infertility caused by VC.

To the Editor: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a group of serious complications of systemic lupus erythematosus (SLE) with poor prognosis and high mortality.^[1]Therefore, identifying risk factors for NPSLE is particularly crucial for the improvement of the outcomes of patients. Magnetic resonance imaging (MRI) is currently the imaging test of choice for diagnosing patients with NPSLE. However, almost half of the patients with NPSLE show no abnormalities on conventional MRI.^[2]Therefore, the correlation between neuropsychiatric symptoms, which refer to multiple neuropsychiatric manifestations directly related to SLE, and MRI findings should be urgently studied. In this study, we investigated the clinical features, outcomes, and prognostic factors of NPSLE and analyzed the correlation of neuropsychiatric symptoms with MRI features.

To the Editor:Parathyroid tumors are endocrine tumors that can lead to disorders of calcium and phosphorus metabolism and involve multiple organ systems. In the past, the genetics of parathyroid tumors have been well established, and the significant roles of genes such asMEN1,CDC73, andCCND1in the process of parathyroid tumorigenesis have been identified and confirmed [Table 1]. However, with further research and the widespread use of sequencing technology, "new" roles for "old" genes and new pathogenic mechanisms have been discovered.