2023年 · 第136卷第18期

Inflammatory bowel disease (IBD) is a debilitating chronic inflammatory disorder that primarily affects the digestive system, which mainly encompasses Crohn’s disease (CD) and ulcerative colitis (UC). Currently, the exact pathogenesis of IBD has not reached a unified conclusion, and most theories attribute it to the result of a combination of genetic, environmental, immunological, and microbial factors. Despite the availability of various treatment options such as biological agents, the management of IBD remains a significant challenge owing to the complicated and heterogeneous nature of this disease. An updated understanding of its pathogenesis and the development of potential molecular targeting agents is required.^[1]

Incomplete immune reconstitution remains a global challenge for human immunodeficiency virus (HIV) treatment in the present era of potent antiretroviral therapy (ART), especially for those individuals referred to as immunological non-responders (INRs), who exhibit dramatically low CD4⁺ T-cell counts despite the use of effective antiretroviral therapy, with long-term inhibition of viral replication. In this review, we provide a critical overview of the concept of ART-treated HIV-positive immunological non-response, and also explain the known mechanisms which could potentially account for the emergence of immunological non-response in some HIV-infected individuals treated with appropriate and effective ART. We found that immune cell exhaustion, combined with chronic inflammation and the HIV-associated dysbiosis syndrome, may represent strategic aspects of the immune response that may be fundamental to incomplete immune recovery. Interestingly, we noted from the literature that metformin exhibits properties and characteristics that may potentially be useful to specifically target immune cell exhaustion, chronic inflammation, and HIV-associated gut dysbiosis syndrome, mechanisms which are now recognized for their critically important complicity in HIV disease-related incomplete immune recovery. In light of evidence discussed in this review, it can be seen that metformin may be of particularly favorable use if utilized as adjunctive treatment in INRs to potentially enhance immune reconstitution. The approach described herein may represent a promising area of therapeutic intervention, aiding in significantly reducing the risk of HIV disease progression and mortality in a particularly vulnerable subgroup of HIV-positive individuals.

Immune checkpoint inhibitors (ICIs) are standard treatments for advanced non-small cell lung cancer (NSCLC); however, evidence regarding their relative efficacy and safety is lacking. This study compared the efficacy and safety of all currently available ICI treatments in patients with advanced NSCLC to identify optimal treatment regimens.

PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase databases were systematically searched for randomized controlled trials (RCTs) published up to August 8, 2022. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes included objective response rate (ORR) and adverse events (AEs).

Forty RCTs involving 22,526 patients were selected, and a total of 26 treatment regimens were identified. Treatment with anti-programmed cell death protein-1 (anti-PD-1) provided superior OS compared with anti-programmed death ligand 1 (anti-PD-L1) treatment. ICIs plus platinum-based chemotherapy (PBC) were superior to ICIs treatment alone, although the addition of PBC increased treatment toxicity. Cemiplimab ranked first for OS and lowest for any-grade AEs in advanced NSCLC patients without PD-L1 selection. Regarding grade ≥3 AEs, the toxicity of ICI monotherapy or ICI-ICI combination was consistently lower than that of the other treatments. For patients without PD-L1 selection, cemiplimab showed the best OS, pembrolizumab plus docetaxel (Pem-DXT) showed the best PFS, and atezolizumab plus bevacizumab and PBC (Atezo-Beva-PBC) showed the best ORR. Pembrolizumab plus PBC and Atezo-Beva-PBC were the most likely optimal treatments for OS and PFS in patients with PD-L1 expression <1%, respectively. In patients with PD-L1 expression ≥1%, treatment regimens containing anti-PD-1 provided superior OS benefits compared with those of anti-PD-L1 treatment, and sintilimab plus PBC (Sint-PBC) provided the best OS benefit; as for PFS, ICI plus PBC consistently showed greater PFS benefits than ICI or PBC alone. For patients with anti-PD-L1 expression of 1-49%, camrelizumab plus PBC provided the best benefit for OS and PFS among included treatment. Durvalumab-tremelimumab-PBC and Atezo-Beva-PBC respectively presented the highest OS and PFS for patients with PD-L1 expression ≥50%. Moreover, cemiplimab and Atezo-Beva-PBC yielded the best OS and PFS benefits as first-line treatments for patients with advanced NSCLC, respectively.

Although ICI plus PBC likely resulted in superior survival outcomes compared to ICI treatment alone, it did increase toxicity. Cemiplimab presented a well-balanced efficacy and safety profile in advanced NSCLC treatment. Our findings with the current ICIs comparisons will aid future trials for cancer immunotherapy.

PROSPERO, https://www.crd.york.ac.uk/PROSPERO/, CRD42022323879.

As oncology surgeons, we always adhere to the norms of medicine and abide by the medical ethics and morals in our clinical practice. However, we often encounter professional dilemmas resulting in conflicts between surgical or clinical medicine principles and medical ethics in the practice of medicine, although such conflicts are not always equally divided along these lines. Herein, I present two such cases. Three years ago, I met a 32-year-old male patient.^[1]After undergoing abdominoperineal resection for rectal cancer, the patient’s cancer recurred at the stoma site. The tumor was so large that no stoma protector could cover it at the stoma site. The large amount of feces, coupled with local tumor ulceration and infection, caused critical contamination at the patient’s stoma site. Suffering greatly, the patient had an extremely poor quality of life. After completing various examinations, we could not exclude that the patient had microscopic metastases in the lungs. Cancer of the stoma is clinically exceedingly rare, with only sporadic cases reported.^[2,3]In terms of general surgical principles, performing surgery in a case where a massive stoma tumor has distant metastases is considered pointless. However, this patient confided, "I have no dignity at all; I can not go out and my daughter refuses to let me hug her." He continued, "What is the point of living?" I have been practicing medicine for 40 years, but this was the first time I encountered a conflict between surgical norms and a patient’s dignity. Hence, I operated on the patient in consideration of their circumstances, specifically their dignity and quality of life. The patient was overjoyed post-surgery and told me that he could once more hug his daughter; unfortunately, the patient died 6 months later due to tumor recurrence. The second case occurred just last week. A female patient with gastric cancer, also 33 years old, presented with bilateral huge ovarian metastases and massive ascites. The patient had severe abdominal distention and was unable to sit. The initial intention was to surgically remove her enlarged ovaries to relieve the clinical symptoms. However, intraoperative exploration revealed rice-like microscopic, disseminated foci throughout the peritoneum, multiple visible microscopic metastatic nodules in the greater omentum and peritoneum, with a large amount of ascites. Subsequently, after conferring with colleagues in the field, we agreed that surgery should not be performed and aborted the planned oophorectomy. I remember seeing the young patient curled up with great pain in her hospital bed. I felt guilty, because if I had performed the surgery on her, she would now be comfortably lying flat on her back. While the surgery would not have prolonged her life, it would have at least significantly improved her quality of life in her last moments. Nonetheless, at this point, she would continue to struggle in pain on her bed and wait for her life to end. This kind of predicament has been bothering me recently. As physicians, especially oncology surgeons, there are surgical interventions that significantly improve the quality of life of patients in advanced stages of cancer; however, these practices may sometimes conflict with medical norms. The patient with advanced stoma cancer had surgery that allowed them to spend their remaining 6 months with dignity, whereas this female patient of the same age was in severe pain, waiting to die. In the former case, my medical decisions might provoke doubts among professional peers and be deemed controversial, whereas in the latter case, I abided by the principles of medicine. Despite practicing medicine for 40 years, these two unique results made me feel uncertain and confused about my profession. Not all doctors would have made the same clinical decisions, and I do not proclaim that mine were necessarily correct. In thinking this matter through, I return to the same questions: What is the original intention of medicine? How can the conflict between the norms and ethics of medicine be resolved? At times, surgeons are confronted with many choices that directly alter a patient’s outcomes, even though some of these outcomes may only be short-lived. We can neither take the moral high ground by denigrating the clinical decisions made by surgeons based on clinical norms nor overly praise the "benefits." These decisions may lead to short-term positive results, which physicians offer to patients out of compassion and responsibility at considerable risk-this made me consider certain things. First, although surgeons abide by the principles of medical ethics, the benefit to the patient is often difficult to define and the surgeon’s subjective judgment might be considered rational. In many cases, this judgment of patient benefit varies between individuals, with the decision maker often being the most senior physician involved at the operating table. Second, we must consider whether the surgeon’s decisions are consistent with the patient’s subjective wishes. Sometimes the decisions made by physicians according to the wishes of the patient and their family are at odds with the objective outcomes of such decisions, at times contradicting them, which could affect the physician-patient relationship and lead to legal disputes. Third, the mutual trust between physicians and patients is a basic and essential requirement of the practice of medicine. In its absence, the unpredictable and sometimes adverse results produced by physicians’ best efforts could have a significantly adverse impact on the relationship between physicians and patients. Rationality, compassion, a professional attitude, and upholding professional standards are attributes expected from the surgical profession. Concomitantly, we must ask how surgeons, especially young physicians, can adhere to the principles of medical ethics and maintain their original aspirations in medicine. This question must be answered to ensure that every patient can receive the appropriate treatment made available through medical technology in this information age and, further, allow them to spend their remaining time in dignity and peace, enjoying the best possible quality of life through the professionalism of surgeons. These remain pivotal topics in the continuous medical education of surgeons.

Women comprise more than half of people living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) worldwide and incomplete immune recovery and metabolic abnormalities affect them deeply. Studies of HIV antiretroviral therapy (ART) have a low female representation in China. We aimed to investigate immune reconstitution and metabolic changes of female HIV-positive cohort in China longitudinally.

HIV-positive women who initiated ART from January 2005 to June 2021 and were followed up regularly at least once a year were included in this study. Immunological indicators (cluster of differentiation 4 [CD4] counts and CD8 counts), viral load (VL), and metabolic indicators were collected at follow-up. All data were collected from the China Disease Prevention and Control Information System (CDPCIS). VL was tested half a year, 1 year after receiving ART, and every other year subsequently according to local policy. CD4/CD8 ratio normalization was considered as the primary outcome and defined as a value ≥1. Incidence rate and probability of CD4/CD8 ratio normalization were estimated through per 100 person-years follow-up (PYFU) and Kaplan-Meier curve, respectively. Multivariate Cox regression was used to identify independent risk factors associated with CD4/CD8 ratio normalization. We further studied the rate of dyslipidemia, hyperuricemia, diabetes, liver injury, and renal injury after ART initiation with the chi-squared tests or Fisher’s exact probability tests, and a generalized estimating equation model was used to analyze factors of dyslipidemia and hyperuricemia.

A total of 494 female patients with HIV/AIDS started ART within 16 years from January 2005 to June 2021, out of which 301 women were enrolled with a median duration of ART for 4.1 years (interquartile range, 2.3-7.0 years). The overall incidence rate of CD4/CD8 ratio normalization was 8.9 (95% confidence interval [CI], 7.4-10.6) per 100 PYFU, and probabilities of CD4/CD8 normalization after initiating ART at 1 year, 2 years, 5 years, and 10 years follow-up were 11.7%, 23.2%, 44.0%, and 59.0%, respectively. Independent risk factors associated with CD4/CD8 normalization were baseline CD4 cell counts <200 cells/μL, CD8 counts >1000 cells/μL, and more than 6 months from the start of combined ART (cART) to first virological suppression. Longitudinally, the rate of hypercholesterolemia (total cholesterol [TC]) and high triglyceride (TG) showed an increasing trend, while the rate of low high-density lipoprotein cholesterol (HDL) showed a decreasing trend. The rate of hyperuricemia presented a downtrend at follow-up. Although liver and renal injury and diabetes persisted during ART, the rate was not statistically significant. Older age and protease inhibitors were independent risk factors for increase of TC and TG, and ART duration was an independent factor for elevation of TC and recovery of HDL-C.

This study showed that women were more likely to normalize CD4/CD8 ratio in comparison with findings reported in the literature even though immune reconstruction was incomplete.

Changes in white matter (WM) underlie the neurocognitive damages induced by a human immunodeficiency virus (HIV) infection. This study aimed to examine using a bundle-associated fixel-based analysis (FBA) pipeline for investigating the microstructural and macrostructural alterations in the WM of the brain of HIV patients.

This study collected 93 HIV infected patients and 45 age/education/handedness matched healthy controls (HCs) at the Beijing Youan Hospital between January 1, 2016 and December 30, 2016. All HIV patients underwent neurocognitive evaluation and laboratory testing followed by magnetic resonance imaging (MRI) scanning. In order to detect the bundle-wise WM abnormalities accurately, a specific WM bundle template with 56 tracts of interest was firstly generated by an automated fiber clustering method using a subset of subjects. Fixel-based analysis was used to investigate bundle-wise differences between HIV patients and HCs in three perspectives: fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC). The between-group differences were detected by a two-sample t-test with the false discovery rate (FDR) correction (P <0.05). Furthermore, the covarying relationship in FD, FC and FDC between any pair of bundles was also accessed by the constructed covariance networks, which was subsequently compared between HIV and HCs via permutation t-tests. The correlations between abnormal WM metrics and the cognitive functions of HIV patients were explored via partial correlation analysis after controlling age and gender.

Among FD, FC and FDC, FD was the only metric that showed significant bundle-wise alterations in HIV patients compared to HCs. Increased FD values were observed in the bilateral fronto pontine tract, corona radiata frontal, left arcuate fasciculus, left corona radiata parietal, left superior longitudinal fasciculus III, and right superficial frontal parietal (SFP) (all FDR P <0.05). In bundle-wise covariance network, HIV patients displayed decreased FD and increased FC covarying patterns in comparison to HC (P <0.05), especially between associated pathways. Finally, the FCs of several tracts exhibited a significant correlation with language and attention-related functions.

Our study demonstrated the utility of FBA on detecting the WM alterations related to HIV infection. The bundle-wise FBA method provides a new perspective for investigating HIV-induced microstructural and macrostructural WM-related changes, which may help to understand cognitive dysfunction in HIV patients thoroughly.

Clinical trial evidence is limited to identify better topical non-steroidal anti-inflammatory drugs (NSAIDs) for treating knee osteoarthritis (OA). We aimed to compare the clinical efficacy and safety of flurbiprofen cataplasms (FPC) with loxoprofen sodium cataplasms (LSC) in treating patients with knee OA.

This is an open-label, non-inferiority randomized controlled trial conducted at Peking University Shougang Hospital. Overall, 250 patients with knee OA admitted from October 2021 to April 2022 were randomly assigned to FPC and LSC treatment groups in a 1: 1 ratio. Both medications were administered to patients for 28 days. The primary outcome was the change of pain measured by visual analog scale (VAS) score from baseline to day 28 (range, 0-10 points; higher score indicates worse pain; non-inferiority margin: 1 point; superiority margin: 0 point). There were four secondary outcomes, including the extent of pain relief, the change trends of VAS scores, joint function scores measured by the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and adverse events.

Among 250 randomized patients (One patient without complete baseline record in the flurbiprofen cataplasms was excluded; age, 62.8 ± 10.5 years; 61.4% [153/249] women), 234 (93.6%) finally completed the trial. In the intention-to-treat analysis, the decline of the VAS score for the 24-h most intense pain in the FPC group was non-inferior, and also superior to that in the LSC group (differences and 95% confidence interval, 0.414 (0.147-0.681); P <0.001 for non-inferiority; P = 0.001 for superiority). Similar results were observed of the VAS scores for the current pain and pain during exercise. WOMAC scores were also lower in the FPC group at week 4 (12.50 [8.00-22.50] vs. 16.00 [11.00-27.00], P = 0.010), mainly driven by the dimension of daily activity difficulty. In addition, the FPC group experienced a significantly lower incidence of adverse events (5.6% [7/124] vs. 33.6% [42/125], P <0.001), including irritation, rash and pain of the skin, and sticky hair uncovering pain.

This study suggested that FPC is superior to LSC for treating patients with knee OA in pain relief, joint function improvement, and safety profile.

ChiCTR.org.cn, ChiCTR2100054822

The relationship between the elevation of cardiac troponin and the increase of mortality and hospitalization rate in patients with heart failure with reduced ejection fraction is clear. This study investigated the association between the extent of elevated levels of high-sensitivity cardiac troponin I (hs-cTnI) and the prognosis in heart failure with preserved ejection fraction patients.

A retrospective cohort study consecutively enrolled 470 patients with heart failure with preserved ejection fraction from September 2014 to August 2017. According to the level of hs-cTnI, the patients were divided into the elevated level group (hs-cTnI >0.034 ng/mL in male and hs-cTnI >0.016 ng/mL in female) and the normal level group. All of the patients were followed up once every 6 months. Adverse cardiovascular events were cardiogenic death and heart failure hospitalization.

The mean follow-up period was 36.2 ± 7.9 months. Cardiogenic mortality (18.6% [26/140] vs. 1.5% [5/330], P <0.001) and heart failure (HF) hospitalization rate (74.3% [104/140] vs. 43.6% [144/330], P <0.001) were significantly higher in the elevated level group. The Cox regression analysis showed that the elevated level of hs-cTnI was a predictor of cardiogenic death (hazard ratio [HR]: 5.578, 95% confidence interval [CI]: 2.995-10.386, P <0.001) and HF hospitalization (HR: 3.254, 95% CI: 2.698-3.923, P <0.001). The receiver operating characteristic curve demonstrated that a sensitivity of 72.6% and specificity of 88.8% for correct prediction of adverse cardiovascular events when a level of hs-cTnI of 0.1305 ng/mL in male and a sensitivity of 70.6% and specificity of 90.2% when a level of hs-cTnI of 0.0755 ng/mL in female were used as the cut-off value.

Significant elevation of hs-cTnI (≥0.1305 ng/mL in male and ≥0.0755 ng/mL in female) is an effective indicator of the increased risk of cardiogenic death and HF hospitalization in heart failure with preserved ejection fraction patients.

Limited data are available on the changes in the quality of care for ST elevation myocardial infarction (STEMI) during China’s health system reform from 2009 to 2020. This study aimed to assess the changes in care processes and outcome for STEMI patients in Henan province of central China between 2011 and 2018.

We compared the data from the Henan STEMI survey conducted in 2011-2012 (n = 1548, a cross-sectional study) and the Henan STEMI registry in 2016-2018 (n = 4748, a multicenter, prospective observational study). Changes in care processes and in-hospital mortality were determined. Process of care measures included reperfusion therapies, aspirin, P2Y12 antagonists, β-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins. Therapy use was analyzed among patients who were considered ideal candidates for treatment.

STEMI patients in 2016-2018 were younger (median age: 63.1 vs. 63.8 years) with a lower proportion of women (24.4% [1156/4748] vs. 28.2% [437/1548]) than in 2011-2012. The composite use rate for guideline-recommended treatments increased significantly from 2011 to 2018 (60.9% [5424/8901] vs. 82.7% [22,439/27,129], P <0.001). The proportion of patients treated by reperfusion within 12 h increased from 44.1% (546/1237) to 78.4% (2698/3440) (P <0.001) with a prolonged median onset-to-first medical contact time (from 144 min to 210 min, P <0.001). The use of antiplatelet agents, statins, and β-blockers increased significantly. The risk of in-hospital mortality significantly decreased over time (6.1% [95/1548] vs. 4.2% [198/4748], odds ratio [OR]: 0.67, 95% confidence interval [CI]: 0.50-0.88, P = 0.005) after adjustment.

Gradual implementation of the guideline-recommended treatments in STEMI patients from 2011 to 2018 has been associated with decreased in-hospital mortality. However, gaps persist between clinical practice and guideline recommendation. Public awareness, reperfusion strategies, and construction of chest pain centers need to be further underscored in central China.

Gallbladder cancer (GBC) is the most common malignant tumor of biliary tract. Isoliquiritigenin (ISL) is a natural compound with chalcone structure extracted from the roots of licorice and other plants. Relevant studies have shown that ISL has a strong anti-tumor ability in various types of tumors. However, the research of ISL against GBC has not been reported, which needs to be further investigated.

The effects of ISL against GBC cells in vitro and in vivo were characterized by cytotoxicity test, RNA-sequencing, quantitative real-time polymerase chain reaction, reactive oxygen species (ROS) detection, lipid peroxidation detection, ferrous ion detection, glutathione disulphide/glutathione (GSSG/GSH) detection, lentivirus transfection, nude mice tumorigenesis experiment and immunohistochemistry.

ISL significantly inhibited the proliferation of GBC cells in vitro. The results of transcriptome sequencing and bioinformatics analysis showed that ferroptosis was the main pathway of ISL inhibiting the proliferation of GBC, and HMOX1 and GPX4 were the key molecules of ISL-induced ferroptosis. Knockdown of HMOX1 or overexpression of GPX4 can reduce the sensitivity of GBC cells to ISL-induced ferroptosis and significantly restore the viability of GBC cells. Moreover, ISL significantly reversed the iron content, ROS level, lipid peroxidation level and GSSG/GSH ratio of GBC cells. Finally, ISL significantly inhibited the growth of GBC in vivo and regulated the ferroptosis of GBC by mediating HMOX1 and GPX4.

ISL induced ferroptosis in GBC mainly by activating p62-Keap1-Nrf2-HMOX1 signaling pathway and downregulating GPX4 in vitro and in vivo. This evidence may provide a new direction for the treatment of GBC.

The effect of arteriosclerotic intracranial arterial vessel wall enhancement (IAVWE) on downstream collateral flow found in vessel wall imaging (VWI) is not clear. Regardless of the mechanism underlying IAVWE on VWI, damage to the patient’s nervous system caused by IAVWE is likely achieved by affecting downstream cerebral blood flow. The present study aimed to investigate the effect of arteriosclerotic IAVWE on downstream collateral flow.

The present study recruited 63 consecutive patients at the Second Hospital of Hebei Medical University from January 2021 to November 2021 with underlying atherosclerotic diseases and unilateral middle cerebral artery (MCA) M1-segment stenosis who underwent an magnetic resonance scan within 3 days of symptom onset. The patients were divided into 4 groups according to IAVWE and the stenosis ratio (Group 1, n = 17; Group 2, n = 19; Group 3, n = 13; Group 4, n = 14), and downstream collateral flow was analyzed using three-dimensional pseudocontinuous arterial spin labeling (3D-pCASL) and RAPID software. The National Institutes of Health Stroke Scale (NIHSS) scores of the patients were also recorded. Two-factor multivariate analysis of variance using Pillai’s trace was used as the main statistical method.

No statistically significant difference was found in baseline demographic characteristics among the groups. IAVWE, but not the stenosis ratio, had a statistically significant significance on the late-arriving retrograde flow proportion (LARFP), hypoperfusion intensity ratio (HIR), and NIHSS scores (F = 20.941, P <0.001, Pillai’s trace statistic = 0.567). The between-subject effects test showed that IAVWE had a significant effect on the three dependent variables: LARFP (R² = 0.088, F = 10.899, P = 0.002), HIR (R² = 0.234, F = 29.354, P <0.001), and NIHSS (R² = 114.339, F = 33.338, P <0.001).

Arteriosclerotic IAVWE significantly reduced downstream collateral flow and affected relevant neurological deficits. It was an independent factor affecting downstream collateral flow and NIHSS scores, which should be a focus of future studies.

ChiCTR.org.cn, ChiCTR2100053661

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The ubiquitin-specific peptidase 25 (USP25) protein has been reported to participate in the development of several cancers. However, few studies have reported its association with HCC. In this study, we aimed to investigate the function and mechanism of USP25 in the progression of HCC.

We analyzed USP25 protein expression in HCC based on The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database cohorts. Then, we constructed USP25-overexpressing and USP25-knockdown HepG2, MHCC97H, and L-O2 cells. We detected the biological function of USP25 by performing a series of assays, such as Cell Counting Kit-8 (CCK-8), colony formation, transwell, and wound healing assays. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) analyses were performed to detect the interaction between USP25 and the Wnt/β-catenin signaling pathway. The relationship between USP25 and tripartite motif-containing 21 (TRIM21) was assessed through mass spectrometry and co-immunoprecipitation (Co-IP) analysis. Finally, we constructed a mouse liver cancer model with the USP25 gene deletion to verify in vivo role of USP25.

USP25 was highly expressed in HCC tissue and HCC cell lines. Importantly, high expression of USP25 in tissues was closely related to a poor prognosis. USP25 knockdown markedly reduced the proliferation, migration, and invasion of HepG2 and MHCC97H cells, whereas USP25 overexpression led to the opposite effects. In addition, we demonstrated that USP25 interacts with TRIM21 to regulate the expression of proteins related to epithelial-mesenchymal transition (EMT; E-cadherin, N-cadherin, and Snail) and the Wnt/β-catenin pathway (β-catenin, Adenomatous polyposis coli, Axin2 and Glycogen synthase kinase 3 beta) and those of their downstream proteins (C-myc and Cyclin D1). Finally, we verified that knocking out USP25 inhibited tumor growth and distant metastasis in vivo.

In summary, our data showed that USP25 was overexpressed in HCC. USP25 promoted the proliferation, migration, invasion, and EMT of HCC cells by interacting with TRIM21 to activate the β-catenin signaling pathway.

To the Editor:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that caused the 2019 coronavirus disease (COVID-19) pandemic. Over two years after the initial outbreak, several more infectious variations of the virus continue to pose a grave threat to global public health.^[1]Intense, worldwide efforts for vaccine development have led to several candidate vaccines utilizing a variety of platforms; moreover, new vaccines are gradually entering the clinical evaluation stages, including inactivated vaccines, recombinant protein vaccines, and DNA or RNA vaccines. The safety and immunogenicity of several vaccine platforms, such as BNT162b2 and ChAdOx1, in patients diagnosed with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) have been published.^[2]Minor side effects have been reported in some people living with HIV-1 (PLWH) who received the SARS-COV-2 mRNA vaccine.^[2]Two inactivated SARS-CoV-2 vaccines produced by Chinese companies have been approved for emergency use by the World Health Organization (WHO) (Sinopharm and Sinovac CoronaVac, Beijing, China); however, there is a paucity in the availability of data pertaining to the use of inactivated vaccines in HIV-infected people. Huanget al^[3]addressed the safety and immunogenicity of the inactivated vaccine in HIV-infected people with no serious adverse reactions reported.^[4]Among HIV-infected people with less than 500 CD4⁺T cells/μL, the serum conversion rate, neutralizing antibody (nAb) positive rate, and the nAb activity rate were lower than in patients with levels greater than 500 CD4⁺T cells/μL. Furthermore, alterations in HIV-1 viral load were not significantly associated with vaccine-induced CD4⁺T cell activation.^[5]Another study testing the effect of low CD4⁺T cell counts showed that the immunogenicity elicited by BNT162b2 was dramatically lower in PLWH who had less than 250 CD4⁺T cells/μL.^[6]

To the Editor:Lung cancer, one of the most common types of tumor, is also the leading cause of cancer death, accounting for an estimated 1.8 million deaths worldwide. Early recognition of lung cancer is critical. It has been established that nitric oxide and its byproducts play a role in pathophysiological processes of lung cancer, such as tumor immunity, inflammation, and lung tumor progression.^[1]Exhaled nitric oxide (eNO) concentrations can be measured by non-invasive devices. The alveolar concentration of nitric oxide (CaNO) has been proposed as a marker of distal airway inflammation, but its value in non-small cell lung cancer (NSCLC) is unknown.

To the Editor: Acute concomitant esotropia (ACE) is an acquired esotropia with a sudden appearance and no pathologic changes on cerebral imaging. There are various treatments for ACE, including extraocular muscle surgery, botulinum toxin A (BTA) injection, prisms, and divergence training.^[1]BTA had been used in the treatment of ACE since it was approved by Food and Drug Administration (FDA, USA) in 1989.^[2]Some researchers have confirmed that its effect is stable and has unique advantages in the treatment of ACE, such as less trauma, shorter anesthesia time and earlier intervention, etc.^[3]

To the Editor:Neurovascular injury is an uncommon complication of clavicle fractures, and occurs in at most 1% of all clavicle fractures. Neurovascular injury is mostly caused by high-energy blunt injury to the clavicle.^[1]Because its symptoms are less prominent, these vascular injuries are easily neglected and may result in severe consequences. However, few studies have reported a standardized management for this rare trauma. Here, we present a case of a 30-year-old man who suffered an open clavicle fracture with acute subclavian artery and brachial plexus injuries. After treating this case, we concluded that neurovascular examinations and multidisciplinary therapeutic strategies are urgently needed for clavicle fractures with associated neurovascular injury. The authors certify that they have obtained the patient’s consent to the publication of information about him in a journal or thesis. The information will be published without the patient’s name attached and every attempt will be made to ensure anonymity.

To the Editor:Parkinson’s disease (PD) is one of the most common neurodegenerative movement disorders.^[1]Its cardinal symptoms include bradykinesia, tremor, and rigidity.^[2]The severity of PD-related motor symptoms is usually semiquantitatively evaluated by the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)^[3]part three (MDS-UPDRS III). A series of machine perception and machine learning technologies have been applied to assist the manual rating of motor symptoms.^[4,5]Machine vision, which does not require physical contact between the examiner and the patient, has the potential for real-world application in remote assessments.^[5]

To the Editor: Thermal ablation (TA) techniques have been widely used for the management of benign thyroid nodules (BTNs) and have been suggested as an alternative to surgery in some authoritative guidelines.^[1]In theory, TA causes follicle destruction in the BTNs and a large release of the thyroid hormone stored in the follicles into the bloodstream; then, a dramatic change in thyroid function may occur. However, for euthyroid patients, researchers believe that TA treatment can preserve thyroid function and that these patients rarely develop thyroid dysfunction in the long term.^[2]Nevertheless, for patients with pre-existing thyrotoxicosis, whether the release of thyroid hormone causes thyroid storm (TS) and how their thyroid function changes after TA are unknown. Therefore, we retrospectively summarized these cases of patients with subclinical or overt thyrotoxicosis before TA in our institute, aiming to provide more information about the effects of TA on these patients with pre-existing thyrotoxicosis.

Lymphadenopathy is defined as lymph nodes (LN) that are abnormal in size or consistency, usually with a diameter >1 cm. Common etiologies include malignancy, infection, autoimmune disorders, and medications.^[1]Most patients obtain a definite diagnosis after undergoing a series of examinations. However, the etiology remains unclear in a small number of patients.

To the Editor: Intranasal spray vaccines (ISVs) can produce cellular immunity against severe acute respiratory syndrome virus 2 (SARS-CoV-2) variants and have good safety and protective effects.^[1]However, the attitudes of vaccination service providers toward ISVs have rarely been studied. This study investigated the attitudes of service providers towards vaccination processes that require optimization and improvement.

To the Editor: Unanticipated hypertension during emergence refers to acutely elevated blood pressure following general anesthesia in individuals with normal preoperative baseline blood pressure.^[1]Due to their normal preoperative blood pressure, inadequate attention was paid to this population. Acute postoperative hypertension, if left untreated, has been linked to serious postoperative consequences such as vascular anastomosis rupture, and cardiovascular and cerebrovascular accidents, affecting the outcome of critically ill and surgical patients.^[2]Few studies have revealed the risk factors for unanticipated hypertension after general anesthesia. We performed this retrospective study to identify the factors responsible for unexpected hypertension in adult surgical patients resuscitated from anesthesia based on real-world data from an anesthesia center in eastern China, to provide evidence for perioperative management within this surgical patient population.