2023年 · 第136卷第11期

In the last decade, it has become increasingly recognized that a balanced gut microbiota plays an important role in maintaining the health of the host. Numerous clinical and preclinical studies have shown that changes in gut microbiota composition are associated with a variety of neurological diseases, e.g., Parkinson’s disease, Alzheimer’s disease, and myasthenia gravis. However, the underlying molecular mechanisms are complex and remain unclear. Behavioral phenotypes can be transmitted from humans to animals through gut microbiota transplantation, indicating that the gut microbiota may be an important regulator of neurological diseases. However, further research is required to determine whether animal-based findings can be extended to humans and to elucidate the relevant potential mechanisms by which the gut microbiota regulates neurological diseases. Such investigations may aid in the development of new microbiota-based strategies for diagnosis and treatment and improve the clinical management of neurological disorders. In this review, we describe the dysbiosis of gut microbiota and the corresponding mechanisms in common neurological diseases, and discuss the potential roles that the intestinal microbiome may play in the diagnosis and treatment of neurological disorders.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by progressive lung fibrogenesis and histological features of usual interstitial pneumonia. IPF has a poor prognosis and presents a spectrum of disease courses ranging from slow evolving disease to rapid deterioration; thus, a differential diagnosis remains challenging. Several biomarkers have been identified to achieve a differential diagnosis; however, comprehensive reviews are lacking. This review summarizes over 100 biomarkers which can be divided into six categories according to their functions: differentially expressed biomarkers in the IPF compared to healthy controls; biomarkers distinguishing IPF from other types of interstitial lung disease; biomarkers differentiating acute exacerbation of IPF from stable disease; biomarkers predicting disease progression; biomarkers related to disease severity; and biomarkers related to treatment. Specimen used for the diagnosis of IPF included serum, bronchoalveolar lavage fluid, lung tissue, and sputum. IPF-specific biomarkers are of great clinical value for the differential diagnosis of IPF. Currently, the physiological measurements used to evaluate the occurrence of acute exacerbation, disease progression, and disease severity have limitations. Combining physiological measurements with biomarkers may increase the accuracy and sensitivity of diagnosis and disease evaluation of IPF. Most biomarkers described in this review are not routinely used in clinical practice. Future large-scale multicenter studies are required to design and validate suitable biomarker panels that have diagnostic utility for IPF.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a membrane receptor on myeloid cells and plays an important role in the body’s immune defense. Recently, TREM2 has received extensive attention from researchers, and its activity has been found in Alzheimer’s disease, neuroinflammation, and traumatic brain injury. The appearance of TREM2 is usually accompanied by changes in apolipoprotein E (ApoE), and there has been a lot of research into their structure, as well as the interaction mode and signal pathways involved in them. As two molecules with broad and important roles in the human body, understanding their correlation may provide therapeutic targets for certain diseases. In this article, we reviewed several diseases in which TREM2 and ApoE are synergistically involved in the development. We further discussed the positive or negative effects of the TREM2-ApoE pathway on nervous system immunity and inflammation.

Accumulating studies have demonstrated that non-coding RNAs (ncRNAs), functioning as important regulators of transcription and translation, are involved in the establishment and maintenance of pregnancy, especially the maternal immune adaptation process. The endometrial stromal cells (ESCs), trophoblast cells, and decidua immune cells that reside at the maternal-fetal interface are thought to play significant roles in normal pregnancy and pregnancy-associated diseases. Here, we reviewed the up-to-date evidence on how microRNA, long non-coding RNA, and circular RNA regulate ESCs, trophoblast cells, and immune cells and discussed the potential applications of these ncRNAs as diagnostic and therapeutic markers in pregnancy complications.

It remains unclear whether circulating malondialdehyde (MDA) levels change in people with diabetic retinopathy (DR). This systematic review compared circulating MDA levels in diabetic people with and without DR.

PubMed, Medline (Ovid), Embase (Ovid), and Web of Science were searched for case-control studies conducted before May 2022 in English that compared circulating MDA levels in people with and without DR. The following MeSH search terms were used: ( "malondialdehyde" or "thiobarbituric acid reactive substances [TBARS]" or "lipid peroxidation" or "oxidative stress" ) and "diabetic retinopathy." Newcastle-Ottawa Quality Assessment Scale was used to evaluate the quality of the included studies. Random-effects pairwise meta-analysis pooled the effect size with standardized mean difference (SMD) and 95% confidence intervals (CIs).

This meta-analysis included 29 case-control studies with 1680 people with DR and 1799 people with diabetes but not DR. Compared to people without DR, the circulating MDA levels were higher in those with DR (SMD, 0.897; 95% CI, 0.631 to 1.162; P < 0.001). The study did not identify credible subgroup effects or publication bias and the sensitivity analysis confirmed the robustness of the study.

Circulating MDA levels are higher in people with DR compared to those without. Future comparative studies that use more specific methods are required to draw firm conclusions.

PROSPERO; https://www.crd.york.ac.uk/PROSPERO/; No. CRD42022352640.

Current guidelines recommend hepatocellular carcinoma (HCC) screening in high-risk populations. However, the ideal HCC screening interval and screening modality have not been determined. This study aimed to compare the screening efficacy among different modalities with various intervals.

PubMed and other nine databases were searched through June 30, 2021. Binary outcomes were pooled using risk ratio (RR) with 95% confidence intervals (CIs). Survival rates were also pooled using RR with 95% CIs because most eligible studies only provided the number of survival patients instead of hazard ratio.

In all, 13 studies were included. Two random controlled trials (RCTs) and six cohort studies compared screening intervals for ultrasonography (US) screening and found no significant differences between shorter (3- or 4-month) and longer (6- or 12-month) screening intervals in terms of early HCC proportion, HCC significant mortality, 1-year survival rate; screening at 6-month interval significantly increased the proportion of early HCC (RR = 1.17, 95% confidence interval [CI]: 1.08-1.26) and prolonged the 5-year survival rate (RR = 1.39, 95% CI: 1.07-1.82) relative to the 12-month interval results. Three other RCTs and two cohort studies compared different screening modalities in cirrhosis or chronic hepatitis B, which indicated no statistical differences in the proportion of early HCC (RR = 0.89, 95% CI: 0.40-1.96) and HCC mortality (RR = 0.69, 95% CI: 0.23-2.09) between the biannual US and annual computed tomography (CT screening). Biannual US screening showed a lower proportion of early HCC than biannual magnetic resonance imaging (MRI) (RR = 0.60, 95% CI: 0.37-0.97) and biannual US combined with annual CT (RR = 1.31, 95% CI: 1.13-1.51) screening. The proportion of early HCC in the contrast-enhanced US group was slightly higher than that in the B-mode US (RR= 1.08, 95% CI: 1.00-1.23) group.

The evidence suggests that 6 months may be the best HCC screening interval for US screening. The effectiveness of CT and MRI is better than US during same screening intervals. However, MRI and CT are more expensive than US, and CT also can increase the risk of radiation exposure. The selection of CT or MRI instead of US should be carefully considered.

No. CRD42020148258 at PROSPERO website (https://www.crd.york.ac.uk/PROSPERO/).

Amygdala plays an important role in the neurobiological basis of panic disorder (PD), and the amygdala contains different subregions, which may play different roles in PD. The aim of the present study was to examine whether there are common or distinct patterns of functional connectivity of the amygdala subregions in PD using resting-state functional magnetic resonance imaging and to explore the relationship between the abnormal spontaneous functional connectivity patterns of the regions of interest (ROIs) and the clinical symptoms of PD patients.

Fifty-three drug-naïve, non-comorbid PD patients and 70 healthy controls (HCs) were recruited. Seed-based resting-state functional connectivity (rsFC) analyses were conducted using the bilateral amygdalae and its subregions as the ROI seed. Two samples t test was performed for the seed-based Fisher's z-transformed correlation maps. The relationship between the abnormal spontaneous functional connectivity patterns of the ROIs and the clinical symptoms of PD patients was investigated by Pearson correlation analysis.

PD patients showed increased rsFC of the bilateral amygdalae and almost all the amygdala subregions with the precuneus/posterior cingulate gyrus compared with the HC group (left amygdala [lAMY]: t = 4.84, P <0.001; right amygdala [rAMY]: t= 4.55, P <0.001; left centromedial amygdala [lCMA]: t= 3.87, P <0.001; right centromedial amygdala [rCMA]: t= 3.82, P= 0.002; left laterobasal amygdala [lBLA]: t= 4.33, P <0.001; right laterobasal amygdala [rBLA]: t= 4.97, P <0.001; left superficial amygdala [lSFA]: t= 3.26, P = 0.006). The rsFC of the lBLA with the left angular gyrus/inferior parietal lobule remarkably increased in the PD group (t = 3.70, P = 0.003). And most of the altered rsFCs were located in the default mode network (DMN). A significant positive correlation was observed between the severity of anxiety and the rsFC between the lSFA and the left precuneus in PD patients (r = 0.285, P = 0.039).

Our research suggested that the increased rsFC of amygdala subregions with DMN plays an important role in the pathogenesis of PD. Future studies may further explore whether the rsFC of amygdala subregions, especially with the regions in DMN, can be used as a biological marker of PD.

Tri-ponderal mass index (TMI) has been reported to be a more accurate estimate of body fat than body mass index (BMI). This study aims to compare the effectiveness of TMI and BMI in identifying hypertension, dyslipidemia, impaired fasting glucose (IFG), abdominal obesity, and clustered cardio-metabolic risk factors (CMRFs) in 3- to 17-year-old children.

A total of 1587 children aged 3 to 17 years were included. Logistic regression was used to evaluate correlations between BMI and TMI. Area under the curves (AUCs) were used to compare discriminative capability among indicators. BMI was converted to BMI-z scores, and accuracy was compared by false-positive rate, false-negative rate, and total misclassification rate.

Among children aged 3 to 17 years, the mean TMI was 13.57 ± 2.50 kg/m³ for boys and 13.3 ± 2.33 kg/m³ for girls. Odds ratios (ORs) of TMI for hypertension, dyslipidemia, abdominal obesity, and clustered CMRFs ranged from 1.13 to 3.15, higher than BMI, whose ORs ranged from 1.08 to 2.98. AUCs showed similar ability of TMI (AUC: 0.83) and BMI (AUC: 0.85) in identifying clustered CMRFs. For abdominal obesity and hypertension, the AUC of TMI was 0.92 and 0.64, respectively, which was significantly better than that of BMI, 0.85 and 0.61. AUCs of TMI for dyslipidemia and IFG were 0.58 and 0.49. When 85th and 95th of TMI were set as thresholds, total misclassification rates of TMI for clustered CMRFs ranged from 6.5% to 16.4%, which was not significantly different from that of BMI-z scores standardized according to World Health Organization criteria.

TMI was found to have equal or even better effectiveness in comparison with BMI in identifying hypertension, abdominal obesity, and clustered CMRFs TMI was more stable than BMI in 3- to 17-year-old children, while it failed to identify dyslipidemia and IFG. It is worth considering the use of TMI for screening CMRFs in children and adolescents.

Dysfunction of the gap junction channel protein connexin 43 (Cx43) contributes to myocardial ischemia/reperfusion (I/R)-induced ventricular arrhythmias. Cx43 can be regulated by small ubiquitin-like modifier (SUMO) modification. Protein inhibitor of activated STAT Y (PIASy) is an E3 SUMO ligase for its target proteins. However, whether Cx43 is a target protein of PIASy and whether Cx43 SUMOylation plays a role in I/R-induced arrhythmias are largely unknown.

Male Sprague-Dawley rats were infected with PIASy short hairpin ribonucleic acid (shRNA) using recombinant adeno-associated virus subtype 9 (rAAV9). Two weeks later, the rats were subjected to 45 min of left coronary artery occlusion followed by 2 h reperfusion. Electrocardiogram was recorded to assess arrhythmias. Rat ventricular tissues were collected for molecular biological measurements.

Following 45 min of ischemia, QRS duration and QTc intervals statistically significantly increased, but these values decreased after transfecting PIASy shRNA. PIASy downregulation ameliorated ventricular arrhythmias induced by myocardial I/R, as evidenced by the decreased incidence of ventricular tachycardia and ventricular fibrillation, and reduced arrythmia score. In addition, myocardial I/R statistically significantly induced PIASy expression and Cx43 SUMOylation, accompanied by reduced Cx43 phosphorylation and plakophilin 2 (PKP2) expression. Moreover, PIASy downregulation remarkably reduced Cx43 SUMOylation, accompanied by increased Cx43 phosphorylation and PKP2 expression after I/R.

PIASy downregulation inhibited Cx43 SUMOylation and increased PKP2 expression, thereby improving ventricular arrhythmias in ischemic/reperfused rats heart.

Low-density lipoprotein cholesterol (LDL-C) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Even after lipid-lowering therapy (LLT) with statins or statin-ezetimibe, a large proportion of patients at very high risk still do not reach the LDL-C targets (<1.4 mmol/L and ≥50% reduction).^[1,2]Proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) is recommended for patients at high or very high cardiovascular risk in whom LDL-C reduction is not adequate with statin therapy or in those with statin intolerance. Limited data are available regarding the use of PCSK9i in China. Evolocumab, a PCSK9i, was approved as the first PCSK9i of its kind in China in 2019. However, there remains a paucity of real-world evidence for evolocumab use in the treatment of high-risk patients in China, exploring its efficacy and tolerance. This study aimed to report the results of evolocumab administered to very high-risk patients (n= 63) but did not achieve adequate LDL-C reductions with statins in a real-world setting at a single-center practice.

Viral pneumonia has recently been defined as a risk factor for invasive pulmonary aspergillosis (IPA). Wauterset al^[1]reported that 23% of critically ill patients who were admitted to the intensive care unit (ICU) with swine-origin influenza A (H1N1) viral infection had developed invasive aspergillosis. IPA was diagnosed in 83 of 432 (19%) patients who were admitted with influenza; for patients with influenza who were immunocompromised, the incidence of IPA reached up to 32% (38 of 117 patients), whereas in the non-immunocompromised influenza group, the incidence was 14% (45 of 315 patients).^[2]The 90-day mortality was 51% in patients in the influenza cohort with IPA and 28% in the influenza cohort without IPA.^[2]The prevalence of IPA is reported between 4% and 9% in critically ill patients with coronavirus disease.^[3]Magiraet al^[4]found that respiratory viral infections caused by both parainfluenza virus and respiratory syncytial virus frequently preceded IPA in patients with leukemia and those who underwent hematopoietic stem cell transplantation. Considering the high incidence and mortality of viral pneumonia complicated with IPA, the risk factors for it should be identified. Hence, we performed a study to explore the risk factors for viral pneumonia complicated with IPA.

An increase in coronary heart disease (CHD) risk factors can account for the progressively increasing burden in young patients with CHD. The association between modifiable risk factors and acute myocardial infarction (AMI) is well established, and control of cardiovascular risk factors can reduce the risk of subsequent events.^[1]The short-term prognosis in young individuals with CHD may be acceptable compared with older patients; however, the long-term prognosis is poorer in young patients with CHD than in an age-matched population, and these patients have high rates of recurrent events and mortality.^[2]Significant disparities have been observed in the prevalence of cardiovascular risk factors between young and older patients with CHD.^[2,3]Control of cardiovascular risk factors is insufficient in young patients with CHD,^[4]and little is known about whether treatment targets are achieved in young Chinese patients. Therefore, this study aimed to assess the control of cardiovascular risk factors and AMI to identify what risk factors are associated with poor outcomes in young patients with CHD.

Staphylococcus lugdunensis(S. lugdunensis) is a coagulase-negativeStaphylococcuscomprising the normal skin microbiota, primarily colonizing the lower abdomen and extremities.^[1]S. lugdunensishas attracted substantial attention in recent years since the discovery of lugdunin by Zippereret al^[2]in 2016. Lugdunin is a secondary metabolite synthesized by non-ribosomal peptide synthetase (NRPS) that inhibits the growth of various gram-positive bacteria, including methicillin-resistantS. aureus(MRSA),^[2]suggesting its potential as an antibiotic. To date, 28 complete genome sequences and 11 partial-assembly genome sequences ofS. lugdunensishave been published and uploaded to the GenBank database (https://www.ncbi.nlm.nih.gov/genome/browse/#!/prokaryotes/2548/, January 18, 2022). However, there are limited data on the genome sequences ofS. lugdunensisfrom China, and the effects of geographical origin on genetic variations inS. lugdunensisremain unknown.

To the Editor:Chemotherapy-induced nausea and vomiting (CINV) is the most common and feared side effect reported by patients receiving chemotherapy. Despite significant progress, the incidence of CINV remains high.^[1]Prevention is the key for controlling CINV. Evidence-based antiemetic guidelines recommend that strategies to prevent CINV should consider both the emetic risk of chemotherapeutic agents and patients' individual risk factors.^[2]To date, several personal factors predicting a high risk of CINV have been identified, including expectancy of CINV, female sex, younger age, history of morning sickness, and anxiety.^[3]Efforts have been made to develop different CINV risk predictive models incorporating all of the aforementioned factors to guide individualized antiemetic prevention. Among these models, the most commonly recommended model is the large-scale investigation published in 2017 inAnnals of Oncologybased on a non-Asian population.^[4]However, the applicability of this model to Chinese patients has not been investigated. Thus, we conducted a prospective study to validate the existing CINV predictive model and optimize it for identifying high-risk Chinese patients.

To the Editor:Patients with coronary heart disease (CHD) complicated by coronavirus disease 2019 (COVID-19) are at an increased risk of coronary events. Many studies have reported an association between cardiovascular disease and COVID-19. It is also known that patients with COVID-19 have worse outcomes and an increased mortality risk if they have cardiovascular disease.^[1]According to a report by the World Health Organization, the estimated COVID-19 mortality rate is about 3.4% overall; however, in patients with cardiovascular disease, this figure increases to 10.5%, which is higher than the death rate in those with underlying diabetes (7.3%) or chronic respiratory diseases (6.3%).^[2]

To the Editor:Total knee arthroplasty (TKA) is a safe and effective treatment for patients with end-stage knee osteoarthritis, with the conventional medial parapatellar (MP) approach for TKA, good visualization of the knee can be obtained, helping to achieve correct osteotomy, proper ligament balance and good prosthesis position, which are all important for good long-term results.^[1]To improve functional recovery and rehabilitation, some studies have adopted a relatively small incision operation to improve operation. Among them, two of the most commonly used procedures are named mini-medial parapatellar (MMP) and quadriceps-sparing (QS) approaches.^[2]But other studies suggested that minimally invasive approaches may compromise the advantages of correct osteotomy, proper ligament balance, and good prosthesis position to achieve potentially rapid rehabilitation, potentially sacrificing the long-term clinical outcomes and survival of the prostheses.^[3]At present, most of the studies compared different approaches that evaluated the follow-up of no more than 5 years. Thus, it is crucial to obtain the data of long-term clinical comparison. Based on the longitudinal cohort results of previous studies, a follow-up study for more than 10 years was conducted.

To the Editor: Acoustic neuroma is the most common tumor in the cerebellopontine angle (CPA) area. The surgical approaches used for acoustic neuroma include the labyrinth, middle cranial fossa, posterior sigmoid sinus, and posterior labyrinth routes. However, regardless of the approach used to expose the tumor in the internal auditory canal (IAC), the bone around the IAC must be abraded, which inevitably exposes the surrounding air cells to damage and increases the risk of cerebrospinal fluid (CSF) leak after surgery. CSF leak is the most common postoperative complication after the removal of a tumor from the CPA area and has a reported incidence of 2% to 10% after acoustic neuroma surgery.^[1,2,3]Clinical treatment of CSF leak is challenging; and continuous lumbar puncture and drainage or reoperation are sometimes required to avoid meningitis. Therefore, prevention of postoperative CSF leak is a key issue to consider when surgery is performed to remove a tumor in the CPA area.

To the Editor:The fusion geneE2A::HLF(TCF3::HLF) is formed by t(17;19) (q21-22;p13), which presents in <1% of B-cell acute lymphoblastic leukemia (B-ALL) and mainly occurs in older children and adolescents.^[1]Such patients were often accompanied by drug resistance and early relapse, which confer an extremely poor prognosis, and even intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) cannot improve their survival.^[2]A few studies suggested that chimeric antigen receptor T (CAR-T) cell therapy or BCL-2 inhibitors might benefit such patients, but the effectiveness needed to be further verified since the superiority of CAR-T cell therapy was restricted to individual case reports, and the efficacy of BCL-2 inhibitors was demonstrated only in vitro tests on cell lines.^[1,3]Here, we retrospectively analyzed the clinical data of six patients withE2A::HLF-positive B-ALL to further validate the effectiveness of CAR-T cell therapy and BCL-2 inhibitor, which could be considered as salvage treatments in these poor-risk patients.

To the Editor:Toxic epidermal necrosis (TEN) is a severe dermal-mucous reaction characterized by rashes, blisters, and a generalized laxity of the epidermis.^[1]Blockade of the programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway could activate and proliferate auto-reactive CD8+ T-cells, which is a crucial step in TEN. The efficacy of anti-CD19 chimeric antigen receptor-T (CAR-T) cells can be inhibited by activating the PD-1/PD-L1 pathway.^[2]As a result, the combination of PD-1 blockade and CAR-T cell therapy would increase the functions of CAR-T cells.^[3]This case report describes a patient with refractory diffuse large B-cell lymphoma (DLBCL) who had severe TEN after CAR-T cell therapy and PD-1 blockade.