2022年 · 第135卷第09期

Epigenetic regulation is a pivotal mechanism that controls gene transcription and cell fate. During the past decades, it has been observed that histone, DNA, and RNA modifications participate in determining the fate of neural stem cells (NSCs). These modifications include histone acetylation and methylation, as well as DNA and RNA methylation. Of note, non-coding RNAs also participate in neural differentiation.^[1]In addition to acetylation, many other types of acylations to histone lysines, including crotonylation, propionylation, succinylation, and malonylation, have been identified.^[2]The roles of these histone acylations in neuroscience remain elusive.

Heart failure (HF) represents one of the major disease burdens worldwide now. Congestive HF-related medicare expenditures remain high, constituting a global challenge. After manifestation, patients with HF face significantly increased risk of recurrent hospitalizations, morbidity, and mortality despite modern therapy strategies.^[1]

There are so many of our patients who have had heart failure with preserved ejection fraction (HFpEF) and management really remains problematic. Approximately half of the patients with heart failure have preserved left ventrical (LV) systolic function and usually have some degree of diastolic dysfunction. Patients with reduced or preserved systolic function may have similar symptoms and it may be difficult to distinguish clinically between the two based on signs and symptoms. In developed countries, coronary artery disease (CAD) with resulting myocardial infarction and loss of functioning myocardium (ischemic cardiomyopathy) is the most common cause of systolic heart failure. Systemic hypertension remains an important cause of heart failure and, even more commonly in the United States, an exacerbating factor in patients with cardiac dysfunction because of other causes, such as CAD. Several processes may present with dilated or congestive cardiomyopathy, which is characterized by LV or biventricular dilation and generalized systolic dysfunction. Rare causes of dilated cardiomyopathy include infiltrative diseases (hemochromatosis, sarcoidosis, and amyloidosis), other infectious agents, metabolic disorders, cardiotoxins, and medication toxicity. Valvular heart diseases—particularly degenerative aortic stenosis and chronic aortic or mitral regurgitation—are frequent causes of heart failure. Persistent tachycardia, often related to atrial arrhythmias, can cause systolic dysfunction that may be reversible with controlling the rate. Diastolic cardiac dysfunction is associated with aging and related myocardial stiffening, as well as left ventricular hypertrophy (LVH), commonly resulting from hypertension. Conditions such as hypertrophic or restrictive cardiomyopathy, diabetes, and pericardial disease can produce the same clinical picture. Atrial fibrillation with or without rapid ventricular response may contribute to impaired left ventricular filling.

Ciprofol (HSK3486; Haisco Pharmaceutical Group Co., Ltd., Chengdu, China), developed as a novel 2,6-disubstituted phenol derivative showed similar tolerability and efficacy characteristics as propofol when applicated as continuous intravenous infusion for 12 h maintenance sedation in a previous phase 1 trial. The phase 2 trial was designed to investigate the safety, efficacy, and pharmacokinetic characteristics of ciprofol for sedation of patients undergoing mechanical ventilation.

In this multicenter, open label, randomized, propofol positive-controlled, phase 2 trial, 39 Chinese intensive care unit patients receiving mechanical ventilation were enrolled and randomly assigned to a ciprofol or propofol group in a 2:1 ratio. The ciprofol infusion was started with a loading infusion of 0.1-0.2 mg/kg for 0.5-5.0 min, followed by an initial maintenance infusion rate of 0.30 mg·kg^-1·h^-1, which could be adjusted to an infusion rate of 0.06 to 0.80 mg·kg^-1·h^-1, whereas for propofol the loading infusion dose was 0.5-1.0 mg/kg for 0.5-5.0 min, followed by an initial maintenance infusion rate of 1.50 mg·kg^-1·h^-1, which could be adjusted to 0.30-4.00 mg·kg^-1·h^-1 to achieve -2 to +1 Richmond Agitation-Sedation Scale sedation within 6-24 h of drug administration.

Of the 39 enrolled patients, 36 completed the trial. The median (min, max) of the average time to sedation compliance values for ciprofol and propofol were 60.0 (52.6, 60.0) min and 60.0 (55.2, 60.0) min, with median difference of 0.00 (95% confidence interval: 0.00, 0.00). In total, 29 (74.4%) patients comprising 18 (69.2%) in the ciprofol and 11 (84.6%) in the propofol group experienced 86 treatment emergent adverse events (TEAEs), the majority being of severity grade 1 or 2. Drug- and sedation-related TEAEs were hypotension (7.7% vs. 23.1%, P = 0.310) and sinus bradycardia (3.8% vs. 7.7%, P = 1.000) in the ciprofol and propofol groups, respectively. The plasma concentration-time curves for ciprofol and propofol were similar.

ciprofol is comparable to propofol with good tolerance and efficacy for sedation of Chinese intensive care unit patients undergoing mechanical ventilation in the present study setting.

ClinicalTrials.gov, NCT04147416.

Time in range (TIR) refers to the time an individual spends within their target glucose range, which now has been popularized as an important metric to classify glycemic management and also recognized as an important outcome of current diabetes therapies. This study aimed to investigate the association between TIR and the severity of the urinary albumin excretion rate (UAER) in patients with type 2 diabetes mellitus (T2DM).

We retrospectively analyzed the data of 1014 inpatients with T2DM at the Department of Endocrinology and Metabolism of Peking University International Hospital, China. TIR was defined as the percentage of blood glucose within the target range of 3.90-10.00 mmol/L. Urine samples for assessment of UAER were collected for 3 consecutive days from the start of hospitalization.

The TIR values for patients with normal urine levels of albumin, microalbuminuria, and macroalbuminuria were 70% ± 20%, 50% ± 20%, and 30% ± 20%, respectively (all P < 0.001). The patients were stratified according to quartiles of TIR as follows: quartile (Q) 1, <55%; Q2, 55%-72%; Q3, 73%-83%; and Q4, >83%. The incidences of microalbuminuria in Q1, Q2, Q3, and Q4 were 41.1%, 21.6%, 7.1%, and 5.5% (all P < 0.001), respectively. The respective incidences of macroalbuminuria were 24.2%, 1.1%, 1.4%, and 0% (all P < 0.001). In multinomial logistic regression analyses, TIR was significantly correlated with microalbuminuria (odds ratio [OR] 0.58, 95% confidence interval [CI]: 0.52-0.65, P < 0.001) and macroalbuminuria (OR 0.26, 95% CI: 0.18-0.38, P < 0.001) after adjusting for age, sex, body mass index, diabetes duration, systolic blood pressure, and levels of triglycerides, glycosylated hemoglobin A1c, and creatinine.

The proportion of blood glucose in TIR is closely related to the severity of UAER in patients with T2DM.

Gestational weight gain (GWG) is associated with the risk of gestational diabetes mellitus (GDM). However, the effect of weight gain in different trimesters on the risk of GDM is unclear. This study aimed to evaluate the effect of GWG on GDM during different trimesters.

A birth cohort study was conducted from 2017 to 2020 in Shenzhen, China. In total, 51,205 participants were included comprising two models (early pregnancy model and middle pregnancy model). Gestational weight (kg) was measured at each prenatal clinical visit using a standardized weight scale. Logistic regression analysis was used to assess the risk of GDM. Interaction analysis and mediation effect analysis were performed in the middle pregnancy model.

In the early pregnancy model, the risk of GDM was 0.858 times lower (95% confidence interval [CI]: 0.786, 0.937) with insufficient GWG (iGWG) and 1.201 times higher (95% CI: 1.097, 1.316) with excessive GWG after adjustment. In the middle pregnancy model, the risk of GDM associated with iGWG increased 1.595 times (95% CI: 1.418, 1.794) after adjustment; for excessive GWG, no significant difference was found (P = 0.223). Interaction analysis showed no interaction between GWG in early pregnancy (GWG-E) and GWG in middle pregnancy (GWG-M) (F = 1.268; P = 0.280). The mediation effect analysis indicated that GWG-M plays a partial mediating role, with an effect proportion of 14.9%.

eGWG-E and iGWG-M are associated with an increased risk of GDM. Strict control of weight gain in early pregnancy is needed, and sufficient nutrition should be provided in middle pregnancy.

It is crucial to improve the quality of care provided to ICU patient, therefore a national survey of the medical quality of intensive care units (ICUs) was conducted to analyze adherence to quality metrics and outcomes among critically ill patients in China from 2015 to 2019.

This was an ICU-level study based on a 15-indicator online survey conducted in China. Considering that ICU care quality may vary between secondary and tertiary hospitals, direct standardization was adopted to compare the rates of ICU quality indicators among provinces/regions. Multivariate analysis was performed to identify potential factors for in-hospital mortality and factors related to ventilator-associated pneumonia (VAP), catheter-related bloodstream infections (CRBSIs), and catheter-associated urinary tract infections (CAUTIs).

From the survey, the proportions of structural indicators were 1.83% for the number of ICU inpatients relative to the total number of inpatients, 1.44% for ICU bed occupancy relative to the total inpatient bed occupancy, and 51.08% for inpatients with Acute Physiology and Chronic Health Evaluation II scores ≥15. The proportions of procedural indicators were 74.37% and 76.60% for 3-hour and 6-hour surviving sepsis campaign bundle compliance, respectively, 62.93% for microbiology detection, 58.24% for deep vein thrombosis prophylaxis, 1.49% for unplanned endotracheal extubations, 1.99% for extubated inpatients reintubated within 48 hours, 6.38% for unplanned transfer to the ICU, and 1.20% for 48-hour ICU readmission. The proportions of outcome indicators were 1.28‰ for VAP, 3.06‰ for CRBSI, 3.65‰ for CAUTI, and 10.19% for in-hospital mortality. Although the indicators varied greatly across provinces and regions, the treatment level of ICUs in China has been stable and improved based on various quality control indicators in the past 5 years. The overall mortality rate has dropped from 10.19% to approximately 8%.

The quality indicators of medical care in China’s ICUs are heterogeneous, which is reflected in geographic disparities and grades of hospitals. This study is of great significance for improving the homogeneity of ICUs in China.

Fibrosis in the peripheral airways contributes to airflow limitation in patients with chronic obstructive pulmonary disease (COPD). However, the key proteins involved in its development are still poorly understood. Thus, we aimed to identify the differentially expressed proteins (DEPs) between smoker patients with and without COPD and elucidate the molecular mechanisms involved by investigating the effects of the identified biomarker candidate on lung fibroblasts.

The potential DEPs were identified by isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis. The messenger RNA and protein levels of clusterin (CLU) in COPD patients and 12% cigarette smoke extract (CSE)-treated human bronchial epithelial cells were determined at the indicated time points. Furthermore, an in vitro COPD model was established via the administration of 8% CSE to normal human lung fibroblasts (NHLFs) at indicated time points. The effects of CSE treatment and CLU silencing on proliferation and activation of lung fibroblasts were analyzed.

A total of 144 DEPs were identified between COPD patients and normal smokers. The iTRAQ-based proteomics and bioinformatics analyses identified CLU as a serum biomarker candidate. We also discovered that CLU levels were significantly increased (P < 0.0001) in Global Initiative for Obstructive Lung Disease II, III, and IV patients and correlated (P < 0.0001) with forced expiratory volume in 1 s (R=-0.7705), residual volume (RV) (R = 0.6281), RV/total lung capacity (R = 0.5454), and computerized tomography emphysema (R = 0.7878). Similarly, CLU levels were significantly increased in CSE-treated cells at indicated time points (P < 0.0001). The CSE treatment significantly inhibited the proliferation, promoted the inflammatory response, differentiation of NHLFs, and collagen matrix deposition, and induced the apoptosis of NHLFs; however, these effects were partially reversed by CLU silencing.

Our findings suggest that CLU may play significant roles during airway fibrosis in COPD by regulating lung fibroblast activation.

The combination of high-frequency oscillations (HFOs) with single-mode imaging methods has been proved useful in identifying epileptogenic zones, whereas few studies have examined HFOs combined with multimodal imaging methods. The aim of this study was to evaluate the prognostic value of ripples, an HFO subtype with a frequency of 80 to 200 Hz is combined with multimodal imaging methods in predicting epilepsy surgery outcome.

HFOs were analyzed in 21 consecutive medically refractory epilepsy patients who underwent epilepsy surgery. All patients underwent positron emission tomography (PET) and deep electrode implantation for stereo-electroencephalography (SEEG); 11 patients underwent magnetoencephalography (MEG). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in predicting surgical outcome were calculated for ripples combined with PET, MEG, both PET and MEG, and PET combined with MEG. Kaplan-Meier survival analyses were conducted in each group to estimate prognostic value.

The study included 13 men and 8 women. Accuracy for ripples, PET, and MEG alone in predicting surgical outcome was 42.9%, 42.9%, and 81.8%, respectively. Accuracy for ripples combined with PET and MEG was the highest. Resection of regions identified by ripples, MEG dipoles, and combined PET findings was significantly associated with better surgical outcome (P < 0.05).

Intracranial electrodes are essential to detect regions which generate ripples and to remove these areas which indicate good surgical outcome for medically intractable epilepsy. With the assistance of presurgical noninvasive imaging examinations, PET and MEG, for example, the SEEG electrodes would identify epileptogenic regions more effectively.

Intracerebral hemorrhage (ICH) is a severe neurological disease with high morbidity and mortality.^[1,2]Infection rates of 26% to 58% have been reported in patients with ICH.^[3]Infections not only increase the length of hospital stay and healthcare costs but also increase mortality, worsen functional outcomes, and increase hospital readmission rates. The current study sought to determine the prevalence of and risk factors associated with infections in patients with ICH and to investigate their impact on patient outcome upon discharge from the hospital.

To the Editor:Heart failure (HF) is currently recognized as a disease that affects approximately 1%-2% of adults worldwide.^[1]The most frequent reasons for HF are valvular heart diseases, chronic or acute cardiac ischemia, and prevalent cardiomyopathies that are caused by alcohol, doxorubicin (Dox), hypertension, diabetes, and metabolic syndrome.^[2]The diverse therapeutic approaches that have been developed in recent years have usually only been successful in preclinical subjects, and efficient treatment for HF still needs to be executed.^[3]Therefore, a more practical therapeutic strategy and therapeutic candidates are urgently needed. Astragaloside IV (AS-IV) is a principle active constituent ofAstragalus membranaceus Bunge,which is a Chinese protective medicine that is widely used in HF patients.^[4]Increasing evidence confirms the efficiency and safety of AS-IV for the treatment of HFin vivoandin vitro.However, to date, the investigations in this field have been limited to the broad roles of AS-IV.

To the Editor:Accumulating evidence has shown that gut microbiota-host interactions play vital roles in human health and disease. However, the dynamic equilibria between microbes and their hosts limit the utility of single strains or microbial signatures as markers for disease risk prediction and outcome assessment.^[1]Analysis of changes in the gut microenvironment using multi-omics approaches has now become routine.^[2]In inflammatory bowel disease, and especially during the acute phase, a significant shift in the gut microenvironment occurs within 2 weeks. Therefore, effective strategies to obtain fecal samples every 2 to 3 days are needed. However, challenges in specimen storage, transport, and handling limit long-term sampling ability. The microbial composition of fecal samples stored at room temperature for >24 h is significantly altered. Storage of fecal specimens at -80°C immediately after evacuation is standard procedure but is impractical in real-life situations. An alternative is a storage at -20°C for up to 1 month followed by sample transport and laboratory analysis. The objective of this study was to evaluate whether the gut microenvironment in fecal specimens collected every 2 to 3 days and stored at home at -20°C for up to 1 month could be preserved.

To the Editor:Hemimasticatory spasm (HMS) is a relatively rare type of unilateral trigeminal nerve (TN) motor branch dysfunction, whose pathogenesis is currently unknown. The clinical manifestations of HMS are involuntary paroxysmal convulsions of the muscles innervated by the associated unilateral trigeminal motor branch. Recently, the academic community has proposed two etiologies for HMS: TN compression and central lesion theory.^[1]Clinically, HMS must be distinguished from oromandibular dystonia, facial muscle spasm, multiple sclerosis pain spasm, and focal epilepsy. Generally, electromyography (EMG) can confirm the diagnosis. The current outcomes of multidrug and botulinum toxin injection treatments remain unsatisfactory. Only patients with cranial neurovascular conflicts have an excellent response to microvascular decompression (MVD) surgery.

To the Editor:Recurrent pregnancy loss (RPL) is defined as the failure of two or more clinically recognized pregnancies.^[1]Both parental and embryonic/fetal factors are associated with RPL. Parental factors include balanced chromosome rearrangements, maternal antiphospholipid syndrome, uterine anomalies, and hormonal or metabolic disorders.^[2]Of the examined products of conception (POC), approximately 60% of early pregnancy losses result from sporadic chromosomal abnormalities in embryos, specifically numeric chromosome errors. However, up to 50% of RPL cases remain unexplainable by known causes. Here, we report a couple who have experienced four consecutive clinical pregnancy losses within 10 weeks of gestation, and describe a novel (elongation factor Tu GTP-binding domain containing 2 [EFTUD2], Online Mendelian Inheritance in Man [MIM] #603892) nonsense mutation (c.1012G>T, p.E338*) found in embryonic tissues from each of the last three miscarriages by whole exome sequencing (WES) analysis. In addition, we generated a zebrafish line with a mutation homologous to the humanEFTUD2disruption to investigate the relationship between this mutation and RPL. We hypothesized that the mutation was associated with embryonic lethality, which may induce RPL in patients. The study was approved by the Medical Ethics Committee of the West China Second University Hospital, Sichuan University, China (No. 2016 [029]). Written informed consent was obtained from the couple before genetic testing.

To the Editor:Left atrial appendage (LAA) is one of the major sources of atrial arrhythmias in children.^[1]But atrial tachycardia (AT) with an epicardial LAA origin is uncommon and usually arises from the base.^[2]Catheter ablation (CA) may be an important strategy for patients with atrial arrhythmia,^[3]especially due to the LAA firing trigger.^[4]Due to a large number of trabeculations and true epicardial location, endocardial CA in LAA may fail or even cause fatal tamponade.^[2,5]The epicardial CA may be an alternative approach.^[6]Because the LAA has a very thin wall and may be prone to perforation, caution should be taken when LAA ablation is performed,^[4]even during an epicardial ablation. There may be recurrence of AT, and surgical left atrial appendectomy (SAE) may be required.

To the Editor:Lung ultrasound (LUS) may be a promising technique to assess lung injury from coronavirus disease 2019 (COVID-19). However, the LUS characteristics and their assessment value have not been well described. We aimed to explore the LUS characteristics and their assessment value in COVID-19 patients with different levels of disease severity.

To the Editor:Hong Kong is a place with a high standard of medical and obstetrical cares. One of the major indicators of health care standard is the rate of maternal death. Over the past few decades, the maternal mortality ratio (MMR) has been gradually decreasing in Hong Kong.^[1]The MMR in Hong Kong, China, was 1.7 in the year 2017, which was lower than or similar to many other high-income countries: the MMR in South Korea was 11, Singapore 8, Japan 5, United Kingdom 7, Australia 6, and Italy and Norway 2.^[2]

To the Editor:Stereotyped behavior refers to a series of behaviors with a high frequency and no obvious purpose and meaning. It also includes narrow interest and difficulty in accepting changes in things. In addition to autism spectrum disorder (ASD), stereotyped behavior also exists in various neurodevelopmental disorders, such as Tourette syndrome, Fragile X syndrome, Prader-Willi syndrome, obsessive-compulsive disorder, and many other diseases, which are considered to be related to dysfunction of the striatum.

To the Editor:Out-of-hospital cardiac arrest (OHCA) is a major public health challenge. Early initiation, good quality cardiopulmonary resuscitation (CPR), and the use of an automated external defibrillator (AED) have been reported to significantly improve the survival and longterm outcomes in survivors of OHCA.^[1]

To the Editor:Osteosarcoma (OS) is the most common malignant primary bone tumor majorly affecting children, adolescents, and young adults. Statistic studies showed that up to 20% of OS patients have clinically detectable metastatic tumor at presentation, and >85% of metastases occurs in the lung. Thus, identifying risk factors that reflect the biological characteristics and survival of OS could lead to better interventions for patients.

Following the original article’s publication,^[1]the authors informed us of the following error. During the final compound of high-resolution figures, a wrong picture was inadvertently put for the Western blot β-actin and matriptase images of NHK in Figure 3f. The published version of Figure 3f is therefore incorrect. The corrected version of the figure is shown below. The only change is in Figure 3f, and the rest of all the figures are identical to the published version. The error does not affect the results and conclusions of the article. The corrected version of the figure is shown below. The authors sincerely apologize for this oversight and for any confusion that caused.