2024年 · 第137卷第20期

Parkinson’s disease (PD) is a neurodegenerative disease characterized by various motor and non-motor symptoms. The complexity of its symptoms suggests that PD is a heterogeneous neurological disorder. Its pathological changes are not limited to the substantia nigra-striatal system, but gradually extending to other regions including the cerebellum. The cerebellum is connected to a wide range of central nervous system regions that form essential neural circuits affected by PD. In addition, altered dopaminergic activity and α-synuclein pathology are found in the cerebellum, further suggesting its role in the PD progression. Furthermore, an increasing evidence obtained from imaging studies has demonstrated that cerebellar structure, functional connectivity, and neural metabolism are altered in PD when compared to healthy controls, as well as among different PD subtypes. This review provides a comprehensive summary of the cerebellar pathophysiology and results from neuroimaging studies related to both motor and non-motor symptoms of PD, highlighting the potential significance of cerebellar assessment in PD diagnosis, differential diagnosis, and disease monitoring.

Tuberculosis (TB) is a prominent infectious disease globally that imposes a substantial health burden. Genital TB (GTB), an extrapulmonary manifestation, leads to complications such as tubal adhesions, blockage, and diminished ovarian function, culminating in infertility, and is recognized as a prevalent cause of infertility in nations with high-burden TB. In regions with low TB rates, infertility and active TB during pregnancy have been reported to be most common among female immigrants from countries with high-burden TB. In the context of TB, pregnant women often exhibit exacerbated symptoms after in vitro fertilization-embryo transfer (IVF-ET), heightening the risk of dissemination. Miliary pulmonary TB and tuberculous meningitis pose a serious threat to maternal and fetal health. This article integrates recent epidemiological data and clinical research findings, delineating the impact of TB on infertility and assisted reproduction and particularly focusing on the diagnosis and treatment of GTB, underscored by the imperative of TB screening before IVF-ET. Our objective is to increase awareness among respiratory and reproductive health professionals, promoting multidisciplinary management to enhance clinical vigilance. This approach seeks to provide patients with judicious reproductive plans and scientifically rigorous pregnancy management, thereby mitigating adverse pregnancy outcomes related to TB activity.

Alcohol-associated liver disease (ALD) is caused by long-term heavy alcohol consumption. The disease is still a significant contributor to the morbidity burden of liver diseases in America and some European countries. A trend of increasing incidence of ALD has also been observed in Asia over the past two decades.^[1]

Pancreatic ductal adenocarcinoma (PDAC) is one of the main types of malignant tumor of the digestive system, and patient prognosis is affected by difficulties in early diagnosis, poor treatment response, and a high postoperative recurrence rate. Carbohydrate antigen 19-9 (CA19-9) has been widely used as a biomarker for the diagnosis and postoperative follow-up of PDAC patients. Nevertheless, the production mechanism and potential role of CA19-9 in PDAC progression have not yet been elucidated.

We performed single-cell RNA sequencing on six samples pathologically diagnosed as PDAC (three CA19-9-positive and three CA19-9-negative PDAC samples) and two paracarcinoma samples. We also downloaded and integrated PDAC samples (each from three CA19-9-positive and CA19-9-negative patients) from an online database. The dynamics of the proportion and potential function of each cell type were verified through immunofluorescence. Moreover, we built an in vitro coculture cellular model to confirm the potential function of CA19-9.

Three subtypes of cancer cells with a high ability to produce CA19-9 were identified by the markers TOP2A, AQP5, and MUC5AC. CA19-9 production bypass was discovered on antigen-presenting cancer-associated fibroblasts (apCAFs). Importantly, the proportion of immature ficolin-1 positive (FCN1+) macrophages was high in the CA19-9-negative group, and the proportion of mature M2-like macrophages was high in the CA19-9-positive group. High proportions of these two macrophage subtypes were associated with an unfavourable clinical prognosis. Further experiments indicated that CA19-9 could facilitate the transformation of M0 macrophages into M2 macrophages in the tumor microenvironment.

Our study described CA19-9 production at single-cell resolution and the dynamics of the immune atlas in CA19-9-positive and CA19-9-negative PDAC. CA19-9 could promote M2 polarization of macrophage in the pancreatic tumor microenvironment.

Breast cancer is ranked among the most prevalent malignancies in the Chinese female population. However, comprehensive reports detailing the latest epidemiological data and attributable disease burden have not been extensively documented.

In 2018, high-quality cancer surveillance data were recorded in 700 population-based cancer registries in China. We extracted data on female breast cancers (International Classification of Diseases, Tenth Revision [ICD-10]: C50) and estimated the incidence and mortality in 2022 according to the baseline data and corresponding trends from 2010 to 2018. Pathological types were classified according to the ICD for Oncology, 3rd Edition codes. Disability-adjusted life years (DALYs) were calculated as the sum of the years of life lost (YLLs) and years lived with disability (YLDs).

In 2022, approximately 357,200 new female breast cancer cases and 75,000 deaths occurred in China, accounting for 15.59% and 7.94% of total new cancer cases and deaths, respectively. The age-standardized incidence rate (ASIR) was 33.04 per 100,000. When analyzed by pathological type, the ASIRs for papillary neoplasms, invasive breast carcinoma, rare and salivary gland-type tumors, and other types were 1.13, 29.79, 0.24, and 1.88 per 100,000, respectively. The age-standardized mortality rate (ASMR) was 6.10 per 100,000. A total of 2,628,000 DALYs were found to be attributable to female breast cancer in China, comprising 2,278,300 YLLs and 349,700 YLDs. The ASIR, ASMR, and age-standardized rate (ASR) for DALYs in urban areas were consistently higher than those in rural areas. We observed a four-fold increase in the ASIR and ASR for DALYs and an eight-fold increase in the ASMR among females over 55 years compared with those aged under 55 years.

These data provide invaluable insights into the latest epidemiology of female breast cancer in China and highlight the urgency for disease prevention and control strategy formulation.

Gastric cancer (GC), a malignant tumor with poor prognosis, is one of the leading causes of cancer-related deaths worldwide; consequently, identifying novel therapeutic targets is crucial for its corresponding treatment. NUF2, a component of the NDC80 kinetochore complex, promotes cancer progression in multiple malignancies. Therefore, this study aimed to explore the potential of NUF2 as a therapeutic target to inhibit GC progression.

Clinical samples were obtained from patients who underwent radical resection of GC at Lanzhou University Second Hospital from 2016 to 2021. Cell count assays, colony formation assays, and cell-derived xenotransplantation (CDX) models were used to determine the effects of NUF2 on GC progression. Flow cytometry was used to detect the effect of NUF2 or quercetin on cell cycle progression and apoptosis. A live-cell time-lapse imaging assay was performed to determine the effect of NUF2 on the regulation of mitotic progression. Transcriptomics was used to investigate the NUF2-associated molecular mechanisms. Virtual docking and microscale thermophoresis were used to identify NUF2 inhibitors. Finally, CDX, organoid, and patient-derived xenograft (PDX) models were used to examine the efficacy of the NUF2 inhibitor in GC.

NUF2 expression was significantly increased in GC and was negatively correlated with prognosis. The deletion of NUF2 suppressed GC progression both in vivo and in vitro. NUF2 significantly regulated the mitogen-activated protein kinase (MAPK) pathway, promoted G2/M phase transition, and inhibited apoptosis in GC cells. Additionally, quercetin was identified as a selective NUF2 inhibitor with low toxicity that significantly suppressed tumor growth in GC cells, organoids, CDX, and PDX models.

Collectively, NUF2-mediated G2/M phase transition and apoptosis inhibition promoted GC progression; additionally, NUF2 inhibitors exhibited potent anti-GC activity. This study provides a new strategy for targeting NUF2 to suppress GC progression in clinical settings.

Very low birth weight (VLBW) infants are the key populations in neonatology, wherein morbidity and mortality remain major challenges. The study aimed to analyze the clinical characteristics of VLBW infants.

A retrospective cohort study was conducted in West China Second Hospital between January 2016 and December 2021. Neonates with a birth weight of <1500 g were included. Mortality, care practices, and major morbidities were analyzed, and compared with those of previous 7 years (2009-2015).

Of the total 1750 VLBW, 1386 were infants born with birth weight between 1000-1499 g and 364 infants were born with weight below 1000 g; 42.9% (751/1750) required delivery room resuscitation; 53.9% (943/1750) received non-invasive ventilation only; 38.2% (669/1750) received invasive ventilation; 1517 VLBW infants received complete treatment. Among them, 60.1% (912/1517) of neonates had neonatal respiratory distress syndrome (NRDS), 28.7% (436/1517) had bronchopulmonary dysplasia (BPD), 22.0% (334/1517) had apnea, 11.1% (169/1517) had culture-confirmed sepsis, 8.4% (128/1517) had pulmonary hemorrhage, 7.6% (116/1517) had severe intraventricular hemorrhage (IVH)/periventricular leukomalacia (PVL), 5.7% (87/1517) had necrotizing enterocolitis (NEC), and 2.0% (31/1517) had severe retinopathy of prematurity. The total and in-hospital mortality rates were 9.7% (169/1750) and 3.0% (45/1517), respectively. The top three diagnoses of death among those who had received complete treatment were sepsis, NRDS, and NEC. In 2009-2015, 1146 VLBW were enrolled and 895 infants received complete treatment. The proportions of apnea, IVH, and IVH stage ≥3/PVL, were higher in 2009-2015 compared with those in 2016-2021, while the proportions of NRDS and BPD were characterized by significant increases in 2016-2021. The total and in-hospital mortality rates were 16.7% (191/1146) and 5.6% (50/895) respectively in 2009-2015.

Among VLBW infants born in 2016-2021, the total and in-hospital mortality rates were lower than those of neonates born in 2009-2015. Incidences of NRDS and BPD increased in 2016-2021, which affected the survival rates and long-term prognosis of VLBW.

Hypothermia therapy has been suggested to attenuate myocardial necrosis; however, the clinical implementation as a valid therapeutic strategy has failed, and new approaches are needed to translate into clinical applications. This study aimed to assess the feasibility, safety, and efficacy of a novel selective intracoronary hypothermia (SICH) device in mitigating myocardial reperfusion injury.

This study comprised two phases. The first phase of the SICH was performed in a normal porcine model for 30 minutes (n = 5) to evaluate its feasibility. The second phase was conducted in a porcine myocardial infarction (MI) model of myocardial ischemia/reperfusion which was performed by balloon occlusion of the left anterior descending coronary artery for 60 minutes and maintained for 42 days. Pigs in the hypothermia group (n = 8) received hypothermia intervention onset reperfusion for 30 minutes and controls (n = 8) received no intervention. All animals were followed for 42 days. Cardiac magnetic resonance analysis (five and 42 days post-MI) and a series of biomarkers/histological studies were performed.

The average time to lower temperatures to a steady state was 4.8 ± 0.8 s. SICH had no impact on blood pressure or heart rate and was safely performed without complications by using a 3.9 F catheter. Interleukin-6 (IL-6), tumor necrosis factor-α, C-reactive protein (CRP), and brain natriuretic peptide (BNP) were lower at 60 min post perfusion in pigs that underwent SICH as compared with the control group. On day 5 post MI/R, edema, intramyocardial hemorrhage, and microvascular obstruction were reduced in the hypothermia group. On day 42 post MI/R, the infarct size, IL-6, CRP, BNP, and matrix metalloproteinase-9 were reduced, and the ejection fraction was improved in pigs that underwent SICH.

The SICH device safely and effectively reduced the infarct size and improved heart function in a pig model of MI/R. These beneficial effects indicate the clinical potential of SICH for treatment of myocardial reperfusion injury.

Ainuovirine (ANV) is a new generation of non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus (HIV) type 1 infection. This study aimed to evaluate the population pharmacokinetic (PopPK) profile and exposure-response relationship of ANV among people living with HIV.

Plasma concentration-time data from phase 1 and phase 3 clinical trials of ANV were pooled for developing the PopPK model. Exposure estimates obtained from the final model were used in exposure-response analysis for virologic responses and safety responses.

ANV exhibited a nonlinear pharmacokinetic profile, which was best described by a two-compartment model with first-order elimination. There were no significant covariates correlated to the pharmacokinetic parameters of ANV. The PopPK parameter estimate (relative standard error [%]) for clearance adjusted for bioavailability (CL/F) was 6.46 (15.00) L/h, and the clearance of ANV increased after multiple doses. The exposure-response model revealed no significant correlation between the virologic response (HIV-RNA <50 copies/mL) at 48 weeks and the exposure, but the incidence of adverse events increased with the increasing exposure (P value of steady-state trough concentration and area under the steady-state curve were 0.0177 and 0.0141, respectively).

Our PopPK model supported ANV 150 mg once daily as the recommended dose for people living with HIV, requiring no dose adjustment for the studied factors. Optimization of ANV dose may be warranted in clinical practice due to an increasing trend in adverse reactions with increasing exposure.

Chinese Clinical Trial Registry https://www.chictr.org.cn (Nos. ChiCTR1800018022 and ChiCTR1800019041).

Chronic spontaneous urticaria (CSU) is defined as the spontaneous appearance of wheals, angioedema, or both for more than six weeks due to known or unknown causes. The prevalence of CSU was found to be higher in Asian studies (1.4%) compared to studies conducted in Europe (0.5%) and North America (0.1%). Guidelines suggest second-generation H1-antihistamines (sgAHs) at standard doses as the first-line treatment for CSU.^[1]However, studies on patients with CSU have shown that certain individuals may have a limited response to conventional doses of H1-antihistamines (AHs).^[2]

The loss of laryngeal function profoundly impacts the quality of life for specific patients with distorted laryngeal structure or total laryngectomy, particularly in social contexts. Consequently, allotransplantation has emerged as a potential solution for restoring laryngeal function. A significant milestone in this field was the successful total laryngeal transplant conducted by Stromeet al^[1]in 1998, demonstrating graft viability for an impressive 13-year postoperative period. Building upon this progress, Farwellet al^[2]and Grajeket al^[3]performed the second and third surgeries in 2012 and 2015, respectively.

To the Editor: Dual antiplatelet therapy (DAPT), which comprises aspirin plus a P2Y₁₂receptor inhibitor, is the standard approach for reducing cardiac and systemic ischemic events in individuals with coronary artery disease.^[1]Although DAPT reduces ischemic episodes, it also increases the risk of bleeding. In individuals with acute coronary syndrome (ACS), bleeding incidents during hospitalization not only greatly increase the risk of in-hospital death but also increase the risk of long-term mortality and major adverse cardiovascular events.^[2]Therefore, the management of DAPT must consider both bleeding and ischemic risks.

To the Editor: Swallowing-related cough is a common manifestation of oropharyngeal dysphagia, and confirms the risk of aspiration and choking.^[1,2]Choking-related death was the common cause of accidental death in old adults. Because of the difficulty of first aid, 80% of choked people died before the emergency team arrived, which stresses the importance of monitor and prevention of swallowing-related cough.^[3]Additionally, swallowing disorder intertwines with various aging-related conditions, such as frailty, sarcopenia, and dementia, and is the crossed manifestation of aging-related health decline.^[2]Currently, swallowing-related cough was mainly considered as one of the screening criteria of dysphagia and risk indicator of aspiration pneumonia, while the actual screening rates in clinical practice were extremely low.^[1,2]Clinical guidelines on aspiration pneumonia and dysphagia, which involve swallowing-related cough, recommend to intensify oral care, test for dysphagia, and initiate swallowing rehabilitation early. But these actions highly depend on formal caregivers and specialists. Considering the circumstances lacking formal caregivers, it would be more pragmatic to find an easy-to-notice risk factor. Comprehensive geriatric assessment (CGA) was the consented solution of multidisciplinary healthcare of old adults. However, the initiation of CGA in the circumstances lacking formal caregiver remains unsettled. In the perspective of health monitor, the advantage of swallowing-related cough is easy-to-notice. It is valuable to investigate the clinical significance of swallowing-related cough on health decline in old adults and determine whether it is a worth-to-use indicator. Besides, it is also essential to explore the related factor of swallowing-related cough, which could guide the prevention and management of swallowing-related cough, minimizing the need for intensified care among high-risk population. Therefore, the present study investigated the prevalence and related factor of swallowing-related cough, and evaluated its association with health decline of old adults.

To the editor: Stroke is the foremost cause of death and disability worldwide.^[1]A stroke event can cause severe motor sequelae, including motor dyscoordination, hemiparesis, and hemiplegia. Although rehabilitation training is an essential part of post-stroke treatment, rehabilitation training alone may not significantly improve motor function in patients with chronic stroke. Recently, numerous preclinical studies and animal experiments have preliminarily validated the safety and efficacy of electrical nerve stimulation technology for chronic post-stroke motor rehabilitation, which awaits large-scale clinical application. Motor cortex stimulation (MCS), vagus nerve stimulation (VNS), deep brain stimulation (DBS), and spinal cord stimulation (SCS) are invasive electrical neurostimulation techniques for patients with chronic stroke [Supplementary Figure 1, http://links.lww.com/CM9/C135]. We reviewed the progress of research into the mechanism, efficacy, targets, and loops of these techniques.

To the Editor: Salivary adenoid cystic carcinoma (SACC) is characterized by the high frequency of perineural invasion (PNI) behavior during tumor progression. However, the impact of intercellular communication between SACC cells and surrounding non-malignant cells on PNI remains unclear. As the main constituent cells of the peripheral nervous system, Schwann cells have been reported to be closely associated with the process of PNI. Cancer cell-derived exosomes often serve as important signaling mediators between cancer cells and the local microenvironment. Therefore, this study aimed to elucidate the reciprocal interplay between cancer cells and Schwann cells via exosomes during cancer PNI and to identify potential therapeutic target for PNI.

To the Editor: Genomic instability is a hallmark of cancer, with increasing genetic changes and DNA damage. The accumulated mutations in the tumor genome can generate neoantigens, which can trigger an antitumor immune response. Moreover, as a consequence of genomic instability, the leakage of nuclear DNA can directly alert the immune system to the presence of malignant cells. Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is a major DNA sensor that triggers the innate immune response.^[1]The accumulation of doublestranded DNA fragments in the cytoplasm can directly bind to cGAS, functioning as an activator or stimulator of interferon genes (STING). STING acts as a signaling platform to recruit TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) for phosphorylation. Phosphorylated IRF3 translocates to the nuclei, where it functions as a transcription factor to promote the expression of type I interferon (IFN) and immune-stimulated cytokines. This leads to the migration and activation of various immune cells.

To the Editor: China now has the largest number of patients with diabetes mellitus (DM) worldwide, making diabetic retinopathy (DR) the leading cause of blindness in the Chinese working-age population.^[1]Fundus screening for patients with DM is important so that ophthalmologists treat retinopathy in a timely manner and delay the development of vision loss. However, we found some problems in the clinical practice of fundus screening. Microaneurysm (MA) and small dot intraretinal hemorrhage (HEM), although described precisely by the Early Treatment Diabetic Retinopathy Study (ETDRS) group,^[2]are red and round spots on dilated ophthalmoscopy and cannot be easily differentiated due to incompletely transparent dioptric media of patients unless fundus fluorescein angiography (FFA) is performed. Questions always come up: Do we have to differentiate these two lesions when grading the severity of DR?

To the Editor:Androgenic alopecia (AGA) is a common chronic hair loss disorder that usually begins in adolescence, with hair follicle miniaturization.^[1]Clinical manifestations include reduced hair diameter and volume, potentially leading to baldness. AGA, characterized by progressive hair loss, can affect both sexes. Inflammation around the hair follicle, stress, emotional tension, and poor lifestyle and eating habits can further aggravate the symptoms of AGA.^[2]Currently, minoxidil and finasteride (FNS) are the only drug therapies specifically approved for AGA by the FDA.^[3]However, these two drugs have obvious side effects and poor patient compliance, so it is urgent to find a safe and effective clinical treatment method for AGA.

To the Editor: Irritable bowel syndrome (IBS) is one of the most common adult functional gastrointestinal disorders (FGIDs), with an estimated global prevalence of 1.5-11.2%. The prevalence rates for anxiety and depressive symptoms and disorders underscore the psychological impact on IBS patients, emphasizing the need for comprehensive diagnostic tools tailored to specific populations.^[1]The main diagnostic reference for IBS is the Rome criteria which is now the standard practice for IBS diagnosis worldwide. The most recent iteration is Rome IV [Supplementary Table 1, http://links.lww.com/CM9/C102]. Despite its broad acceptance, validation studies demonstrated that the Rome criteria only performed modestly in diagnosing IBS and, in clinical practice, Rome criteria are not commonly used. The overlap between the symptoms of IBS and FGIDs must be considered in the diagnosis of IBS and should be taken into consideration in the development of symptom-based diagnostic tools.

To the Editor:The abdominal surgical procedures are linked to a high incidence of postoperative pulmonary complications (PPCs) and may be mitigated by administration of lung-protective mechanical ventilation during anesthesia.^[1,2]To date, no relevant studies have focused on protective lung ventilation strategies specifically for laparoscopic colorectal cancer (CRC). Herein, we propose an innovative easy-to-use lung-protective strategy with lower tidal volume (VT), pneumoperitoneum pressure (PnP) and deep neuromuscular blockade (NMB) and assess whether it is superior to conventional lung protection strategies in reducing PPCs.

To the Editor:Bone is a complex tissue that continually undergoes dynamic biological remodeling. However, when bone defects exceed the self-repair threshold, they are regarded as critical-sized bone defects (CBDs),^[1]and artificial interventions are required to assist the repair process. Implanting three-dimensional (3D)-printed prostheses is a promising candidate for reconstructing limb CBDs. The geometry, pore size, and porosity of these printed prostheses can be customized via a layer-by-layer manufacturing process based on patient-specific model data.^[2]Many studies have been conducted to introduce 3D-printed prostheses for repairing CBDs, confirming their biocompatibility, stability, and osteogenesis. However, systematic clinical reports of serial cases are still lacking so far.