BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a progressive disease that predominantly affects older adults and is frequently accompanied by multiple chronic comorbidities. Although individual comorbidities have been widely reported, the prognostic impact of cumulative comorbidity burden in routine clinical practice remains incompletely understood. OBJECTIVES:To investigate the prevalence of comorbidities in patients with IPF and to evaluate the association between comorbidity burden and all-cause mortality in a real-world clinical cohort. METHODS:We conducted a retrospective cohort study including 328 patients with IPF diagnosed between 2011 and 2021 at the Second Xiangya Hospital. Comorbidities were systematically assessed at baseline and quantified using a structured comorbidity index. Associations between comorbidity burden and all-cause mortality were evaluated using Cox proportional hazards models and Kaplan-Meier survival analysis, with follow-up until May 2022. RESULTS:Among the 328 patients, 78.7% had at least one comorbidity at baseline, and >60% had two or more comorbidities. Cardiovascular disease (32.6%), hyperlipidemia (26.5%), hypertension (25.9%), and diabetes (16.4%) were the most common conditions. In multivariable analysis, higher comorbidity burden was independently associated with increased mortality. Patients with ≥2 comorbidities had significantly shorter survival compared with those with 0-1 comorbidity (log-rank P < 0.001). Cardiovascular disease and diabetes were significant predictors of adverse outcomes. CONCLUSION:In this real-world IPF cohort, comorbidities were common and associated with reduced survival. Assessment of comorbidity burden provides complementary prognostic information beyond traditional pulmonary parameters and supports a more holistic approach to risk stratification in IPF.

Stroke represents a major cause of mortality and long-term disability in China, placing a substantial burden on the healthcare system. Within the tiered healthcare framework, an effective two-way referral system is crucial for ensuring timely acute care and coordinated rehabilitation. However, current research primarily focuses on aggregate metrics like referral rates, leaving the structural characteristics of the referral network underexplored. This study uses social network analysis to assess upward and downward referrals for stroke inpatients. Based on provincial inpatient data, we constructed upward and downward referral networks and analyzed patterns using social network analysis. Indicators at the network, subgroup, and node levels were assessed, including density, K-core, degree centrality, and betweenness centrality. Network visualization was performed using NetDraw 2.140 and Gephi 0.9.2. The study included 14,334 inpatient stroke cases, of which 4,948 (34.52

Ischaemic stroke (IS) has a heavy disease burden. Although epidemiological research has suggested that heatwaves are associated with cardiovascular disease, there is a lack of empirical evidence for a correlation between heatwaves and IS. The China Meteorological Administration defines a heatwave as a wave lasting ≥ 3 days, with a maximum temperature of ≥ 35℃. We collected data on daily meteorological conditions, air pollution, and IS admissions in Hunan Province from 2018 to 2019. A generalized additive model and distributed lag nonlinear model were used to determine the associations between heatwaves and IS admissions. We analysed 329,876 admitted patients with IS in Hunan Province from 2018 to 2019. The main effect of heatwaves was that they significantly increased the risk of hospitalization for IS. The single-day lag maximum risk occurred at a daily average temperature of 30.88℃ (RR = 1.05, 95% CI: 1.04–1.06) and at a daily maximum temperature of 35.82℃ (RR = 1.05, 95% CI: 1.03–1.06). The use of the 5th and subsequent days of a heatwave as a reference showed that the 1st–2nd days (RR = 1.07, 95% CI: 1.02–1.12) and the 3rd–4th days (RR = 1.06, 95% CI: 1.03–1.10) of the heatwave increased the risk of hospitalization for IS. Compared with the third and subsequent heatwaves, the first (RR = 1.27, 95% CI: 1.19–1.35) and second (RR = 1.24, 95% CI: 1.16–1.32) heatwaves had greater impacts on the risk of hospitalization for IS. The risk of IS hospitalization was also exacerbated by high relative humidity (RR = 1.25, 95% CI: 1.16–1.35) and a low diurnal temperature range (RR = 1.08, 95% CI: 1.02–1.14) during the heatwave period. In our study, the main effects of heatwaves increased the risk of IS hospitalization. The effects varied according to the day of the heatwave, the timing of the heatwave, the DTR during the heatwave, and the humidity during the heatwave. This evidence has significant implications for the strategic planning of public health interventions to mitigate adverse health outcomes associated with heatwaves.

Objective:This study evaluated the diagnostic accuracy of the 2012 SLICC and 2019 EULAR/ACR criteria in Chinese cSLE patients and aimed to develop an optimized classification schema based on the 2019 EULAR/ACR criteria, specifically tailored for cSLE. Methods:Data from cSLE and control cases were extracted from the CAPRID database. Gold-standard diagnosis were established by consensus among 43 rheumatologists (≥80% agreement). From 1,390 consensus cases, a random selection of 1,045 cases (512 cSLE/533 non-cSLE) were allocated to derivation (n=522) and validation (n=523) cohorts. The 2012 SLICC and 2019 EULAR/ACR criteria were evaluated in the total cohort. Multiple optimization schemes were then developed through LASSO regression with expert consultation in the derivation cohort. All potential optimization schemes underwent validation in the validation cohort, from which the optimal scheme was selected and further evaluated in an ANA-positive subgroup. Results:The 2012 SLICC criteria demonstrated sensitivity of 96.7% and specificity of 96.5%, while the 2019 EULAR/ACR criteria had sensitivity of 95.3% and specificity of 97.8%, with an optimal total score threshold of 10. When both the non-scarring alopecia and arthritis criteria were removed alongside the redefined urinary protein criterion, specificity significantly improved to 99.3% (P < 0.05), while sensitivity remained unaffected at 94.1% (P = 0.210). In the ANA-positive cohort, the optimized integrated scheme significantly improved specificity (97.7% vs. 86.4%, P = 0.012) while maintaining comparable sensitivity (96.2% vs. 97.8%, P = 0.138). Conclusion:Both criteria performed well in Chinese cSLE patients. Optimizing the 2019 EULAR/ACR criteria by removing alopecia and arthritis criteria and modifying the urinary protein criterion enhanced specificity without compromising sensitivity.

Background:Hand-foot syndrome (HFS) and oral mucositis (OM) are common adverse events during cancer chemotherapy and can significantly decrease patients' quality of life and chemotherapy adaptation, however, prevention strategies of these complications yet to be established. Methods:Patients with stages I-III breast cancer, who had surgery and needed pegylated liposomal doxorubicin (PLD)-based adjuvant chemotherapy were screened, recruited and randomly assigned to receive either probiotics or placebo (three capsules, twice/day) treatment during the course of chemotherapy from November 2019 to August 2020. The incidence and severity of PLD related HFS and OM, and patients' quality of life were assessed. Their plasma biomarkers, metabolites and fecal microbiota compositions were measured. And the results were further verified in animal experiments. Results:Probiotics supplement during PLD treatment significantly decreased the incidence and the severity of HFS and OM (P < 0.001), improved patients' life quality (P < 0.001), increased the relative abundance of intestinal Enterococcus (P = 0.025) and mitigated the changes of seven plasma metabolites. Among these metabolites, the changes of p-Mentha-1,8-dien-7-ol (MDO) (B = - 0.441, P = 0.02) and L-arginine (B = - 0.586, P = 0.002) were negatively correlated with the occurrence of severe HFS and OM. MDO can partly reproduce the preventive effects of probiotics on PLD-related skin cell proliferating inhibition, DNA damage, and local inflammation in rats. Conclusion:Probiotics supplement during PLD-based chemotherapy prevents the incidence and severity of HFS and OM, which may be associated with modulating plasma metabolites including the MDO.

Background Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. There is no nomogram model available for mortality prediction of stable COPD. We intended to develop and validate a nomogram model to predict mortality risk in stable COPD patients for personalised prognostic assessment. Methods A prospective observational study was made of COPD outpatients registered in the RealDTC study between December 2016 and December 2019. Patients were randomly assigned to the training cohort and validation cohort in a ratio of 7:3. We used Lasso regression to screen predicted variables. Further, we evaluated the prognostic performance using the area under the time-dependent receiver operating characteristic curve (AUC) and calibration curve. We used the AUC, concordance index, and decision curve analysis to evaluate the net benefits and utility of the nomogram compared with three earlier prediction models. Results Of 2499 patients, the median follow-up was 38 months. The characteristics of the patients between the training cohort (n = 1743) and the validation cohort (n = 756) were similar. ABEODS nomogram model, combining age, body mass index, educational level, airflow obstruction, dyspnoea, and severe exacerbation in the first year, was constructed to predict mortality in stable COPD patients. In the integrative analysis of training and validation cohorts of the nomogram model, the three-year mortality prediction achieved AUC = 0.84; 95% confidence interval (CI) = 0.81, 0.88 and AUC = 0.80; 95% CI = 0.74, 0.86, respectively. The ABEODS nomogram model preserved excellent calibration in both the training cohort and validation cohort. The time-dependent AUC, concordance index, and net benefit of the nomogram model were higher than those of BODEx, updated ADO, and DOSE, respectively. Conclusions We developed and validated a prognostic nomogram model that accurately predicts mortality across the COPD severity spectrum. The proposed ABEODS nomogram model performed better than earlier models, including BODEx, updated ADO, and DOSE in Chinese patients with COPD. Registration ChiCTR-POC-17010431.

BackgroundPrompt professional care for postpartum depression (PPD) is difficult to obtain in China. Though online consultations improve accessibility and reduce stigma, the quality of services compared to in-person consultations is unclear.MethodsFive trained, undisclosed “standardized patients” (SPs) made “asynchronous webchats” visits and in-person visits with psychiatrists. Visits were made to 85 psychiatrists who were based in 69 hospitals in ten provincial capital cities. The care between online and in-person consultations with the same psychiatrist was compared, including diagnosis, guideline adherence, and patient-centeredness. False discovery rate (FDR) was used to adjust p values. Third visits using asynchronous webchats were made to psychiatrists who offered discrepant diagnoses. Thematic content analysis was used for the discrepancies.FindingsThe proportion of diagnostic accuracy was lower for online than in-person visits (76.5% [65/85] vs 91.8% [78/85]; pFDR = 0.0066), as were the proportions of completing questions involving clinical history (16.6% vs 42.7%; pFDR < 0.0001), and management decisions (16.2% vs 27.5%; pFDR < 0.0001) consistent with recommended guidelines. Patient-centeredness was lower online than in-person (pFDR < 0.0001). Fifteen of 16 psychiatrists completed third visits, most of them considered lack of nonverbal information online as a key barrier.InterpretationOnline consultations using asynchronous webchats were inferior to in-person consultations, with respect to diagnostic accuracy, adherence to recommended clinical guidelines, and patient-centeredness. To fully realise the potential benefits of online consultations and to prevent safety issues, there is an urgent need for major improvement in the quality and oversight of these consultations.FundingChina Medical Board, National Natural Science Foundation of China, and Swiss Agency for Development and Cooperation Global Cooperation Department.

OBJECTIVES: This study investigated the seasonal impact of diurnal temperature range (DTR) on hospitalization rates for intracerebral hemorrhage (ICH) in middle-aged and elderly adults.METHODS: We collected data on the DTR and hospitalization records of ≥45-year-old patients with ICH in 2019 in Hunan Province, central China. Time-series analyses were performed using a distributed lag non-linear model.RESULTS: Overall, 54,690 hospitalizations for ICH were recorded. DTR showed a non-linear relationship with ICH hospitalization in both middle-aged and elderly populations (45-59 and ≥60 years, respectively). During spring, a low DTR coupled with persistently low temperatures increased ICH risk in both age groups, while a high DTR was associated with an increased risk in the middle-aged group only (relative risk [RR], 1.24; 95% confidence interval [CI], 1.21 to 1.27). In the summer, a low DTR combined with persistently high temperatures was linked to a higher risk exclusively in the middle-aged group. A high DTR in the autumn was correlated with increased risk in both age groups. In winter, either a low DTR with a continuously low temperature or a high DTR elevated the risk solely in the elderly population (RR, 1.37; 95% CI, 1.00 to 1.69). In the elderly group, the impact of DTR on hospitalization risk manifested within a 5-day period.CONCLUSIONS: The impact of DTR on ICH hospitalization risk differed significantly across seasons and between age groups. Elderly individuals demonstrated greater sensitivity to the impact of DTR. Weather forecasting services should emphasize DTR values, and interventions targeting sensitive populations are needed.

Knowledge graph (KG) fact prediction aims to complete a KG by determining the truthfulness of predicted triples. Reinforcement learning (RL)-based approaches have been widely used for fact prediction. However, the existing approaches largely suffer from unreliable calculations on rule confidences owing to a limited number of obtained reasoning paths, thereby resulting in unreliable decisions on prediction triples. Hence, we propose a new RL-based approach named EvoPath in this study. EvoPath features a new reward mechanism based on entity heterogeneity, facilitating an agent to obtain effective reasoning paths during random walks. EvoPath also incorporates a new postwalking mechanism to leverage easily overlooked but valuable reasoning paths during RL. Both mechanisms provide sufficient reasoning paths to facilitate the reliable calculations of rule confidences, enabling EvoPath to make precise judgments about the truthfulness of prediction triples. Experiments demonstrate that EvoPath can achieve more accurate fact predictions than existing approaches.

Objective:To study the effect of diurnal temperature range on the number of elderly inpatients with ischemic stroke in Hunan Province.Method:Demographic and disease data, meteorological data, air quality data, population, economic and health resource data of elderly inpatients with ischemic stroke were collected in 122 districts/counties of Hunan Province from January to December 2019. The relationships between the diurnal temperature range and the number of elderly inpatients with ischemic stroke were analyzed by using the distributed lag non-linear model, including the cumulative lag effect of the diurnal temperature range in different seasons, extremely high diurnal temperature range and extremely low diurnal temperature range.Results:In 2019, 152 875 person-times were admitted to the hospital for ischemic stroke in the elderly in Hunan Province. There was a non-linear relationship between the diurnal temperature range and the number of elderly patients with ischemic stroke, with different lag periods. In spring and winter, with the decrease in diurnal temperature range, the risk of admission of elderly patients with ischemic stroke increased ( Ptrend<0.001, Ptrend=0.002);in summer, with the increase in diurnal temperature range, the risk of admission of elderly patients with ischemic stroke increased ( Ptrend=0.024);in autumn, the change in the diurnal temperature range would not cause a change in admission risk ( Ptrend=0.089). Except that the lag effect of the extremely low diurnal temperature range in autumn was not obvious, the lag effect occurred in other seasons under extremely low and extremely high diurnal temperature ranges. Conclusion:The high diurnal temperature range in summer and the low diurnal temperature range in spring and winter will increase the risk of admission of elderly patients with ischemic stroke, and the risk of admission of elderly patients with ischemic stroke will lag under the extremely low and extremely high diurnal temperature ranges in the above three seasons.

目的 了解湖南省脑出血(intracerebral hemorrhage,ICH)患者住院费用及构成,并对其影响因素进行分析,为控制和降低ICH住院费用提供依据.方法 利用湖南省二级以上公立医院ICH患者的住院费用相关信息,进行住院费用构成的描述并探讨影响住院费用的因素.结果 共13518例ICH患者纳入研究,住院费用中占比最高的为药费(27.1％).三级医院住院费用的治疗费用占比高于二级医院,而康复费用和药费占比低于二级医院.住院天数越长住院费用越高,手术、重症监护、急诊入院、入院时危重、男性、三级医院患者的住院费用更高,65～岁患者的住院费用最高,未愈和死亡患者的住院费用高于治愈/好转患者.结论 建议从适当减少住院天数、合理使用中草药替代西药等方面来控制和降低ICH患者的住院费用.

Objective Little is known about spatial variability of hospitalisation rate (HR) of patients with rheumatoid arthritis (RA) worldwide, especially in China. Methods A cross-sectional study was conducted among patients with RA admitted to hospitals in Hunan Province. Global Moran’s I and local indicators of spatial association were used to explore the geospatial pattern of the HR of patients with RA. Generalised estimating equation analysis and geographically weighted regression were used to identify the potential influencing factors of the HR of patients with RA. Results There were a total of 11 599 admissions, and the average HR was 1.57 per 10 000 population in Hunan. We detected different cluster patterns of the HR among patients with RA by local indicators of spatial association. Age, ethnicity, average temperature, average temperature range, average rainfall, regions, gross domestic product per capita, and doctors and hospitals per 10 000 people were risk factors for the HR. However, only average temperature, gross domestic product per capita and hospitals per 10 000 people showed different regression coefficients on the HR in different counties. The increase in hospitals increased the probability of HR from east to west in Hunan with a positive coefficient, while temperature decreases increased the risk of HR from south to north negatively. Similarly, the growth of gross domestic product per capita decreased the probability of HR from southwest to northeast. Conclusion A non-random spatial distribution of the HR of patients with RA was demonstrated in Hunan, and average temperature, gross domestic product per capita and hospitals per 10 000 people showed different regression coefficients on the HR in different counties. Our study indicated that spatial and geostatistics may be useful approaches for further study among patients with RA.

A graph is an abstract model that represents relations among entities, for example, the interactions between characters in a novel. A background story endows entities and relations with real-world meanings and describes the semantics and context of the abstract model, for example, the actual story that the novel presents. Considering practical experience and prior research, human viewers who are familiar with the background story of a graph and those who do not know the background story may perceive the same graph differently. However, no previous research has adequately addressed this problem. This research article thus presents an evaluation that investigated the effects of background stories on graph perception. Three hypotheses that focused on the role of visual focus areas, graph structure identification, and mental model formation on graph perception were formulated and guided three controlled experiments that evaluated the hypotheses using real-world graphs with background stories. An analysis of the resulting experimental data, which compared the performance of participants who read and did not read the background stories, obtained a set of instructive findings. First, having knowledge about a graph's background story influences participants’ focus areas during interactive graph explorations. Second, such knowledge significantly affects one's ability to identify community structures but not high degree and bridge structures. Third, this knowledge influences graph recognition under blurred visual conditions. These findings can bring new considerations to the design of storytelling visualizations and interactive graph explorations.

OBJECTIVESStroke readmission increases financial burden on the family and the consumption of medical resources, and 30-day readmission rate is an important indicator for quality evaluation on health services. The influential factors for readmission mainly include patient-related factors, hospital factors, and society-related factors, with regional differences. This study aims to explore the spatial distribution and its main relevant factors for 30-day readmission of stroke patients in Hunan Province, and to provide the useful information for the improvement of regional prevention and control of stroke readmission.METHODSStroke patients in Hunan Province who were hospitalized in 2018 and readmitted within 30 days were included in the study. The vector map of the county boundary in Hunan Province was used as the basic map since county was the spatial analysis unit. SPSS 26.0 and ArcGIS 10.8 were used for statistical analysis that contains descriptive analysis of the general situation and the distribution map of readmission rate within 30 days of stroke patients. Spatial autocorrelation analysis and spatial regression analysis were further used to find the spatial clusters of the 30-day readmission rate of stroke and the local relationship between the readmission rate and main influential factors.RESULTSIn 2018, a total of 172 800 stroke patients were hospitalized in Hunan Province, of which 6 953 patients were re-hospitalized within 30 days after discharging due to stroke. The 30-day readmission rate was 4.09% in Hunan Province. The clusters of stroke readmission rates were mainly concentrated in the northeast and western regions in Hunan Province. The geographically weighted regression revealed that proportion of patients with complications, number of hospitals per 10 000 population and number of primary medical and health care institution per 10 000 population were the main relevant factors for stroke readmission, and there were differences both in the direction and degree of the effect on readmission in different regions.CONCLUSIONSThe 30-day readmission rate for stroke patients in Hunan province and its main influential factors had spatial heterogeneity. The key prevention and control areas were mainly concentrated in the northeast and western regions. It is recommended that the prevention and treatment of stroke complications and the construction of medical institutions need to be strengthened to improve the quality of medical services, particularly in the western region. The importance to the treatment of stroke complications should be attached in the northern region, and the primary health care should be reinforced in the northeast region. All counties should take prevention and control measures according to local conditions, so as to effectively control the readmission rate of stroke within 30 days.

强化科研育人是深化本科生教育教学改革的重要内容之一[1].我国实行的医师资格考试制度中明确提出了执业医师应具备的基本科研素质[2] ,这对医学教育具有导向作用[3].医学科学研究设计是一门培养医学生科研能力的基础课程之一[4].该课程的绝大部分内容是医学生必修课医学(卫生)统计学的一部分,如:统计设计中的研究对象、因素、指标、设计类型和样本含量的选择等内容[5].为进一步完善医学科学研究设计课程,深化医学生教育教学改革,本文系统梳理相关文献,从《医师资格考试大纲》所涉及知识点、课程需求、参考书籍、课程情况和教学模式五个方面对国内医学科学研究设计课程现状进行介绍,并提出改进建议.

Abstract Background The colposcopy-conization inconsistency is common in women with cervical intraepithelial neoplasia grade 3 (CIN3). No adequate method has been reported to identify the final pathology of conization. In this study, we explored the ability of PAX1 and ZNF582 methylation to predict the pathological outcome of conization in advance. Methods This was a multicenter study and included 277 histologically confirmed CIN3 women who underwent cold knife conization (CKC) from January 2019 to December 2020. The methylation levels of PAX1 (PAX1m) and ZNF582 (ZNF582m) were determined by quantitative methylation-specific polymerase chain reaction (qMSP) and expressed in ΔCp. Receiver operating characteristic curves were used to evaluate predictive accuracy. Results The final pathological results in 48 (17.33%) patients were inflammation or low-grade squamous intraepithelial lesion (LSIL), 190 (68.59%) were high-grade squamous intraepithelial lesion (HSIL), and 39 (14.08%) were squamous cervical cancer (SCC). PAX1m and ZNF582m increased as lesions progressed from inflammation/LSIL, HSIL, to SCC. PAX1 and ZNF582 methylation yielded better prediction performance compared with common screening strategies, whether individually or combined. A 4.33-fold increase in the probability of inflammation/LSIL was observed in patients with lower ZNF582 methylation levels (ΔCpZNF582 ≥ 19.18). A 6.53-fold increase in SCC risk was observed in patients with elevated ZNF582 methylation (ΔCpZNF582 < 7.09). Conclusions DNA methylation would be an alternative screening method to triage and predict the final outcome of conization in CIN3 cases.

Purpose To compare the characteristics of depression-related symptoms identified by individual EPDS items in women who screened positive and negative, and to describe the occurrence of thoughts of self-harm in these women.Methods Based on a Chinese cohort of 1,112 women, scores on each EPDS item were analyzed at 7 time points from the first trimester to 6 weeks postpartum. Scores greater than 0 indicated the presence of symptoms, and higher scores indicated more severe symptoms. We defined the most frequent, serious and important symptoms for screening-positive and screening-negative groups as the item with the highest proportion of respondents scoring 1 or higher, highest proportion scoring 3, and highest average score, respectively.Results In screened positive women the most frequent symptom was feeling sad or miserable, and the most serious and important symptoms were both sleeping problems. Among those screened negative, self-blame was the most frequent, serious and important item. For women who screened positive in the first trimester, only self-blame and feeling overwhelmed showed stability over time. Symptoms in women screened negative were relatively stable. Four in ten women who had self-harm thoughts were screened negative.Conclusion Women who screened positive in EPDS differed from those screened negative in the characteristics in depressive symptoms. Intervention strategies focusing on the most frequent, serious and important symptoms (such as sadness and insomnia) may be worthwhile. Health practitioners should be trained to respond to a positive response to thoughts of self-harm, regardless of whether the women are screened positive or negative.

Although three monovalent EV-A71 vaccines have been launched in mainland China since 2016, hand, foot, and mouth disease (HFMD) still causes a considerable disease burden in China. Vaccines' use may change the epidemiological characters of HFMD. Spatial autocorrelation analysis and space-time scan statistics analysis were used to explore the spatiotemporal distribution pattern of this disease at the provincial level in mainland China. The effects of meteorological factors, socio-economic factors, and health resources on HFMD incidence were analyzed using Geodetector. Interrupted time series (ITS) was used to analyze the impact of the EV-A71 vaccine on the incidence of HFMD. This study found that the median annual incidence of HFMD was 153.78 per 100,000 (ranging from 120.79 to 205.06) in mainland China from 2011 to 2018. Two peaks of infections were observed per year. Children 5 years and under were the main morbid population. The spatial distribution of HFMD was presented a significant clustering pattern in each year (P<0.001). The distribution of HFMD cases was clustered in time and space. The range of cluster time was between April and October. The most likely cluster appeared in the southern coastal provinces (Guangxi, Guangdong, Hainan) from 2011 to 2017 and in the eastern coastal provinces (Shanghai, Jiangsu, Zhejiang) in 2018. The spatial heterogeneity of HFMD incidence could be attributed to meteorological factors, socioeconomic factors, and health resource. After introducing the EV-A71 vaccine, the instantaneous level of HFMD incidence decreased at the national level, and HFMD incidence trended downward in the southern coastal provinces and increased in the eastern coastal provinces. The prevention and control policies of HFMD should be adapted to local conditions in different provinces. It is necessary to advance the EV-A71 vaccination plan, expand the vaccine coverage and develop multivalent HFMD vaccines as soon as possible.

Background: Chemotherapy-related cognitive impairment (CRCI) is highly preva-lent in patients with cancer and is associated with poor outcomes and quality of life. To date, the management of CRCI remains a clinical challenge. Herein, we aim to determine the pre-ventive effects of probiotics on CRCI development and underlying mechanisms.Methods: We conducted a randomised, double-blind and placebo-controlled trial (ChiCTRINQ-17014181) of 159 patients with breast cancer and further investigated the underlying mechanism in a pre-clinical setting. From 2018 to 2019, patients with breast cancer (Stage I-III) who needed adjuvant chemotherapy were screened, enrolled and randomly assigned to receive either probiotics or placebo (three capsules, twice/day) during chemotherapy. Their cognition, anxiety and depression were assessed with well-established assays; their plasma biomarkers, metabolites and faecal microbiota compositions were measured. In addition, the systemic effects of the metabolites found in the clinical trial on long-term potentiation, synapse injury, oxidative stress and glial activation were assessed in rats.Results: Probiotics supplement significantly decreased the incidence of CRCI, improved the allover cognitive functions, changed the gut microbial composition and modulated nine plasma metabolite changes. Among these metabolites, p-Mentha-1,8-dien-7-ol, Linoelaidyl carnitine and 1-aminocyclopropane-1-carboxylic acid were negatively correlated with the occurrence of CRCI. Furthermore, probiotics supplement increased plasma p-Mentha-1,8dien-7-ol in rats. Administration of exogenous p-Mentha-1,8-dien-7-ol significantly alleviated chemotherapy-induced long-term potentiation impairment, synapse injury, oxidative stress and glial activation in the hippocampus of rats.Conclusion: Our data indicated that probiotics supplement prevents the occurrence of CRCI in patients with breast cancer via modulating plasma metabolites, including p-Mentha-1,8dien-7-ol. Trial registration: Chinese Clinical Trial Registry (ChiCTR-INQ-17014181) [http://www. chictr.org.cn/showproj.aspx?projZ24294].(c) 2021 Elsevier Ltd. All rights reserved.

Abstract BackgroundAlthough three monovalent EV-A71 vaccines have been launched in mainland China since 2016, hand, foot, and mouth disease (HFMD) still causes a considerable disease burden in China. Vaccines’ use may change the epidemiological characters of HFMD. This study aims to analyze the spatiotemporal cluster of HFMD at the province level in mainland China from 2009 to 2018 and compare the difference before and after the vaccines were launched. MethodsAll HFMD cases’ data from January 2009 to December 2018 were obtained from the public health science data center given by the Chinese Center for Diseases Control and Prevention. Spatial autocorrelation analysis and space-time scan statistics analysis were used to explore the spatiotemporal distribution pattern of this disease at the provincial level in mainland China. ResultsThe median annual incidence of HFMD was 143.22 per 100,000 (ranging from 87.01 to 205.06) in mainland China from 2009 to 2018. Two peaks of infections were observed per year. Children 5 years and under were the main morbid population. The global autocorrelation analysis showed that the spatial distribution of HFMD was presented a significant clustering pattern in each year (P<0.001), and the local autocorrelation analysis indicated that the high incidence areas were clustered in the southern and southeastern coastal provinces. The distribution of HFMD cases was clustered in time and space. The range of cluster time was between April and October. The most likely cluster appeared in the southern coastal provinces (Guangxi, Guangdong, Hainan) from 2010 to 2017 and in the southeastern coastal provinces (Shanghai, Jiangsu, Zhejiang) in 2018. ConclusionChanges in the spatiotemporal cluster of HFMD after the launch of EV-A71 vaccines were observed at the province level in mainland China in 2018. It is necessary to advance the EV-A71 vaccination plan, analyze the spatial-temporal distribution characteristics of different enterovirus pathogens of HFMD, and promote HFMD multivalent vaccines.