Osteoblast-specific down-regulation of NLRP3 inflammasome by aptamer-functionalized liposome nanoparticles improves bone quality in postmenopausal osteoporosis rats.

Rationale: NLRP3 inflammasome is critical in the development and progression of many metabolic diseases driven by chronic inflammation, but its effect on the pathology of postmenopausal osteoporosis (PMOP) remains poorly understood. Methods: We here firstly examined the levels of NLRP3 inflammasome in PMOP patients by ELISA. Then we investigated the possible mechanisms underlying the effect of NLRP3 inflammasome on PMOP by RNA sequencing of osteoblasts treated with NLRP3 siRNA and qPCR. Lastly, we accessed the effect of decreased NLRP3 levels on ovariectomized (OVX) rats. To specifically deliver NLRP3 siRNA to osteoblasts, we constructed NLRP3 siRNA wrapping osteoblast-specific aptamer (CH6)-functionalized lipid nanoparticles (termed as CH6-LNPs-siNLRP3). Results: We found that the levels of NLRP3 inflammasome were significantly increased in patients with PMOP, and were negatively correlated with estradiol levels. NLRP3 knock-down influenced signal pathways including immune system process, interferon signal pathway. Notably, of the top ten up-regulated genes in NLRP3-reduced osteoblasts, nine genes (except Mx2) were enriched in immune system process, and five genes were related to interferon signal pathway. The in vitro results showed that CH6-LNPs-siNLRP3 was relatively uniform with a dimeter of 96.64 ± 16.83 nm and zeta potential of 38.37 ± 1.86 mV. CH6-LNPs-siNLRP3 did not show obvious cytotoxicity and selectively delivered siRNA to bone tissue. Moreover, CH6-LNPs-siNLRP3 stimulated osteoblast differentiation by activating ALP and enhancing osteoblast matrix mineralization. When administrated to OVX rats, CH6-LNPs-siNLRP3 promoted bone formation and bone mass, improved bone microarchitecture and mechanical properties by decreasing the levels of NLRP3, IL-1ß and IL-18 and increasing the levels of OCN and Runx2. Conclusion: NLRP3 inflammasome may be a new biomarker for PMOP diagnosis and plays a key role in the pathology of PMOP. CH6-LNPs-siNLRP3 has potential application for the treatment of PMOP.

Differences in inpatient performance of public general hospitals following implementation of a points-counting payment based on diagnosis-related group: a robust multiple interrupted time series study in Wenzhou, China.

OBJECTIVES: This study measures the differences in inpatient performance after a points-counting payment policy based on diagnosis-related group (DRG) was implemented. The point value is dynamic; its change depends on the annual DRGs' cost settlements and points of the current year, which are calculated at the beginning of the following year. DESIGN: A longitudinal study using a robust multiple interrupted time series model to evaluate service performance following policy implementation. SETTING: Twenty-two public general hospitals (8 tertiary institutions and 14 secondary institutions) in Wenzhou, China. INTERVENTION: The intervention was implemented in January 2020. OUTCOME MEASURES: The indicators were case mix index (CMI), cost per hospitalisation (CPH), average length of stay (ALOS), cost efficiency index (CEI) and time efficiency index (TEI). The study employed the means of these indicators. RESULTS: The impact of COVID-19, which reached Zhejiang Province at the end of January 2020, was temporary given rapid containment following strict control measures. After the intervention, except for the ALOS mean, the change-points for the other outcomes (p<0.05) in tertiary and secondary institutions were inconsistent. The CMI mean turned to uptrend in tertiary (p<0.01) and secondary (p<0.0001) institutions compared with before. Although the slope of the CPH mean did not change (p>0.05), the uptrend of the CEI mean in tertiary institutions alleviated (p<0.05) and further increased (p<0.05) in secondary institutions. The slopes of the ALOS and TEI mean in secondary institutions changed (p<0.05), but not in tertiary institutions (p>0.05). CONCLUSIONS: This study showed a positive effect of the DRG policy in Wenzhou, even during COVID-19. The policy can motivate public general hospitals to improve their comprehensive capacity and mitigate discrepancies in treatment expenses efficiency for similar diseases. Policymakers are interested in whether the reform successfully motivates hospitals to strengthen their internal impetus and improve their performance, and this is supported by this study.

Deep learning for locally advanced nasopharyngeal carcinoma prognostication based on pre- and post-treatment MRI.

PURPOSE: We aimed to predict the prognosis of advanced nasopharyngeal carcinoma (stage Ⅲ-Ⅳa) using Pre- and Post-treatment MR images based on deep learning (DL). METHODS: A total of 206 patients with primary nasopharyngeal carcinoma who were diagnosed and treated at the Renmin Hospital of Wuhan University between June 2012 and January 2018 were retrospectively selected. A rectangular region of interest (ROI), which included the tumor area, surrounding tissues and organs, was delineated on each Pre- and Post-treatment MR image. Two Inception-Resnet-V2 based transfer learning models, named Pre-model and Post-model, were trained with the Pre-treatment images and the Post-treatment images, respectively. In addition, an ensemble learning model based on the Pre-model and Post-models was established. The three established models were evaluated by receiver operating characteristic curve (ROC), confusion matrix, and Harrell's concordance indices (C-index). High-risk-related gradient-weighted class activation mapping (Grad-CAM) images were developed according to the DL models. RESULTS: The Pre-model, Post-model, and ensemble model displayed a C-index of 0.717 (95% CI: 0.639 to 0.795), 0.811 (95% CI: 0.745-0.877), 0.830 (95% CI: 0.767-0.893), and AUC of 0.741 (95% CI: 0.584-0.900), 0.806 (95% CI: 0.670-0.942), and 0.842 (95% CI: 0.718-0.967) for the test cohort, respectively. In comparison with the models, the performance of Post-model was better than the performance of Pre-model, which indicated the importance of Post-treatment images for prognosis prediction. All three DL models performed better than the TNM staging system (0.723, 95% CI: 0.567-0.879). The captured features presented on Grad-CAM images suggested that the areas around the tumor and lymph nodes were related to the prognosis of the tumor. CONCLUSIONS: The three established DL models based on Pre- and Post-treatment MR images have a better performance than TNM staging. Post-treatment MR images are of great significance for prognosis prediction and could contribute to clinical decision-making.

Early warning of hand, foot, and mouth disease transmission: A modeling study in mainland, China.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is a global infectious disease; particularly, it has a high disease burden in China. This study was aimed to explore the temporal and spatial distribution of the disease by analyzing its epidemiological characteristics, and to calculate the early warning signals of HFMD by using a logistic differential equation (LDE) model. METHODS: This study included datasets of HFMD cases reported in seven regions in Mainland China. The early warning time (week) was calculated using the LDE model with the key parameters estimated by fitting with the data. Two key time points, "epidemic acceleration week (EAW)" and "recommended warning week (RWW)", were calculated to show the early warning time. RESULTS: The mean annual incidence of HFMD cases per 100,000 per year was 218, 360, 223, 124, and 359 in Hunan Province, Shenzhen City, Xiamen City, Chuxiong Prefecture, Yunxiao County across the southern regions, respectively and 60 and 34 in Jilin Province and Longde County across the northern regions, respectively. The LDE model fitted well with the reported data (R2 > 0.65, P < 0.001). Distinct temporal patterns were found across geographical regions: two early warning signals emerged in spring and autumn every year across southern regions while one early warning signals in summer every year across northern regions. CONCLUSIONS: The disease burden of HFMD in China is still high, with more cases occurring in the southern regions. The early warning of HFMD across the seven regions is heterogeneous. In the northern regions, it has a high incidence during summer and peaks in June every year; in the southern regions, it has two waves every year with the first wave during spring spreading faster than the second wave during autumn. Our findings can help predict and prepare for active periods of HFMD.

A five-compartment model of age-specific transmissibility of SARS-CoV-2.

BACKGROUND: The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, also called 2019-nCoV) causes different morbidity risks to individuals in different age groups. This study attempts to quantify the age-specific transmissibility using a mathematical model. METHODS: An epidemiological model with five compartments (susceptible-exposed-symptomatic-asymptomatic-recovered/removed [SEIAR]) was developed based on observed transmission features. Coronavirus disease 2019 (COVID-19) cases were divided into four age groups: group 1, those ≤ 14 years old; group 2, those 15 to 44 years old; group 3, those 45 to 64 years old; and group 4, those ≥ 65 years old. The model was initially based on cases (including imported cases and secondary cases) collected in Hunan Province from January 5 to February 19, 2020. Another dataset, from Jilin Province, was used to test the model. RESULTS: The age-specific SEIAR model fitted the data well in each age group (P < 0.001). In Hunan Province, the highest transmissibility was from age group 4 to 3 (median: ß43 = 7.71 × 10- 9; SAR43 = 3.86 × 10- 8), followed by group 3 to 4 (median: ß34 = 3.07 × 10- 9; SAR34 = 1.53 × 10- 8), group 2 to 2 (median: ß22 = 1.24 × 10- 9; SAR22 = 6.21 × 10- 9), and group 3 to 1 (median: ß31 = 4.10 × 10- 10; SAR31 = 2.08 × 10- 9). The lowest transmissibility was from age group 3 to 3 (median: ß33 = 1.64 × 10- 19; SAR33 = 8.19 × 10- 19), followed by group 4 to 4 (median: ß44 = 3.66 × 10- 17; SAR44 = 1.83 × 10- 16), group 3 to 2 (median: ß32 = 1.21 × 10- 16; SAR32 = 6.06 × 10- 16), and group 1 to 4 (median: ß14 = 7.20 × 10- 14; SAR14 = 3.60 × 10- 13). In Jilin Province, the highest transmissibility occurred from age group 4 to 4 (median: ß43 = 4.27 × 10- 8; SAR43 = 2.13 × 10- 7), followed by group 3 to 4 (median: ß34 = 1.81 × 10- 8; SAR34 = 9.03 × 10- 8). CONCLUSIONS: SARS-CoV-2 exhibits high transmissibility between middle-aged (45 to 64 years old) and elderly (≥ 65 years old) people. Children (≤ 14 years old) have very low susceptibility to COVID-19. This study will improve our understanding of the transmission feature of SARS-CoV-2 in different age groups and suggest the most prevention measures should be applied to middle-aged and elderly people.

Nodule Localization in Thyroid Ultrasound Images with a Joint-Training Convolutional Neural Network.

The accurate localization of nodules in ultrasound images can convey crucial information to support a reliable diagnosis. However, this is usually challenging due to low contrast and image artifacts, especially in thyroid ultrasound images where nodules are relatively small in most cases. To address these problems, in this paper, we propose a joint-training convolutional neural network (CNN) for thyroid nodule localization in ultrasound images. Considering the advantage of the faster region-based CNN (Faster R-CNN) in detecting natural targets, we adopt it as the basic framework. To boost the representative power and noise suppression capability of the network, the attention mechanism module is embedded for adaptive feature refinement along the channel and spatial dimensions. Furthermore, in the training process, we annotate the training set in a novel way, called joint-training annotation, by exploiting the fake foreground (FFG) area around the nodule as a spatial prior constraint to improve the sensitivity to small nodules. Ablation experiments are conducted to verify the effectiveness of our proposed method. The experimental results show that our method outperforms others by a mean average precision (mAP) of 0.93 and achieves an intersection over union (IoU) of 0.9, indicating that the localization results agree well with the ground truth. Furthermore, extended experiments on breast nodule datasets are also conducted to verify the generalizability of the proposed approach. Above all, the proposed algorithm is of considerable significance for accurate thyroid nodule localization in ultrasound images and can be generalized to other types of nodules, thereby providing trustworthy assistance for clinical diagnosis.

Transmissibility of acute haemorrhagic conjunctivitis in small-scale outbreaks in Hunan Province, China.

Acute haemorrhagic conjunctivitis (AHC) outbreaks are reported frequently in China. However, the transmissibility of AHC remains unclear. This study aimed to calculate the transmissibility of the disease with and without interventions. An AHC outbreak dataset from January 2007 to December 2016 in different schools was built in Hunan Province. A Susceptible-Infectious-Recovered (SIR) model was adopted to calculate the effective reproduction number (Reff) of AHC. Reff was divided into two parts (Runc and Rcon) where Runc and Rcon represent the uncontrolled and controlled Reff , respectively. Based on Runc and Rcon, an index of effectiveness of countermeasures (Ieff) was developed to assess the effectiveness of countermeasures in each outbreak. During the study period, 34 AHC outbreaks were reported in 20 counties of 9 cities in Hunan Province, with a mean total attack rate of 7.04% (95% CI: 4.97-9.11%). The mean Runc of AHC outbreaks was 8.28 (95% CI: 6.46-10.11). No significance of Runc was observed between rural and urban areas (t = -1.296, P = 0.205), among college, secondary, and primary schools (F = 0.890, P = 0.459), different levels of school population (F = 0.738, P = 0.538), and different number of index cases (F = 1.749, P = 0.180). The most commonly implemented countermeasures were case isolation, treatment, and health education, followed by environment disinfection, symptom surveillance, and school closure. Social distance, prophylaxis, and stopping eye exercises temporary were implemented occasionally. The mean value of Rcon was 0.16 (range: 0.00-1.50). The mean value of Ieff was 97.16% (range: 71.44-100.00%). The transmissibility of AHC is high in small-scale outbreaks in China. Case isolation, treatment, and health education are the common countermeasures for controlling the disease.

Effect of Frequency of Exercise on Cognitive Function in Older Adults: Serial Mediation of Depression and Quality of Sleep.

BACKGROUND: Sleep quality and depression are two reciprocal causation socioemotional factors and their roles in the relationship between physical exercise and cognition are still unclear. METHODS: A face-to-face survey of 3230 older adults aged 60+ was conducted in Xiamen, China, in 2016. Frequency of exercise (FOE) referred to the number of days of exercise per week. Quality of sleep (QOS) was categorized into five levels: very poor/poor/fair/good/excellent. The 15-item Geriatric Depression Scale (GDS-15) and the Montreal Cognitive Assessment (MoCA) were used to measure depression (DEP) and cognitive function (CF), respectively. Serial multiple mediator models were used. All mediation analyses were analyzed using the SPSS PROCESS macro. RESULTS: 2469 respondents had valid data with mean scores for GDS-15 and MoCA being 1.87 and 21.61, respectively. The direct path from FOE to CF was significant (c'= 0.20, p < 0.001). A higher FOE was associated with better QOS (B = 0.04, p < 0.01), which in turn was associated with fewer symptoms of DEP (B = -0.40, p < 0.001), and further contributed to better CF (B = -0.24, p < 0.001). Similarly, a higher FOE was associated with lower GDS-15 scores (B = -0.17, p < 0.001) which then resulted in higher MoCA scores (B = -0.24, p < 0.001). However, QOS alone did not alter the relationship between FOE and CF. CONCLUSIONS: FOE is a protective factor of CF in older adults. Moreover, CF is influenced by QOS through DEP, without which the working path may disappear.