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ObjectiveTo construct an evaluation index system for the development level of county-level chronic disease management centers, providing a basis for evaluating and comparing the construction of these centers. MethodsFocusing on the key points of county-level chronic disease management center construction and combining relevant literature, a candidate index database was constructed. Twenty-nine experts in the field of chronic disease management were selected to conduct two rounds of Delphi consultation to determine the evaluation index system for the development level of county-level chronic disease management centers, and the analytic hierarchy process was used to determine the index weights. ResultsThe active participation rates of experts in the two rounds of Delphi consultation were 90.91% and 96.67%, respectively, with expert authority coefficients of 0.85 and 0.84, and Kendall′s W of 0.15 and 0.20 (both P < 0.001). After two rounds of consultation, a final evaluation index system for the development level of county-level chronic disease management centers was constructed, consisting of 5 dimensions and 45 indicators: organizational management and basic conditions, chronic disease management informatization, county-township collaborative management of chronic diseases, capacity building and quality control of chronic disease management, and quality and effectiveness of chronic disease management. The weights of the 5 dimensions were 0.212 2, 0.180 1, 0.219 4, 0.179 4, and 0.208 9, respectively. ConclusionThe evaluation index system for the development level of county-level chronic disease management centers constructed in this study is reasonable, practical, representative, and instructive, providing a reference basis for evaluating the development level of these centers and key directions for subsequent construction.

Abstract Osteoporotic tendon‐to‐bone healing (TBH) after rotator cuff repair (RCR) is a significant orthopedic challenge. Considering the aligned architecture of the tendon, inflammatory microenvironment at the injury site, and the need for endogenous cell/tissue infiltration, there is an imminent need for an ideal scaffold to promote TBH that has aligned architecture, ability to modulate inflammation, and macroporous structure. Herein, a novel macroporous hydrogel comprising sodium alginate/hyaluronic acid/small extracellular vesicles from adipose‐derived stem cells (sEVs) (MHA‐sEVs) with aligned architecture and immunomodulatory ability is fabricated. When implanted subcutaneously, MHA‐sEVs significantly improve cell infiltration and tissue integration through its macroporous structure. When applied to the osteoporotic RCR model, MHA‐sEVs promote TBH by improving tendon repair through macroporous aligned architecture while enhancing bone regeneration by modulating inflammation. Notably, the biomechanical strength of MHA‐sEVs is approximately two times higher than the control group, indicating great potential in reducing postoperative retear rates. Further cell‐hydrogel interaction studies reveal that the alignment of microfiber gels in MHA‐sEVs induces tenogenic differentiation of tendon‐derived stem cells, while sEVs improve mitochondrial dysfunction in M1 macrophages (Mφ) and inhibit Mφ polarization toward M1 via nuclear factor‐kappaB (NF‐κb) signaling pathway. Taken together, MHA‐sEVs provide a promising strategy for future clinical application in promoting osteoporotic TBH.

Abstract Background Distant metastasis is the prominent factor for cancer-induced death of gastric cancer in which peritoneum is one of the dominating targets of gastric cancer metastasis. However, there is still a lack of effective predictive indicators and treatment methods for gastric cancer patients with peritoneal metastasis. Methods A clustering assay was used to investigate the cell aggregates formation ability. While the soft agar assay and anoikis assay were performed to detect the anchorage-independent growth and anoikis-resistant ability respectively. Luciferase activity assay, western blotting and immunofluorescence were used to explore the effect of HMMR on AKT signaling activity. The peritoneal implantation model was examined to explore the role of HMMR in vivo. Results Silencing of HMMR expression markedly reduced the peritoneal metastasis of gastric cancer cells through reducing cell–cell interactions. Mechanistically, HA-HMMR could activate Akt signaling, thus succeeding in distant colonization and metastatic outgrowth. Importantly, inducible depletion of HMMR significantly abrogates peritoneal implantation of gastric cancer in vitro and in vivo. Conclusion Our study highlights that HMMR promotes peritoneal implantation of gastric cancer. A better understanding of HMMR’s functions and mechanism might provide a novel therapeutic target and prognostic marker for metastatic gastric cancer.

Human epidermal growth factor receptor 2–targeted (HER2-targeted) therapy is the mainstay of treatment for HER2+ breast cancer. However, the proteolytic cleavage of HER2, or HER2 shedding, induces the release of the target epitope at the ectodomain (ECD) and the generation of a constitutively active intracellular fragment (p95HER2), impeding the effectiveness of anti-HER2 therapy. Therefore, identifying key regulators in HER2 shedding might provide promising targetable vulnerabilities against resistance. In the current study, we found that upregulation of dolichyl-phosphate N-acetylglucosaminyltransferase (DPAGT1) sustained high-level HER2 shedding to confer trastuzumab resistance, which was associated with poor clinical outcomes. Upon trastuzumab treatment, the membrane-bound DPAGT1 protein was endocytosed via the caveolae pathway and retrogradely transported to the ER, where DPAGT1 induced N-glycosylation of the sheddase — ADAM metallopeptidase domain 10 (ADAM10) — to ensure its expression, maturation, and activation. N-glycosylation of ADAM10 at N267 protected itself from ER-associated protein degradation and was essential for DPAGT1-mediated HER2 shedding and trastuzumab resistance. Importantly, inhibition of DPAGT1 with tunicamycin acted synergistically with trastuzumab treatment to block HER2 signaling and reverse resistance. These findings reveal a prominent mechanism for HER2 shedding and suggest that targeting DPAGT1 might be a promising strategy against trastuzumab-resistant breast cancer.

The mechanism of how VEGF-C is regulated to promote lymphatic metastasis of oesophageal cancer is unclear. Here the authors show that nicotine prevents the mRNA decay of VEGF-C mRNA and promotes lymphatic metastasis by downregulating deubiquitinase OTUD3 and RNA binding protein ZFP36.

Subjective tinnitus patients experience more hearing difficulties than normal peers in complex hearing environments, even though most of these patients have normal pure-tone hearing thresholds. Using speech recognition tasks under different masking conditions can provide insight into whether the effects of tinnitus are lateralized and the mechanisms behind the effects. By simulating sound field recordings, we obtain a target speech sentence that can be perceived as presented on one side and noise or speech masking with or without spatial separation from it. Our study used the virtual sound field technique to investigate the difference in speech recognition ability between chronic subjective tinnitus patients and a normal-hearing control group under the four masking conditions (speech-spectrum noise masking or two-talker speech masking, with or without perceived spatial separation). Experiment 1 showed no differences for target speech perceived location (left or right), which rules out a lateralization of the effect of tinnitus patients. Experiment 2 further found that although tinnitus patients had weaker performance than normal people in very complex auditory scenarios, when the spatial cue of the target speech exists, they can make good use of this cue to make up for the original processing disadvantage and achieve a similar performance as the normal-hearing group. In addition, the current study distinguished the effects of informational masking and energetic masking on speech recognition in patients with tinnitus and normal hearing. The results suggest that the impact of tinnitus on speech recognition in patients is more likely to occur in the auditory center rather than the periphery.

Abstract Background Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high proliferative activity. TNBC tumors exhibit elevated MYC expression and altered expression of MYC regulatory genes, which are associated with tumor progression and poor prognosis; however, the underlying mechanisms by which MYC retains its high expression and mediates TNBC tumorigenesis require further exploration. Methods ACTL6A regulation of MYC and its target gene, CDK2, was defined using Co-IP, mass spectrometry and ChIP assays. To study the role of ACTL6A in TNBC, we performed soft-agar, colony formation, flow cytometry and tumor formation in nude mice. CDK2 inhibitor and paclitaxel were used in testing combination therapy in vitro and in vivo. Results ACTL6A bound MYC to suppress glycogen synthase kinase 3 beta (GSK3β)-induced phosphorylation on MYC T58, which inhibited ubiquitination of MYC and stabilized it. Moreover, ACTL6A promoted the recruitment of MYC and histone acetyltransferase KAT5 on CDK2 promoters, leading to hyperactivation of CDK2 transcription. ACTL6A overexpression promoted, while silencing ACTL6A suppressed cell proliferation and tumor growth in TNBC cells in vitro and in vivo, which was dependent on MYC signaling. Furthermore, co-therapy with paclitaxel and CDK2 inhibitor showed synergistic effects in tumor suppression. Notably, ACTL6A/MYC/CDK2 axis was specifically up-regulated in TNBC and high expression of ACTL6A was correlated to shorter survival in patients with TNBC. Conclusions These findings reveal a novel mechanism by which ACTL6A prolongs the retention of MYC in TNBC and suggest that pharmacological targeting ACTL6A/MYC/CDK2 axis might have therapeutic potential in patients with TNBC.

Aim: It is difficult to treat delayed acetabular fractures due to massive blood loss during operation. Temporary balloon occlusion of the abdominal aorta was introduced into sacral tumor surgery to reduce intraoperative hemorrhage. The aim of this study was to investigate the effect of this method on reduction of intraoperative blood loss and analyze the complications of this technique in the treatment of delayed acetabular fracture. Methods: We retrospectively reviewed 43 patients with delayed acetabular fracture who were surgically treated through combined approaches. Nineteen patients underwent temporary balloon occlusion of the abdominal aorta; 10 patients had type B fracture and 9 patients had type C fracture according to the Müller AO classification. The remaining 24 patients were classified into a control group; 14 patients had type B fracture and 10 patients had type C fracture. Surgical time, intraoperative blood loss, blood transfusion, satisfactory reduction rate, and functional recovery were recorded and compared between two groups. Merle d'Aubigné and Postel scoring was applied to evaluate the patients. Results: The patients treated with intra-aortic balloon occlusion had a shorter surgical time (p = 0.008), less intraoperative blood loss (p = 0.005), and less transfused blood units (p = 0.001). No complications caused by balloon occlusion. No significant difference were observed in the outcomes and the complications related to acetabular fractures between two groups. Conclusions: Temporary balloon occlusion of the abdominal aorta is a reliable technique to control bleeding for the surgery of delayed acetabular fracture.

Abstract Triple‐negative breast cancer (TNBC) is fast‐growing and highly metastatic with the poorest prognosis among the breast cancer subtypes. Inactivation of glycogen synthase kinase 3 beta (GSK3β) plays a vital role in the aggressiveness of TNBC; however, the underlying mechanism for sustained GSK3β inhibition remains largely unknown. Here, we find that protein phosphatase 1 regulatory inhibitor subunit 14C (PPP1R14C) is upregulated in TNBC and relevant to poor prognosis in patients. Overexpression of PPP1R14C facilitates cell proliferation and the aggressive phenotype of TNBC cells, whereas the depletion of PPP1R14C elicits opposite effects. Moreover, PPP1R14C is phosphorylated and activated by protein kinase C iota (PRKCI) at Thr73. p‐PPP1R14C then represses Ser/Thr protein phosphatase type 1 (PP1) to retain GSK3β phosphorylation at high levels. Furthermore, p‐PPP1R14C recruits E3 ligase, TRIM25, toward the ubiquitylation and degradation of non‐phosphorylated GSK3β. Importantly, the blockade of PPP1R14C phosphorylation inhibits xenograft tumorigenesis and lung metastasis of TNBC cells. These findings provide a novel mechanism for sustained GSK3β inactivation in TNBC and suggest that PPP1R14C might be a potential therapeutic target.

Background: Frozen shoulders (FS) is a major clinical concern, where chronic synovial inflammation, abnormal angiogenesis, and fibrosis represent the critical pathologies in the glenohumeral capsule. However, no pharmacotherapy has been introduced to treat this pathology. Tetrandrine (TET) has been proposed as a treatment for many diseases due to its strong anti-inflammatory, anti-angiogenic, and anti-fibrotic effects. Purpose: To study the anti-inflammatory, anti-angiogenic, and anti-fibrotic effects of TET on FS, and identify whether TET can prevent the development of FS in rats. Study Design: A controlled laboratory study. Methods: Forty-eight male Sprague-Dawley (SD) rats were randomly divided into control, TET, and FS groups. The TET group was intraperitoneally injected with TET every 2 days. TET and saline treatment were started on the day of FS surgery. After 8 weeks, the animals were sacrificed, and samples were collected for X-ray examination, glenohumeral range of motion (ROM) evaluation, histology and immunohistochemistry analysis, transmission electron microscopy (TEM) observation, and profibrogenic factors as well as proinflammatory cytokines measurements. Results: No significant difference in shoulder ROM was observed between the TET and control groups, but a significant difference was noted between these groups and the FS group (P

This study was to investigate whether human listeners are able to detect a binaurally uncorrelated arbitrary-noise fragment embedded in binaurally identical arbitrary-noise markers [a break in correlation, break in interaural correlation (BIAC)] in either frequency-constant (frequency-steady) or frequency-varied (unidirectionally frequency gliding) noise. Ten participants with normal hearing were tested in Experiment 1 for up-gliding, down-gliding, and frequency-steady noises. Twenty-one participants with normal hearing were tested in Experiment 2a for both up-gliding and frequency-steady noises. Another nineteen participants with normal hearing were tested in Experiment 2b for both down-gliding and frequency-steady noises. Listeners were able to detect a BIAC in the frequency-steady noise (center frequency = 400 Hz) and two types of frequency-gliding noises (center frequency: between 100 and 1,600 Hz). The duration threshold for detecting the BIAC in frequency-gliding noises was significantly longer than that in the frequency-steady noise (Experiment 1), and the longest interaural delay at which a duration-fixed BIAC (200 ms) in frequency-gliding noises could be detected was significantly shorter than that in the frequency-steady noise (Experiment 2). Although human listeners can detect a BIAC in frequency-gliding noises, their sensitivity to a BIAC in frequency-gliding noises is much lower than that in frequency-steady noise.

Electric mechanical transmission (EMT) is a low-cost production for the electric vehicle to expend its torque and speed. Gear shifting is the essential function of EMT, but it is a multi-stage process with nonlinearity and uncertainty. In practice, gear shifting control is a difficult problem because of the bad consistency and large shift shock. Hence, a single control method is hard to solve it with satisfying performance. In this paper, motivated by the analysis of experimental results, a novel multi-stage gear shifting control scheme is proposed to improve shifting position tracking performance and decrease shift shock. First, the entire process is divided into three stages and each stage is modeled based on historical data and theoretical analysis. Then, a multi-stage scheme is designed, which is composed of iterative learning control (ILC), linear quadratic regulator (LQR), and H2 control based on Takagi and Sugeno (T-S) model corresponding to each stage. Finally, the feasibility and effectiveness of the proposed scheme are verified by bench experiments, which might provide guides for the engineering application of the EMT.

Pneumonia remains the leading infectious cause of death in children under the age of five, killing about 700,000 children each year and affecting 7% of the world’s population. X-ray images of lung become the key to the diagnosis of this disease, skilled doctors in the diagnosis of a certain degree of subjectivity, if the use of computer-aided medical diagnosis to automatically detect lung abnormalities, will improve the accuracy of diagnosis. This research aims to introduce a deep learning technology based on the combination of Xception neural network and long-term short-term memory (LSTM), which can realize automatic diagnosis of patients with pneumonia in X-ray images. First, the model uses the Xception network to extract the deep features of the data, passes the extracted features to the LSTM, and then the LSTM detects the extracted features, and finally selects the most needed features. Secondly, in the training set samples, the traditional cross-entropy loss cannot more balance the mismatch between categories. Therefore, this research combines Pearson’s feature selection ideas, fusion of the correlation between the two loss functions, and optimizes the problem. The experimental results show that the accuracy rate of this paper is 96%, the receiver operator characteristic curve accuracy rate is 99%, the precision rate is 98%, the recall rate is 91%, and the F1 score accuracy rate is 94%. Compared with the existing technical methods, the research has achieved expected results on the currently available datasets. And assist doctors to provide higher reliability in the classification task of childhood pneumonia.

The neural mechanisms underlying forward suppression in the auditory cortex remain a puzzle. Little attention is paid to thalamic contribution despite the important fact that the thalamus gates upstreaming information to the auditory cortex. This study compared the time courses of forward suppression in the auditory thalamus, thalamocortical inputs and cortex using the two-tone stimulus paradigm. The preceding and succeeding tones were 20-ms long. Their frequency and amplitude were set at the characteristic frequency and 20 dB above the minimum threshold of given neurons, respectively. In the ventral division of the medial geniculate body of the thalamus, we found that the duration of complete forward suppression was about 75 ms and the duration of partial suppression was from 75 ms to about 300 ms after the onset of the preceding tone. We also found that during the partial suppression period, the responses to the succeeding tone were further suppressed in the primary auditory cortex. The forward suppression of thalamocortical field excitatory postsynaptic potentials was between those of thalamic and cortical neurons but much closer to that of thalamic ones. Our results indicate that early suppression in the cortex could result from complete suppression in the thalamus whereas later suppression may involve thalamocortical and intracortical circuitry. This suggests that the complete suppression that occurs in the thalamus provides the cortex with a "silence" window that could potentially benefit cortical processing and/or perception of the information carried by the preceding sound.

In the continuous variable measurement-device-independent quantum key distribution (CV-MDI-QKD) protocol, both Alice and Bob send quantum states to an untrusted third party, Charlie, for detection through the quantum channel. In this paper, we mainly study the performance of the CV-MDI-QKD system using the noiseless linear amplifier (NLA). The NLA is added to the output of the detector at Charlie’s side. The research results show that NLA can increase the communication distance and secret key rate of the CV-MDI-QKD protocol. Moreover, we find that the more powerful the improvement of the performance with the longer gain of NLA and the optimum gain is given under different conditions.

The subjective representation of the sounds delivered to the two ears of a human listener is closely associated with the interaural delay and correlation of these two-ear sounds. When the two-ear sounds, e.g., arbitrary noises, arrive simultaneously, the single auditory image of the binaurally identical noises becomes increasingly diffuse, and eventually separates into two auditory images as the interaural correlation decreases. When the interaural delay increases from zero to several milliseconds, the auditory image of the binaurally identical noises also changes from a single image to two distinct images. However, measuring the effect of these two factors on an identical group of participants has not been investigated. This study examined the impacts of interaural correlation and delay on detecting a binaurally uncorrelated fragment (interaural correlation = 0) embedded in the binaurally correlated noises (i.e., binaural gap or break in interaural correlation). We found that the minimum duration of the binaural gap for its detection (i.e., duration threshold) increased exponentially as the interaural delay between the binaurally identical noises increased linearly from 0 to 8 ms. When no interaural delay was introduced, the duration threshold also increased exponentially as the interaural correlation of the binaurally correlated noises decreased linearly from 1 to 0.4. A linear relationship between the effect of interaural delay and that of interaural correlation was described for listeners participating in this study: a 1 ms increase in interaural delay appeared to correspond to a 0.07 decrease in interaural correlation specific to raising the duration threshold. Our results imply that a tradeoff may exist between the impacts of interaural correlation and interaural delay on the subjective representation of sounds delivered to two human ears.

In reverberant rooms with multiple-people talking, spatial separation between speech sources improves recognition of attended speech, even though both the head-shadowing and interaural-interaction unmasking cues are limited by numerous reflections. It is the perceptual integration between the direct wave and its reflections that bridges the direct-reflection temporal gaps and results in the spatial unmasking under reverberant conditions. This study further investigated (1) the temporal dynamic of the direct-reflection-integration-based spatial unmasking as a function of the reflection delay, and (2) whether this temporal dynamic is correlated with the listeners' auditory ability to temporally retain raw acoustic signals (i.e., the fast decaying primitive auditory memory, PAM). The results showed that recognition of the target speech against the speech-masker background is a descending exponential function of the delay of the simulated target reflection. In addition, the temporal extent of PAM is frequency dependent and markedly longer than that for perceptual fusion. More importantly, the temporal dynamic of the speech-recognition function is significantly correlated with the temporal extent of the PAM of low-frequency raw signals. Thus, we propose that a chain process, which links the earlier-stage PAM with the later-stage correlation computation, perceptual integration, and attention facilitation, plays a role in spatially unmasking target speech under reverberant conditions.