The olfactory working memory capacity paradigm: A more sensitive and robust method of assessing cognitive function in male 5XFAD mice.

The olfactory working memory capacity (OWMC) paradigm is able to detect cognitive deficits in 5XFAD mice (an animal model of Alzheimer's disease [TG]) as early as 3 months of age, while other behavioral paradigms detect cognitive deficits only at 4-5 months of age. Therefore, we aimed to demonstrate that the OWMC paradigm is more sensitive and consistent in the early detection of declines in cognitive function than other commonly used behavioral paradigms. The prefrontal cortex (PFC), retrosplenial cortex (RSC), subiculum (SUB), and amygdala (AMY) of 5XFAD mice were harvested and subjected to immunostaining to detect the expression of ß-amyloid (Aß). Additionally, we compared the performance of 3-month-old male 5XFAD mice on common behavioral paradigms for assessing cognitive function (i.e., the open field [OF] test, novel object recognition [NOR] test, novel object location [NOL] test, Y-maze, and Morris water maze [MWM]) with that on the OWMC task. In the testing phase of the OWMC task, we varied the delay periods to evaluate the working memory capacity (WMC) of wild-type (WT) mice. Significant amyloid plaque deposition was observed in the PFC, RSC, SUB, and AMY of 3-month-old male 5XFAD mice. However, aside from the OWMC task, the other behavioral tests failed to detect cognitive deficits in 5XFAD mice. Additionally, to demonstrate the efficacy of the OWMC task in assessing WMC, we varied the retention delay periods; we found that the WMC of WT mice decreased with longer delay periods. The OWMC task is a sensitive and robust behavioral assay for detecting changes in cognitive function.

Diminished activation of excitatory neurons in the prelimbic cortex leads to impaired working memory capacity in mice.

BACKGROUND: Working memory capacity impairment is an early sign of Alzheimer's disease, but the underlying mechanisms remain unclear. Clarifying how working memory capacity is affected will help us better understand the pathological mechanism of Alzheimer's disease. We used the olfactory working memory capacity paradigm to evaluate memory capacity in 3-month-old 5XFAD (an animal model of Alzheimer's disease) mice. Immunofluorescence staining of the prefrontal cortex was performed to detect the number of FOS-positive neurons, calmodulin-dependent protein kinase II-positive neurons, and glutamate decarboxylase-positive neurons in the prelimbic cortex and infralimbic cortex. A chemogenetic method was then used to modulate the inhibition and activation of excitatory neurons in the prelimbic cortex of wild-type and 5XFAD mice and to measure the memory capacity of mice. RESULTS: Working memory capacity was significantly diminished in 5XFAD mice compared to littermate wild-type mice. Neuronal activation of the prelimbic cortex, but not the infralimbic cortex, was attenuated in 5XFAD mice performing the olfactory working memory capacity task. Subsequently, the FOS-positive neurons were co-localized with both calmodulin-dependent protein kinase II-positive neurons and glutamate decarboxylase-positive neurons. The results showed that the activation of excitatory neurons in the prelimbic cortex was correlated with working memory capacity in mice. Our results further demonstrate that the chemogenetic inhibition of prelimbic cortex excitatory neurons resulted in reduced working memory capacity in wild-type mice, while the chemogenetic activation of prelimbic cortex excitatory neurons improved the working memory capacity of 5XFAD mice. CONCLUSION: The diminished activation of prelimbic cortex excitatory neurons in 5XFAD mice during task performance is associated with reduced working memory capacity, and activation modulation of excitatory neurons by chemogenetic methods can improve memory capacity impairment in 5XFAD mice. These findings may provide a new direction for exploring Alzheimer's disease therapeutic approaches.

Strain ultrasonic elastography imaging features of locally advanced breast cancer: association with response to neoadjuvant chemotherapy and recurrence-free survival.

BACKGROUND: Due to the highly heterogeneity of the breast cancer, it would be desirable to obtain a non-invasive method to early predict the treatment response and survival outcome of the locally advanced breast cancer (LABC) patients undergoing neoadjuvant chemotherapy (NAC). This study aimed at investigating whether strain elastography (SE) can early predict the pathologic complete response (pCR) and recurrence-free survival (RFS) in LABC patients receiving NAC. METHODS: In this single-center retrospective study, 122 consecutive women with LABC who underwent SE examination pre-NAC and after one and two cycles of NAC enrolled in the SHPD001(NCT02199418) and SHPD002 (NCT02221999) trials between January 2014 and August 2017 were included. The SE parameters (Elasticity score, ES; Strain ratio, SR; Hardness percentage, HP, and Area ratio, AR) before and during NAC were assessed. The relative changes in SE parameters after one and two cycles of NAC were describe as ΔA1 and ΔA2, respectively. Logistic regression analysis and Cox proportional hazards model were used to identify independent variables associated with pCR and RFS. RESULTS: Forty-nine (40.2%) of the 122 patients experienced pCR. After 2 cycles of NAC, SR2 (odds ratio [OR], 1.502; P = 0.003) and ΔSR2 (OR, 0.013; P = 0.015) were independently associated with pCR, and the area under the receiver operating characteristic curve for the combination of them to predict pCR was 0.855 (95%CI: 0.779, 0.912). Eighteen (14.8%) recurrences developed at a median follow-up of 60.7 months. A higher clinical T stage (hazard ratio [HR] = 4.165; P = 0.005.), a higher SR (HR = 1.114; P = 0.002.) and AR (HR = 1.064; P <  0.001.) values at pre-NAC SE imaging were independently associated with poorer RFS. CONCLUSION: SE imaging features have the potential to early predict pCR and RFS in LABC patients undergoing NAC, and then may offer valuable predictive information to guide personalized treatment.

Establishment and validation of an ultrasound-based nomogram with risk stratification for short disease-free survival in breast cancer.

PURPOSE: This retrospective study aimed to develop and validate an Ultrasound (US)-based nomogram to predict short disease-free survival (short-DFS, less than 120 months DFS) in breast cancer (BC). METHODS: Nomogram was established based on a training data of 311 BC patients by multivariable logistic regression, and were assessed by discrimination, calibration, and clinical usefulness. Risk stratification was performed by X-tile. An independent testing data of 200 patients with BC was used for external validation. RESULTS: Nine predictors including three US features and six clinical parameters were screened into the nomogram by Lasso (log λ = -3.594) in training data. Better performance was obtained in the training data (C-index: 0.942) and testing data (C-index: 0.914). Calibration analysis indicated optimal agreement between nomogram predictions and actual observations (p = 0.67). Decision curve analysis showed a great clinical benefit (Youden index: 0.634). Three risk levels are low-risk (<184.0), moderate-risk (184.0-345.3) and high-risk (>345.3). Our nomograms had larger area under the receiver operating characteristic (ROC) curves compared with Magee Equation and Nottingham Prognostic models (0.942 vs. 0.824, 0.790). CONCLUSION: The US-based nomogram and the practical score system facilitate individualized prediction of short-DFS to optimize clinical decisions and improve prognosis in patients with BC.

Randomized Controlled Trial Comparing the Short-term Outcomes of Enhanced Recovery After Surgery and Conventional Care in Laparoscopic Distal Gastrectomy (GISSG1901).

OBJECTIVE: This study aimed to compare the effects of ERAS and conventional programs on short-term outcomes after LDG. SUMMARY OF BACKGROUND DATA: Currently, the ERAS program is broadly applied in surgical areas. Although several benefits of LDG with the ERAS program have been covered, high-level evidence is still limited, specifically in advanced gastric cancer. METHODS: The present study was designed as a randomized, multicenter, unblinded trial. The enrollment criteria included histologically confirmed cT2-4aN0-3M0 gastric adenocarcinoma. Postoperative complications, mortality, readmission, medical costs, recovery, and laboratory outcomes were compared between the ERAS and conventional groups. RESULTS: Between April 2019 and May 2020, 400 consecutive patients who met the enrollment criteria were enrolled. They were randomly allocated to either the ERAS group (n = 200) or the conventional group (n = 200). After excluding patients who did not undergo surgery or gastrectomy, 370 patients were analyzed. The patient demographic characteristics were not different between the 2 groups. The conventional group had a significantly longer allowed day of discharge and postoperative hospital stay (6.96 vs 5.83 days, P < 0.001; 8.85 vs 7.27 days, P < 0.001); a longer time to first flatus, liquid intake and ambulation (3.37 vs 2.52 days, P < 0.001; 3.09 vs 1.13 days, P < 0.001; 2.85 vs 1.38 days, P < 0.001, respectively); and higher medical costs (6826 vs 6328 $, P = 0.027) than the ERAS group. Additionally, patients in the ERAS group were more likely to initiate adjuvant chemotherapy earlier (29 vs 32 days, P = 0.035). There was no significant difference in postoperative complications or in the mortality or readmission rates. Regarding laboratory outcomes, the procalcitonin and C-reactive protein levels on postoperative day 3 were significantly lower and the hemoglobin levels on postoperative day 5 were significantly higher in the ERAS group than in the conventional group. CONCLUSION: The ERAS program provides a faster recovery, a shorter postoperative hospitalization length, and lower medical costs after LDG without increasing complication and readmission rates. Moreover, enhanced recovery in the ERAS group enables early initiation of adjuvant chemotherapy.

Is it important to measure the internal spermatic vein diameter after varicocelectomy? A self-controlled trial.

To analyse spermatic vein parameters and post-varicocelectomy diagnostic ultrasound methods by comparing pre- and post-operative ultrasound parameters and semen quality in patients undergoing varicocelectomy. Ultrasound and semen analyses were performed within 1 week before surgery and 3 months after surgery in 125 patients who underwent varicocelectomy for infertility. Patients were divided into three groups according to the post-operative internal diameter of the spermatic vein and reflux: recovery, dilatation, and reflux. Changes in semen quality before and after surgery were compared between groups. Sperm concentration, motility, and morphology were significantly improved (p < 0.05); however, semen volume did not improve (p > 0.05) in patients in the recovery and dilatation groups compared to those in patients before surgery. Sperm concentration, motility, and semen volume did not improve in patients in the reflux group compared with those in patients before surgery (p > 0.05). Logistic regression analysis revealed that the internal diameter of the spermatic vein and reflux duration were risk factors for post-operative spermatic vein dilatation without reflux. Ultrasonography after varicocelectomy should primarily be used to observe reflux, and should not be used as a diagnostic criterion for varicocele based on the internal diameter of the spermatic vein alone.

Assessing Whether Morphological Changes in Axillary Lymph Node Have Already Occurred Prior to Metastasis in Breast Cancer Patients by Ultrasound.

Background and Objectives: Whether the morphological changes in axillary lymph node (ALN) have occurred prior to metastasis remains unclear in breast cancer (BC) patients. The aim of this study is to investigate the influence of BC for the morphology of non-metastasis ALN (N−) and, further, to improve the performance of ultrasound (US) examination for metastasis ALN (N+). Materials and Methods: In this retrospective study, 653 patients with breast mass were enrolled and divided into normal group of 202 patients with benign breast tumor, N− group of 233 BC patients with negative ALN and N+ group of 218 BC patients with positive ALN. US features of ALN were evaluated and analyzed according to long (L) and short (S) diameter, the (L/S) axis ratio, cortical thickness, lymph node edge, replaced hilum and color Doppler flow imaging (CDFI). Results: ALN US features of short diameter, replaced hilum, cortical thickness and CDFI have significant statistical differences in N− group comparing with normal group and N+ group, respectively (p < 0.05). Conclusions: Therefore, BC can affect ALN and lead to US morphological changes whether lymph node metastasis is present, which reduces the sensitivity of axillary US. The combination of US and other examination methods should be applied to improve the diagnostic performance of N+.

Active circular dichroism coding meta-mirror for flexible beam-forming and dynamic amplitude control.

Equipped with the capability of simultaneous phase and amplitude modulation, the chiral metasurfaces have broken through the weak chiroptical responses of natural media, giving birth to a number of unprecedented phenomena. However, the performance of passive metasurface is inadequate to realize dynamic manipulation to fit the diverse and changeable operation requirements, which would damage their engineering applications. Here, a circular dichroism meta-mirror consisting of Archimedean spiral-based meta-atoms is proposed to achieve dynamic scattering modulation. Combining the strategy of loading active element, the chiroptical responses of a metasurface is smoothly controlled. By controlling bias voltages, continuous scattered reflection amplitude steering can be achieved for the designated spin state while the orthogonal spin state can hardly be influenced. With the assistance of Pancharatnam-Berry phase principle, the metasurface possesses the capability of tailoring waves in coded manner. We experimentally verify the proposed strategy by a 1-bit checkerboard meta-mirror for four-beam scattering pattern. Importantly, the proposed paradigm may find applications in spin-sensitive systems and adaptive camouflage.

Multi-institutional development and validation of a nomogram to predict recurrence after curative resection of gastric neuroendocrine/mixed adenoneuroendocrine carcinoma.

OBJECTIVE: To establish a novel nomogram to predict individual 1, 3, and 5 years disease-free survival (DFS) of patients with gastric neuroendocrine carcinoma/mixed adenoneuroendocrine carcinoma [(MA)NEC]. BACKGROUND: Among patients undergoing radical resection of gastric (MA)NEC, there is still a high tendency for relapse. METHODS: A retrospective analysis of 777 patients with gastric (MA)NEC at 23 centers in China from 2004 to 2015 was performed. Based on the established nomogram, which included age, ASA, pT, pN and Ki67, the overall patients were divided into low-risk group (LRG) and high-risk group (HRG). RESULTS: The median follow-up time was 40 months (1-169 months). The C-index, AUC and time-ROC of the nomogram were significantly higher than that of the 8th edition AJCC and ENETS TNM staging systems. The 3-year DFS of patients in HRG generated by the nomogram was significantly lower than that in LRG (all patients: 35% vs 66.9%, p < 0.001), and there were still significant differences in stratified analysis of the TNM staging systems. The local recurrence rate (10.5% vs 2.6%) and distant recurrence rate (45.1% vs 22.6%) in HRG were significantly higher than those in LRG, especially in anastomotic recurrence (6.3% vs 2%), liver recurrence (20.7% vs 13.4%) and peritoneal metastasis (12.7% vs 2.6%). CONCLUSIONS: Compared with AJCC and ENETS TNM staging systems, the established novel validated nomogram had a significantly better prediction ability for DFS and recurrence patterns in patients with gastric (MA)NEC. It can also compensate for the shortcomings of existing AJCC and ENETS TNM staging in predicting individual recurrence risk.

Textbook Outcome as a measure of surgical quality assessment and prognosis in gastric neuroendocrine carcinoma: A large multicenter sample analysis.

OBJECTIVE: Quality assurance is crucial for oncological surgical treatment assessment. For rare diseases, single-quality indicators are not enough. We aim to develop a comprehensive and reproducible measurement, called the "Textbook Outcome" (TO), to assess the quality of surgical treatment and prognosis of gastric neuroendocrine carcinoma (G-NEC) patients. METHODS: Data from patients with primary diagnosed G-NEC included in 24 high-volume Chinese hospitals from October 2005 to September 2018 were analyzed. TO included receiving a curative resection, ≥15 lymph nodes examined, no severe postoperative complications, hospital stay ≤21 d, and no hospital readmission ≤30 d after discharge. Hospital variation in TO was analyzed using a case mix-adjusted funnel plot. Prognostic factors of survival and risk factors for non-Textbook Outcome (non-TO) were analyzed using Cox and logistic models, respectively. RESULTS: TO was achieved in 56.6% of 860 G-NEC patients. TO patients had better overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) than non-TO patients (P<0.05). Moreover, TO patients accounted for 60.3% of patients without recurrence. Multivariate Cox analysis revealed non-TO as an independent risk factor for OS, DFS, and RFS of G-NEC patients (P<0.05). Increasing TO rates were associated with improved OS for G-NEC patients, but not hospital volume. Multivariate logistic regression revealed that non-lower tumors, open surgery, and >200 mL blood loss were independent risk factors for non-TO patients (P<0.05). CONCLUSIONS: TO is strongly associated with multicenter surgical quality and prognosis for G-NEC patients. Factors predicting non-TO are identified, which may help guide strategies to optimize G-NEC outcomes.

In Vivo Flow Cytometric Evaluation of Circulating Metastatic Pancreatic Tumor Cells after High-Intensity Focused Ultrasound Therapy.

We examined our hypothesis that high-intensity focused ultrasound (HIFU) treatment of pancreatic ductal adenocarcinoma (PDAC) in nude mice models may lead to an increased occurrence of hematogenous metastasis. The human PDAC cell line BxPC-3 transfected with mCherry was implanted into nude mice to establish orthotopic and subcutaneous xenograft (OX and SX) tumor models. Mice were exposed to HIFU when tumor sizes reached approximately 200-300 mm3 . The OX and SX tumor models were monitored continuously for tumor growth characteristics and hematogenous metastasis using in vivo flow cytometric (IVFC) detection of circulating tumor cells (CTCs) from the pancreas. We chose an appropriate mouse model to further examine whether or not HIFU increases the potential risk of hematogenous metastasis, using IVFC detection. Our results showed that the CTC number was greater in the OX model than in the SX model. The CTC number in the OX model increased gradually over time, whereas the CTC number in the SX model remained low. Therefore, the OX model was better for studying tumor metastasis by IVFC detection. We found significantly decreased CTC numbers and tumor volume after HIFU ablation. Our results showed the applicability of the PDAC OX tumor model for studying the occurrence of tumor metastasis due to the generation of CTCs. HIFU ablation substantially restricted PDAC hematogenous metastasis and provided effective tumor control locally. © 2020 The Authors. Cytometry Part A published by Wiley Periodicals Inc., on behalf of International Society for Advancement of Cytometry.

Prognostic Factors for Primary Localized Gastrointestinal Stromal Tumors After Radical Resection: Shandong Gastrointestinal Surgery Study Group, Study 1201.

BACKGROUND: Most previous risk-prediction models for gastrointestinal stromal tumors (GISTs) were based on Western populations. In the current study, we collected data from 23 hospitals in Shandong Province, China, and used the data to examine prognostic factors in Chinese patients and establish a new recurrence-free survival (RFS) prediction model. METHODS: Records were analyzed for 5285 GIST patients. Independent prognostic factors were identified using Cox models. Receiver operating characteristic curve analysis was used to compare a novel RFS prediction model with current risk-prediction models. RESULTS: Overall, 4216 patients met the inclusion criteria and 3363 completed follow-up. One-, 3-, and 5-year RFS was 94.6% (95% confidence interval [CI] 93.8-95.4), 85.9% (95% CI 84.7-87.1), and 78.8% (95% CI 77.0-80.6), respectively. Sex, tumor location, size, mitotic count, and rupture were independent prognostic factors. A new prognostic index (PI) was developed: PI = 0.000 (if female) + 0.270 (if male) + 0.000 (if gastric GIST) + 0.350 (if non-gastric GIST) + 0.000 (if no tumor rupture) + 1.259 (if tumor rupture) + 0.000 (tumor mitotic count < 6 per 50 high-power fields [HPFs]) + 1.442 (tumor mitotic count between 6 and 10 per 50 HPFs) + 2.026 (tumor mitotic count > 10 per 50 HPFs) + 0.096 × tumor size (cm). Model-predicted 1-, 3-, and 5-year RFS was S(12, X) = 0.9926exp(PI), S(36, X) = 0.9739exp(PI) and S(60, X) = 0.9471exp(PI), respectively. CONCLUSIONS: Sex, tumor location, size, mitotic count, and rupture were independently prognostic for GIST recurrence. Our RFS prediction model is effective for Chinese GIST patients.

Nonlinear effect of wind velocity on mumps in Shenzhen, China, 2013-2016.

OBJECTIVES: Plenty of studies have shown that wind velocity has an influence on airborne diseases. There is, however, no consistent conclusion found on the relationship between wind velocity and mumps, and the regional heterogeneity has been largely neglected in previous studies. This study aims to explore the association between wind velocity and mumps in Shenzhen. STUDY DESIGN: Ecological study. METHODS: Sixteen subdistricts with the highest incidence rates of mumps were selected from Shenzhen city, and the multilevel distributed lag-nonlinear model was conducted to explore the relationship between mumps cases and wind velocity via the dlnm and lme4 packages of the software R 3.4.3. RESULTS: In Shenzhen, a total of 16,997 mumps cases were reported between 2013 and 2016, and the means of daily rainfall, temperature, relative humidity, and 10 min wind velocity were 5.74 mm, 23.27 °C, 76.31% and 1.87 m/s, respectively. Obvious nonlinear correlation relationships of wind velocity and mumps risk were found, where a reverse-V curved shape was shown in the exposure dimension with the logRR value of mumps peaking at 2 m/s, and the type of nonlinear correlation varying with the levels of wind velocity in lag dimension with a peak at two lag weeks. CONCLUSIONS: The lag and nonlinear association between wind velocity and number of mumps cases were examined, while there was no statistically significant associations for other meteorological factors accounting for the regional heterogeneity. Results from this study indicated that public health administrators could strengthen health education in schools on ventilation management to prevent and control mumps outbreaks.

Perioperative Rosuvastatin in Cardiac Surgery.

BACKGROUND: Complications after cardiac surgery are common and lead to substantial increases in morbidity and mortality. Meta-analyses of small randomized trials have suggested that perioperative statin therapy can prevent some of these complications. METHODS: We randomly assigned 1922 patients in sinus rhythm who were scheduled for elective cardiac surgery to receive perioperative rosuvastatin (at a dose of 20 mg daily) or placebo. The primary outcomes were postoperative atrial fibrillation within 5 days after surgery, as assessed by Holter electrocardiographic monitoring, and myocardial injury within 120 hours after surgery, as assessed by serial measurements of the cardiac troponin I concentration. Secondary outcomes included major in-hospital adverse events, duration of stay in the hospital and intensive care unit, left ventricular and renal function, and blood biomarkers. RESULTS: The concentrations of low-density lipoprotein cholesterol and C-reactive protein after surgery were lower in patients assigned to rosuvastatin than in those assigned to placebo (P<0.001). However, the rate of postoperative atrial fibrillation did not differ significantly between the rosuvastatin group and the placebo group (21.1% and 20.5%, respectively; odds ratio 1.04; 95% confidence interval [CI], 0.84 to 1.30; P=0.72), nor did the area under the troponin I-release curve (102 ng×hour per milliliter and 100 ng×hour per milliliter, respectively; between-group difference, 1%; 95% CI, -9 to 13; P=0.80). Subgroup analyses did not indicate benefit in any category of patient. Rosuvastatin therapy did not result in beneficial effects on any of the secondary outcomes but was associated with a significant absolute (±SE) excess of 5.4±1.9 percentage points in the rate of postoperative acute kidney injury (P=0.005). CONCLUSIONS: In this trial, perioperative statin therapy did not prevent postoperative atrial fibrillation or perioperative myocardial damage in patients undergoing elective cardiac surgery. Acute kidney injury was more common with rosuvastatin. (Funded by the British Heart Foundation and others; STICS ClinicalTrials.gov number, NCT01573143.).

New-onset metabolic risk factors and the incidence of kidney stones: a prospective cohort study.

OBJECTIVE: To examine the association of kidney stones with new-onset hypertension, diabetes and obesity. PARTICIPANTS AND METHODS: This prospective cohort study included participants in the Qingdao Port Cardiovascular Health Study who were aged ≥18 years and had abdominal ultrasonography results in 2013 that were negative for kidney stones. Multivariable Cox regression models with time-dependent covariates were used to estimate the effects of new-onset hypertension, diabetes and obesity on the incidence of kidney stones. RESULTS: There were 9667 participants without kidney stones in 2013 (mean age 46.2 years; 75.6% men). During a mean (range) follow-up of 33.5 (6-42) months, 676 (7.0%) incident cases of kidney stones were identified. Kidney stones were more frequent among those who had new-onset of a metabolic factor vs those who did not (hypertension: 7.7 vs 6.0%; diabetes: 8.4 vs 6.6%; obesity: 7.4 vs 6.8%). Adjusted Cox models identified that increased risk of kidney stones was associated with new-onset hypertension (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.25-2.27), new-onset diabetes (HR 1.78, 95% CI 1.07-2.96), and new-onset obesity (HR 1.78, 95% CI 1.15-2.74). CONCLUSIONS: New-onset of hypertension, diabetes and obesity were all strongly associated with an increased risk of kidney stones in this prospective cohort study. Results suggest that a substantial proportion of kidney stones are potentially preventable by appropriate control of these metabolic risk factors.

Prevalence, awareness, treatment, and control of hypertension in China: data from 1·7 million adults in a population-based screening study (China PEACE Million Persons Project).

BACKGROUND: Hypertension is common in China and its prevalence is rising, yet it remains inadequately controlled. Few studies have the capacity to characterise the epidemiology and management of hypertension across many heterogeneous subgroups. We did a study of the prevalence, awareness, treatment, and control of hypertension in China and assessed their variations across many subpopulations. METHODS: We made use of data generated in the China Patient-Centered Evaluative Assessment of Cardiac Events (PEACE) Million Persons Project from Sept 15, 2014, to June 20, 2017, a population-based screening project that enrolled around 1·7 million community-dwelling adults aged 35-75 years from all 31 provinces in mainland China. In this population, we defined hypertension as systolic blood pressure of at least 140 mm Hg, or diastolic blood pressure of at least 90 mm Hg, or self-reported antihypertensive medication use in the previous 2 weeks. Hypertension awareness, treatment, and control were defined, respectively, among hypertensive adults as a self-reported diagnosis of hypertension, current use of antihypertensive medication, and blood pressure of less than 140/90 mm Hg. We assessed awareness, treatment, and control in 264 475 population subgroups-defined a priori by all possible combinations of 11 demographic and clinical factors (age [35-44, 45-54, 55-64, and 65-75 years], sex [men and women], geographical region [western, central, and eastern China], urbanity [urban vs rural], ethnic origin [Han and non-Han], occupation [farmer and non-farmer], annual household income [< ¥10 000, ¥10 000-50 000, and ≥¥50 000], education [primary school and below, middle school, high school, and college and above], previous cardiovascular events [yes or no], current smoker [yes or no], and diabetes [yes or no]), and their associations with individual and primary health-care site characteristics, using mixed models. FINDINGS: The sample contained 1 738 886 participants with a mean age of 55·6 years (SD 9·7), 59·5% of whom were women. 44·7% (95% CI 44·6-44·8) of the sample had hypertension, of whom 44·7% (44·6-44·8) were aware of their diagnosis, 30·1% (30·0-30·2) were taking prescribed antihypertensive medications, and 7·2% (7·1-7·2) had achieved control. The age-standardised and sex-standardised rates of hypertension prevalence, awareness, treatment, and control were 37·2% (37·1-37·3), 36·0% (35·8-36·2), 22·9% (22·7-23·0), and 5·7% (5·6-5·7), respectively. The most commonly used medication class was calcium-channel blockers (55·2%, 55·0-55·4). Among individuals whose hypertension was treated but not controlled, 81·5% (81·3-81·6) were using only one medication. The proportion of participants who were aware of their hypertension and were receiving treatment varied significantly across subpopulations; lower likelihoods of awareness and treatment were associated with male sex, younger age, lower income, and an absence of previous cardiovascular events, diabetes, obesity, or alcohol use (all p<0·01). By contrast, control rate was universally low across all subgroups (<30·0%). INTERPRETATION: Among Chinese adults aged 35-75 years, nearly half have hypertension, fewer than a third are being treated, and fewer than one in twelve are in control of their blood pressure. The low number of people in control is ubiquitous in all subgroups of the Chinese population and warrants broad-based, global strategy, such as greater efforts in prevention, as well as better screening and more effective and affordable treatment. FUNDING: Ministry of Finance and National Health and Family Planning Commission, China.

Availability, cost, and prescription patterns of antihypertensive medications in primary health care in China: a nationwide cross-sectional survey.

BACKGROUND: Around 200 million adults in China have hypertension, but few are treated or achieve adequate control of their blood pressure. Available and affordable medications are important for successfully controlling hypertension, but little is known about current patterns of access to, and use of, antihypertensive medications in Chinese primary health care. METHODS: We used data from a nationwide cross-sectional survey (the China Patient-Centered Evaluative Assessment of Cardiac Events Million Persons Project primary health care survey), which was undertaken between November, 2016 and May, 2017, to assess the availability, cost, and prescription patterns of 62 antihypertensive medications at primary health-care sites across 31 Chinese provinces. We surveyed 203 community health centres, 401 community health stations, 284 township health centres, and 2474 village clinics to assess variation in availability, cost, and prescription by economic region and type of site. We also assessed the use of high-value medications, defined as guideline-recommended and low-cost. We also examined the association of medication cost with availability and prescription patterns. FINDINGS: Our study sample included 3362 primary health-care sites and around 1 million people (613 638 people at 2758 rural sites and 478 393 people at 604 urban sites). Of the 3362 sites, 8·1% (95% CI 7·2-9·1) stocked no antihypertensive medications and 33·8% (32·2-35·4) stocked all four classes that were routinely used. Village clinics and sites in the western region of China had the lowest availability. Only 32·7% (32·2-33·3) of all sites stocked high-value medications, and few high-value medications were prescribed (11·2% [10·9-11·6] of all prescription records). High-cost medications were more likely to be prescribed than low-cost alternatives. INTERPRETATION: China has marked deficiencies in the availability, cost, and prescription of antihypertensive medications. High-value medications are not preferentially used. Future efforts to reduce the burden of hypertension, particularly through the work of primary health-care providers, will need to improve access to, and use of, antihypertensive medications, paying particular attention to those with high value. FUNDING: CAMS Innovation Fund for Medical Science, the Entrusted Project from the China National Development and Reform Commission, and the Major Public Health Service Project from the Ministry of Finance of China and National Health and Family Planning Commission of China.

The primary health-care system in China.

China has made remarkable progress in strengthening its primary health-care system. Nevertheless, the system still faces challenges in structural characteristics, incentives and policies, and quality of care, all of which diminish its preparedness to care for a fifth of the world's population, which is ageing and which has a growing prevalence of chronic non-communicable disease. These challenges include inadequate education and qualifications of its workforce, ageing and turnover of village doctors, fragmented health information technology systems, a paucity of digital data on everyday clinical practice, financial subsidies and incentives that do not encourage cost savings and good performance, insurance policies that hamper the efficiency of care delivery, an insufficient quality measurement and improvement system, and poor performance in the control of risk factors (such as hypertension and diabetes). As China deepens its health-care reform, it has the opportunity to build an integrated, cooperative primary health-care system, generating knowledge from practice that can support improvements, and bolstered by evidence-based performance indicators and incentives.

Regulation of Gli2 stability by deubiquitinase OTUB2.

The transcription factor Gli2 plays crucial roles in the transduction of Hedgehog (Hh) signals, yet the mechanisms that control Gli2 degradation remain unclear. Here we have identified the eubiquitinating enzyme otubain2 (OTUB2) as a regulator of Gli2 protein degradation. We found that OTUB2 was coimmunoprecipitated with Gli2. Knockdown of OTUB2 decreased Gli2 protein level while the proteasome inhibitor MG-132 treatment restored Gli2 expression. Additionally, OTUB2 overexpression stabilized Gli2 protein in U2OS cells and extended the half-life of Gli2. We also found that knockdown of OTUB2 reduced deubiquitination of Gli2 in vivo. In vitro deubiquitination assay showed that ubiquitinated Gli2 was decreased by wild-type OTUB2 but not OTUB2 mutations. We also found that OTUB2 knockdown suppressed the ALP activity and the expression of the common markers BMP2 and RUNX2 during osteogenesis of MSCs in response to Shh and Smo agonists, which indicated OTUB2 may have effect on osteogenic differentiation by regulating Hh signaling.

Ticagrelor versus clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: Rationale and design of the ticagrelor in patients with ST elevation myocardial infarction treated with thrombolysis (TREAT) trial.

BACKGROUND: The safety and efficacy of ticagrelor in patients with ST-elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remain uncertain. OBJECTIVES: The primary objective of the TicagRElor in pAtients with ST elevation myocardial infarction treated with Thrombolysis (TREAT) trial is to evaluate the short-term safety of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy. Key secondary objectives are to assess the safety and efficacy of ticagrelor compared with clopidogrel at 12-months. DESIGN: The TREAT trial is a multicenter, randomized, phase III, Prospective randomized open blinded end-point (PROBE) study that enrolled 3,799 patients in 152 sites from 10 countries. Following administration of fibrinolytic therapy patients were randomized to a loading dose of ticagrelor 180 mg or clopidogrel 300 mg followed by a maintenance dose of ticagrelor 90 mg twice daily or clopidogrel 75 mg/day for 12-months. The primary outcome is the rate of TIMI major bleeding at 30-days and will be assessed for non-inferiority using an intention-to-treat analysis. Co-treatments include aspirin and anticoagulants. Other evidence based therapies are also recommended. Secondary efficacy outcome include a composite of death from vascular causes, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack or other arterial thrombotic event. All-cause mortality as well as individual components of the combined efficacy endpoint will also be ascertained. SUMMARY: TREAT is an international randomized controlled trial comparing ticagrelor with clopidogrel in STEMI patients treated with fibrinolytic therapy. The results of this trial will inform clinical practice and international guidelines.