Noncanonical TGF-ß signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis.

Transforming growth factor-ß (TGF-ß) signaling plays a critical role in promoting epithelial-to-mesenchymal transition (EMT), cell migration, invasion, and tumor metastasis. ΔNp63α, the major isoform of p63 protein expressed in epithelial cells, is a key transcriptional regulator of cell adhesion program and functions as a critical metastasis suppressor. It has been documented that the expression of ΔNp63α is tightly controlled by oncogenic signaling and is frequently reduced in advanced cancers. However, whether TGF-ß signaling regulates ΔNp63α expression in promoting metastasis is largely unclear. In this study, we demonstrate that activation of TGF-ß signaling leads to stabilization of E3 ubiquitin ligase FBXO3, which, in turn, targets ΔNp63α for proteasomal degradation in a Smad-independent but Erk-dependent manner. Knockdown of FBXO3 or restoration of ΔNp63α expression effectively rescues TGF-ß-induced EMT, cell motility, and tumor metastasis in vitro and in vivo. Furthermore, clinical analyses reveal a significant correlation among TGF-ß receptor I (TßRI), FBXO3, and p63 protein expression and that high expression of TßRI/FBXO3 and low expression of p63 are associated with poor recurrence-free survival (RFS). Together, these results demonstrate that FBXO3 facilitates ΔNp63α degradation to empower TGF-ß signaling in promoting tumor metastasis and that the TßRI-FBXO3-ΔNp63α axis is critically important in breast cancer development and clinical prognosis. This study suggests that FBXO3 may be a potential therapeutic target for advanced breast cancer treatment.

Trends and patterns of antibiotic using from 2014 to 2018 in stomatology hospitals of China.

OBJECTIVE: To analyze trends of antibiotic consumption and expenditure in Chinese stomatology hospitals between 2014 and 2018 with a longitudinal study design, and show the impacts of the comprehensive policy on dental antibiotic use in China. SUBJECT AND METHODS: Consumption was quantified as the number of daily defined doses (DDDs) and expenditure as the procurement costs, using medical institutions' drug procurement data from the Chinese Monitoring Network for Rational Use of Drugs. Descriptive statistics was employed and the compound annual growth rate (CAGR) was calculated to show the average annual growth rate. RESULTS: Between 2014 and 2018, overall antibiotic consumption increased from 842.6 thousand DDDs to 1376.7 thousand DDDs (p < 0.001) and expenditure increased from 11.6 million RMB to 20.9 million RMB (p < 0.001), where other ß-lactam antibacterials accounted for the largest proportion of total consumption (37.1%-50.1%) and expenditure (52.9%-66.6%), and also increase the largest (CAGR = 18.4%, p < 0.001). The proportion of oral antibiotics was nearly 9 times of parenteral antibiotics in consumption (CAGR = 0.3%, p = 0.023) and only 2 times in expenditure (CAGR = -1.7%, p = 0.112). The non-restricted group accounted for more than 90% of consumption (CAGR = 0.6%, p < 0.001). In 2018, oral first-generation cephalosporins (22.8%), oral imidazole derivatives (22.3%), and oral second-generation cephalosporins (19.2%) were the most frequently used antibiotic classification, while parenteral second-generation cephalosporins were top one (19.8%) for expenditure. At chemical substance levels, the consumption of oral cefradine ranked top one (21.4%) and parenteral cefuroxime accounted for the largest proportion of expenditure (14.5%) in 2018. Oral cefradine, oral metronidazole, and oral cefaclor were the top three frequently consumed antibiotics throughout the five years. CONCLUSIONS: Despite the potential antibiotic overuse, the comprehensive antibiotic stewardship regulations of China got a satisfactory and better performance in dental practices. More effort is needed to establish more explicit guidelines to improve antibiotic stewardship, such as priority recommending amoxicillin and its derivatives for endodontic infections.

Association of potentially inappropriate medications with prognosis among older patients with non-small cell lung cancer.

BACKGROUND: Potentially inappropriate medications (PIMs) are common among older adults with cancer, but their association with overall survival (OS) among non-small cell lung cancer (NSCLC) patients remains unclear. This study aimed to investigate the association between the use of PIMs and OS in patients with NSCLC. METHODS: In this cohort study, we included patients ≥ 65 years with newly diagnosed NSCLC from January 2014 to December 2020. Potentially inappropriate medication (PIM) is defined by the Beers criteria of 2019 at baseline and within six months following the initiation of systemic therapy. Multivariable Cox regression model was built to assess the association between PIMs and overall survival (OS). RESULTS: We finally included 338 patients with a median follow-up for OS of 1777 days. The prevalence of patients receiving at least one PIM was 39.9% (135/338) and 61.2% (71/116) at baseline and after systemic therapy, respectively. The most important factor associated with PIM use was the number of prescribed medications (P < 0.001). Baseline PIM use and PIM after systemic therapy were significantly associated with inferior OS (476 days vs. 844 days, P = 0.044; and 633 days vs. 1600 days, P = 0.007; respectively). In multivariable analysis, both baseline PIM use and PIM after systemic therapy were independent predictors of poor prognosis (adjusted HR, 1.33; 95% CI, 1.01-1.75; P = 0.041; and adjusted HR, 1.86; 95% CI, 1.11-3.14; P = 0.020; respectively). CONCLUSIONS: PIMs are prevalent among older patients with NSCLC and are independent predictors of NSCLC prognosis. There is an urgent need for clinicians to conduct medication reconciliation and appropriate deprescribing for this population, especially for patients with multiple PIMs.

Potentially inappropriate medications among older patients with Parkinson's disease: a cross-sectional analysis of a national health insurance database in China.

BACKGROUND: With the rapid aging trend of China's population, the issue of drug rational use in older adults has become more and more prominent. Parkinson's disease (PD) is the one of the most common age-related neurodegenerative disorders. Pharmaceutical treatment plays a cardinal role in alleviating motor and non-motor symptoms to improve the quality of life of patients with PD. Patients with PD have complex medical needs yet little is known about the use of potentially inappropriate medications (PIM) among them in China. We quantify the prevalence of PIM use and identify its predictors among older persons with PD in China. METHODS: We conducted a cross-sectional analysis using a national representative database of all medical insurance beneficiaries across China, extracting records of ambulatory visits of older adults with PD between 2015 and 2017. Beneficiaries aged 65 and above were eligible for inclusion. The prevalence of patients exposed to overall PIMs and PIMs related to motor and cognitive impairment was calculated based on Beers Criteria 2015 version. Potential predictors of PIM concerning patients' characteristics were estimated using multivariate logistic regression. RESULTS: A total of 14,452 older adults with PD were included. In total, 8,356 (57.8%) patients received at least one PIM; 2,464 (17.1%) patients received at least one motor-impairing PIM and 6,201 (42.9%) patients received at least one cognition-impairing PIM. The prevalence of overall PIM use was higher in patients of older age group (54.7% [65-74] vs. 59.5% [75-84; OR, 1.22; 95% CI, 1.14-1.31] vs.65.5% [≥ 85; OR, 1.58; 95% CI, 1.38-1.80) and females (61.4% [female] vs. 55.0% [males; OR, 0.77; 95% CI, 0.72-0.82). CONCLUSIONS: Prescribing PIMs for older adults with PD was common in China, especially for females and older age groups, yet younger patients were more inclined to be prescribed with motor or cognition-impaired PIMs. Our findings represent a clear target awaiting multidimensional efforts to promote the rational prescribing of medications for this vulnerable population.

A Convenient Procedure for Preparing BiOX-TiO2 Photoelectrocatalytic Electrodes from a Titanium-Oxo Compound-Modified Carbon Fiber Cloth.

Photoelectrocatalysis (PEC) has shown great advantages in sustainable organic synthesis and wastewater treatment because the PEC process can minimize electron-hole recombination, thereby improving the photocatalytic performance. Here, we report a convenient procedure for preparing immobilized BiOX-TiO2 photoelectrocatalytic electrodes from a titanium-oxo compound (TOC)-modified carbon fiber cloth (CFC). Crystalline TOCs composed of Ti12 cations and bismuth halide anions, [Ti12O14(OiPr)18][Bi3Br11(THF)2] (1) and [Ti12O14(OiPr)18][Bi4I14(THF)2] (2), were grown on CFC. Taking advantage of the easy hydrolysis of the titanium-oxo cation and bismuth halide anion, we could easily transform these CFC-immobilized crystals into BiOX-TiO2/CFC (X = Br or I) photocatalysts, which facilitates recycling of the catalysts. The photocatalytic dye degradation test showed that the efficiency did not decrease obviously after 10 photocatalytic cycles. Using BiOX-TiO2-modified CFC as electrodes, electrocatalysis (EC), photocatalysis (PC), and PEC were examined. PEC showed an attractive synergistic effect of EC and PC. These TOC-modified CFCs would be potential candidates for catalytic electrodes for sustainable wastewater purification.

Bearing Fault Feature Extraction Method Based on Enhanced Differential Product Weighted Morphological Filtering.

Aimed at the problem of fault characteristic information bearing vibration signals being easily submerged in some background noise and harmonic interference, a new algorithm named enhanced differential product weighted morphological filtering (EDPWMF) is proposed for bearing fault feature extraction. In this method, an enhanced differential product weighted morphological operator (EDPWO) is first constructed by means of infusing the differential product operation and weighted operation into four basic combination morphological operators. Subsequently, aiming at the disadvantage of the parameter selection of the structuring element (SE) of EDPWO depending on artificial experience, an index named fault feature ratio (FFR) is employed to automatically determine the flat SE length of EDPWO and search for the optimal weighting correlation factors. The fault diagnosis results of simulation signals and experimental bearing fault signals show that the proposed method can effectively extract bearing fault feature information from raw bearing vibration signals containing noise interference. Moreover, the filtering result obtained by the proposed method is better than that of traditional morphological filtering methods (e.g., AVG, STH and EMDF) through comparative analysis. This study provides a reference value for the construction of advanced morphological analysis methods.

Assembly of a Titanium-Oxo Cluster and a Bismuth Iodide Cluster, a Single-Source Precursor of a p-n-Type Photocatalyst.

Titanium oxides and bismuth halides or oxyhalides have been known to be excellent semiconductors with both excellent photocatalytic and photoelectric properties. The design of supersalts assembled by titanium-oxo clusters (TOCs) and bismuth iodide clusters is a hopeful strategy for exploring the chemistry and application of new titanium-oxo clusters. We report herein a series of unusual ionic TOCs with Ti12 oxo cluster cations and bismuth iodide anions, [Ti12O15(OiPr)17]3[Bi3I12] (Bi3), [Ti12O14(OiPr)18][Bi4I14(THF)2] (Bi4), and [Ti12O14(OiPr)18][Ti11BiO14(OiPr)17][Bi6I22] (Bi6). Single-crystal X-ray analysis revealed that the type and charge of the Ti12 clusters varied with the charges of different bismuth iodide clusters. Taking advantage of the easy hydrolysis of the TOCs and BiI clusters in water, we used these supersalt crystals as single-source precursors to prepare a p-n-type BiOI-TiO photocatalyst. The heterojunction materials were carefully characterized by powder X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy, high-resolution transmission electron microscopy, etc. The synergistic effect of the two components of BiOI and TiO on the photocatalytic degradation of RhB in water is demonstrated. This is a very convenient method for obtaining a p-n-type BiOI-TiO heterojuction photocatalyst by just placing the ground TOC crystals into water.

Mono- and Bismetalphenanthroline-Substituted Ti12 Clusters: Structural Variance and the Effect on Electronic State and Photocurrent Property.

Despite the numerous titanium-oxo clusters (TOCs) which have been reported, the nature of small clusters (nuclearity < 10) as model compounds showed large deviation from that of nanoscale TiO materials. Therefore, theoretical and experimental studies for large TOCs merit more attention. We recently prepared and crystallographically characterized a series of large TOCs: Ti11O15(OiPr)16(Cophen) (1), Ti11O15(OiPr)16(Mnphen) (2), Ti10O14(OEt)16(Mnphen)2 (3), and Ti10O14(OEt)16(Mnphphen)2 (4) (phen = 1,10-phenanthroline, phphen = 4,7-biphenyl-phen). These compounds are derivatives of a Ti12 parent cluster by replacing one or two of the five-coordinated titanium atoms of the Ti12 cluster with a transition metal M, Co(II) and Mn(II), that is chelated by a phen group. The effects of mono- and bis-substituted Mphen on the charge and structure of the clusters are discussed. Theoretical evaluation of the frontier orbitals of the clusters is carried out on the basis of the precisely defined crystal structures. Different from the dye molecule to TiO core charge transfer for the dye-modified TOCs, charge transfer in these clusters is from TiO/TiOM to phen/Mphen. The effects of different metal ions and the number of substituted Mphen moieties on the photocurrent properties are evaluated. The results will be of interest to research on cluster chemistry, especially on the TOC chemistry.

Antibiotic use and irrational antibiotic prescriptions in 66 primary healthcare institutions in Beijing City, China, 2015-2018.

OBJECTIVES: To identify the patterns of antibiotic use and irrational antibiotic prescriptions in primary healthcare institutions (PHIs) in Dongcheng District of Beijing, China. MATERIALS AND METHODS: All primary healthcare institutions (7 community healthcare centres and 59 community healthcare stations in total) in Dongcheng District were included in the study. Prescription data from January 2015 to December 2018 was derived from the Beijing Prescription Reviewing System of Primary healthcare institutions and analysed retrospectively. The antibiotic prescription rate was calculated and cases of irrational antibiotic prescriptions were identified. RESULTS: We extracted 11,166,905 prescriptions from the database. Only 189,962 prescriptions were included in the study, among which 9167 (4.8%) contained antibiotics. The antibiotic prescription rate fell from 5.2% in 2015 to 4.1% in 2018 while irrational antibiotic prescription rate increased from 10.4 to 11.8%. Acute Bronchitis was the most prevalent diagnosis (17.6%) for antibiotic prescriptions, followed by Unspecified Acute Respiratory Tract Infection (14.4%), Acute Tonsillitis (9.9%), and Urinary Tract Infection (6.4%). Around 10% of the prescriptions for the top 7 diagnoses identified were rated as irrational. Cephalosporins, fluoroquinolones, and macrolides were the most prescribed antibiotics, which accounted for 89.3% of all antibiotic prescriptions. Of all the antibiotic prescriptions, 7531 were reviewed, among which 939 (12.5%) were rated as irrational because of antibiotic use. Among all the irrational prescriptions, prescriptions with inappropriate antibiotic use and dosage accounted for the majority (54.4%). CONCLUSION: Although a relatively low level of antibiotic utilization was found in PHIs in Dongcheng District of Beijing, the utilization patterns differed considerably from developed countries and irrational prescriptions remained. Considering the imbalanced allocation of medical resources between primary healthcare setting and secondary and tertiary hospitals, there need to be more efforts invested in regions with different levels of economic development.

Eu-phen Bonded Titanium Oxo-Clusters, Precursors for a Facile Preparation of High Luminescent Materials and Films.

Incorporation of Eu complexes into various organic or inorganic matrixes is one of the acceptable strategies to obtain displaying materials having practical applications. In this work, we report a convenient approach to preparing high luminescent organic-inorganic hybrid materials and films from the europium-titanium oxo-clusters (EuTOCs) having photoactive antenna ligands. Three Eu2Ti4 oxo-clusters were synthesized and crystallographically characterized. They are the first reported lanthanide-TOCs coordinated with 1,10-phenanthroline (phen) and 2,2'-bipyridine (bpy) as photoactive ligands, Eu2Ti4O6(phen)2(pa)10 (1) (pa = propionate), Eu2Ti4O6(bpy)2(pa)10 (2), and Eu2Ti4O6(phen)2(MA)10 (3) (MA = methacrylate). Benefitting from the photoactive antenna ligands and the rigid cluster structures, these clusters showed bright red luminescence with quantum yield in the range of 60-80% and long lifetime up to 3.0 ms. Unlike those physically mixed polymeric materials, the MA coordinated compound 3 can be self-polymerized to form a brilliant luminescent film. The film coated slide was used to develop a fluorescence sensor for biomolecule ascorbic acid (AA). The low detection limit and reusable properties suggest great potential for such EuTOC films in real applications.

Potentially inappropriate medications among elderly patients in community healthcare institutions in Beijing, China.

PURPOSE: To evaluate potentially inappropriate medications (PIMs) prevalence and predictors in community healthcare institutions (CHIs) for the elderly. METHODS: We conducted a retrospective observational study, deriving data of patients aged ≥60 from 66 CHIs in Beijing, 2014-2018. The system of Criteria of PIM for Older Adults in China was applied to identify PIMs. The primary outcome was the prevalence of visits with at least one PIM; secondary outcomes were the frequency and rate per thousand visits of specific PIMs. We used descriptive analysis and generalized linear models to analyzed PIMs and the predictors, and marginal effects methods were applied to estimate the mean adjusted PIMs prevalence. RESULTS: Overall, 4 528 884 elderly patient visits from 2014 to 2018 were eligible for inclusion. A total of 719 757 PIMs were detected, with 14.1% of the visits contained at least one PIM. PIM prevalence was significantly correlated with age, number of prescribed medications and number of diagnoses. Overall, 6.0 per thousand elderly patients in CHIs were exposed to at least one high-risk PIM, while 117.5 per thousand were exposed to at least one low-risk PIM. In 2018, 20% of GPs were responsible for more than half of overall PIM visits. CONCLUSION: Prescribing of PIMs for older adults is common in CHIs in China, especially for patients who are aged, having multiple medications and diagnostic diseases. Strategies should be developed to enhance prescribing quality for geriatric patients, with special targeting of doctors responsible for a high number of PIMs.

Self-Healable, Self-Adhesive and Degradable MXene-Based Multifunctional Hydrogel for Flexible Epidermal Sensors.

Conductive hydrogels have garnered significant interest in the realm of wearable flexible sensors due to their close resemblance to human tissue, wearability, and precise signal acquisition capabilities. However, the concurrent attainment of an epidermal hydrogel sensor incorporating reliable self-healing capabilities, biodegradability, robust adhesiveness, and the ability to precisely capture subtle electrophysiological signals poses a daunting and intricate challenge. Herein, an innovative MXene-based composite hydrogel (PBM hydrogel) with exceptional self-healing, self-adhesive, and versatile functionality is engineered through the integration of conductive MXene nanosheets into a well-structured poly(vinyl alcohol) (PVA) and bacterial cellulose (BC) hydrogel three-dimensional (3D) network, utilizing multiple dynamic cross-linking synergistic repeated freeze-thaw strategy. The hydrogel harnesses the presence of dynamically reversible borax ester bonds and multiple hydrogen bonds between its constituents, endowing it with rapid self-healing efficiency (97.8%) and formidable self-adhesive capability. The assembled PBM hydrogel epidermal sensor possesses a rapid response time (10 ms) and exhibits versatility in detecting diverse external stimuli and human movements such as vocalization, handwriting, joint motion, Morse code signals, and even monitoring infusion status. Additionally, the PBM hydrogel sensor offers the added advantage of swift degradation in phosphate-buffered saline solution (within a span of 56 days) and H2O2 solution (in just 53 min), maintaining an eco-friendly profile devoid of any environmental pollution. This work lays the groundwork for possible uses in electronic skins, interactions between humans and machines, and the monitoring of individualized healthcare.

Outpatient Antibiotic Prescribing Patterns in Children among Primary Healthcare Institutions in China: A Nationwide Retrospective Study, 2017-2019.

There is scarce evidence to demonstrate the pattern of antibiotic use in children in China. We aimed to describe antibiotic prescribing practices among children in primary healthcare institutions (PHIs) in China. We described outpatient antibiotic prescriptions for children in PHIs from January 2017 to December 2019 at both the national and diagnostic levels, utilizing the antibiotic prescribing rate (APR), multi-antibiotic prescribing rate (MAPR), and broad-spectrum prescribing rate (BAPR). Generalized estimating equations were adopted to analyze the factors associated with antibiotic use. Among the total 155,262.2 weighted prescriptions for children, the APR, MAPR, and BAPR were 43.5%, 9.9%, and 84.8%. At the national level, J01DC second-generation cephalosporins were the most prescribed antibiotic category (21.0%, N = 15,313.0), followed by J01DD third-generation cephalosporins (17.4%, N = 12,695.8). Watch group antibiotics accounted for 55.0% of the total antibiotic prescriptions (N = 52,056.3). At the diagnostic level, respiratory tract infections accounted for 67.4% of antibiotic prescriptions, among which prescriptions with diagnoses classified as potentially bacterial RTIs occupied the highest APR (55.0%). For each diagnostic category, the MAPR and BAPR varied. Age, region, and diagnostic categories were associated with antibiotic use. Concerns were raised regarding the appropriateness of antibiotic use, especially for broad-spectrum antibiotics.

Evaluation of pharmacist-led medication reconciliation at county hospitals in China: A multicentre, open-label, assessor-blinded, nonrandomised controlled study.

Background: Due to a lack of related research, we aimed to determine the effectiveness of a pharmacist-led medication reconciliation intervention in China. Methods: We conducted a multicentre, prospective, open-label, assessor-blinded, cluster, nonrandomised controlled study at six county-level hospitals, with hospital wards serving as the clusters. We included patients discharged from the sampled hospitals who were aged ≥60 years; had ≥1 studied diagnoses; and were prescribed with ≥3 medications at discharge. Patients in the intervention group received a pharmacist-led medication reconciliation intervention and those in the control group received standard care. We assessed the incidence of medication discrepancies at discharge, patients' medication adherence, and health care utilisation within 30 days after discharge. Results: There were 429 patients in the intervention group (mean age = 72.5 years, standard deviation (SD) = 7.0) and 526 patients in the control group (mean age = 73.6 years, SD = 7.1). Of the 1632 medication discrepancies identified at discharge, fewer occurred in the intervention group (1.9 per patient on average) than the control group (2.6 per patient on average).The intervention significantly reduced the incidence of medication discrepancy by 9.6% (95% confidence interval (CI) = -15.6, -3.6, P = 0.002) and improved patients' medication adherence, with an absolute decrease in the mean adherence score of 2.5 (95% CI = -2.8, -2.2, P < 0.001). There was no significant difference in readmission rates between the intervention and control groups. Conclusions: Pharmacist-led medication reconciliation at discharge from Chinese county-level hospitals reduced medication discrepancies and improved patients' adherence among patients aged 60 years or above, though no impact on readmission after discharge was observed. Registration: ChiCTR2100045668.

Appropriate use of antibiotics for acute respiratory infections at primary healthcare facilities in China: a nationwide cross-sectional study from 2017 to 2019.

Background: The appropriateness of antibiotic use for acute respiratory infections (ARIs) in Chinese primary healthcare facilities (PHFs) remained uncertain. We aimed to evaluate to what degree antibiotic prescribing for ARIs were aligned with guideline recommendations in primary settings across China. Methods: We collected outpatient prescriptions from 262 Chinese PHFs in 27 cities of six provinces between 2017 and 2019. The appropriate antibiotic prescribing was defined as prescribing antibiotic classes that were recommended by Chinese clinical guidelines, if patients were prescribed antibiotics. We evaluated the magnitude of antibiotics prescribed for acute upper respiratory infections (AURIs), acute bronchitis, and community-acquired pneumonia (CAP) and their appropriateness. Findings: Overall, 55.1% (87,684/159,150), 66.8% (30,836/46,153), and 68.5% (4615/6733) of outpatients with AURIs, acute bronchitis, and CAP treated at PHFs in China were prescribed with antibiotics. Of all antibiotic prescriptions, only 20.0% (17,542/87,684), 18.6% (5724/30,836) and 69.6% (3211/4615) used antibiotic classes that were recommended by the guidelines for AURIs, acute bronchitis, and CAP, respectively. Patients residing in the Chinese central region (17.0%, 15.4%, 69.3% for AURIs, acute bronchitis, and CAP, respectively) were less likely to be prescribed with antibiotics that were appropriately selected. Interpretation: Unnecessary antibiotics were widely prescribed for patients with AURIs or acute bronchitis and most patients with ARIs did not receive guideline-recommended antibiotic classes in Chinese PHFs. Interventions to promote evidence-based treatment and the appropriate use of antibiotics are urgently needed at the primary level across China. Funding: This work was supported by the National Natural Science Foundation of China [grant number 72074007, 81973294].

Inappropriate antibiotic prescribing in primary healthcare facilities in China: a nationwide survey, 2017-2019.

OBJECTIVES: We aimed to generate comprehensive estimates of the appropriateness of outpatient antibiotic prescriptions at primary healthcare facilities (PHFs) in China. METHODS: Between 2017 and 2019, we collected outpatient-visit prescriptions from 269 Chinese PHFs in 31 cities located in 6 provinces. Conditions that resulted in antibiotic use were classified into appropriate, potentially appropriate, and inappropriate using a well-established classification approach. We then assessed the magnitude, appropriateness, and costs of antibiotic prescribing, overall and by antibiotic classification group, diagnostic categories, and patient characteristics. RESULTS: Of all eligible 209 662 antibiotic prescriptions, 147 758 (70.5%) were inappropriate, which accounted for 66.8% (558.0/835.3 thousand US dollars) of costs for antibiotics. Upper respiratory tract infections, acute bronchitis, and non-infectious gastroenteritis were responsible for 68.9% (101 744/147 758) of inappropriately antibiotic prescriptions. High inappropriate antibiotic prescribing rates were observed among children aged 0-5 years (78.5% (21 049/26 799)) and patients living in economically undeveloped areas (77.5% (38 430/49 587)). A total of 256 474 individual antibiotics were prescribed, of which 82.2% (210 885/256 474) were broad-spectrum antibiotics, with second-generation cephalosporins (15.1% (38 705/256 474)) and third-generation cephalosporins (14.6% (37 491/256 474)) being the most commonly prescribed subgroups. DISCUSSION: Our findings highlight the excessive and inappropriate use of antibiotics in Chinese PHFs pending multidimensional efforts.

FBXL2 promotes E47 protein instability to inhibit breast cancer stemness and paclitaxel resistance.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high risk of metastasis and recurrence. Although chemotherapy has greatly improved the clinical outcome of TNBC patients, acquired drug resistance remains a huge challenge for TNBC treatment. Breast cancer stem cells (BCSCs) play a critical role in breast cancer development, metastasis, recurrence, and chemotherapy resistance. Thus, it is of great importance to decipher the underlying molecular mechanism of BCSCs regulation for TNBC drug resistance. In this study, we demonstrate that the F-box protein FBXL2 is a critical negative regulator of BCSCs stemness and that downregulation of FBXL2 plays a causal role in TNBC drug resistance. We show that expression levels of FBXL2 significantly influence CD44high/CD24low subpopulation and the mammosphere formation ability of TNBC cells. Ectopic expression of FBXL2 inhibits initiation of TNBC and overcomes paclitaxel resistance in vivo. In addition, activation of FBXL2 by nebivolol, a clinically used small-molecule inhibitor of the beta-1 receptor, markedly overcomes BCSCs-induced paclitaxel resistance. Mechanistically, we show that FBXL2 targets transcriptional factor E47 for polyubiquitin- and proteasome-mediated degradation, resulting in inhibition of BCSC stemness. Clinical analyses indicate that low expression of FBXL2 correlates with high expression of E47 as well as with high stemness features, and is associated with poor clinical outcomes of breast cancer patients. Taken together, these results highlight that the FBXL2-E47 axis plays a critical role in the regulation of BCSC stemness and paclitaxel resistance. Thus, targeting FBXL2 might be a potential therapeutic strategy for drug-resistant TNBC.

Effects of the Full Coverage Policy of Essential Medicines on Inequality in Medication Adherence: A Longitudinal Study in Taizhou, China.

The full coverage policy for essential medicines (FCPEMs) was proposed and implemented in Taizhou city of Zhejiang Province, China, to promote equal access and adherence to medicines. This study aimed to examine the effects of FCPEMs on the income-related inequality in medication adherence among local patients with hypertension or diabetes. We collected electronic health records of patients with hypertension or diabetes of three districts of Taizhou from 2011 to 2016. As the implementation schedule of the FCPEMs varied across districts, we applied a retrospective longitudinal study design and assigned records from 1 year before to 3 years following the implementation of FCPEMs as baseline and follow-up data. We thus generated a dataset with 4-year longitudinal data. The concentration index (CI) and its decomposition method were employed to measure factors contributing to inequality in medication adherence and the role played by FCPEMs. The sample size rose from 264,836 at the baseline to 315,677, 340,512, and 355,676 by each follow-up year, and the proportion of patients taking free medicines rose from 17.6 to 25.0 and 29.8% after FCPEMs implementation. The proportion of patients with high adherence increased from 39.9% at baseline to 51.6, 57.2, and 60.5%, while CI decreased from 0.073 to -0.011, -0.029, and -0.035. The contribution of FCPEMs ranked at 2nd/13, 7th/13, and 2nd/13 after the implementation of FCPEMs. Changes in CI of medication adherence for every 2 years were -0.084, -0.018, and -0.006, and the contribution of FCPEMs was -0.006, 0.006, and 0.007, ranking at 2nd/13, 2nd/13, and 1st/13, respectively. Most changes in CI of medication adherence can be attributed to FCPEMs. The medication adherence of patients with hypertension or diabetes improved after the implementation FCPEMs in Taizhou, although inequality did not improve consistently. In general, FCPEMs could be a protective factor against income-related inequalities in access and adherence to medicines. Future research is needed to investigate the change mechanism and the optimal design of similar interventions.

The Impact of Sanming Healthcare Reform on Antibiotic Appropriate Use in County Hospitals in China.

Background: The excessive use of resources and poor quality of care are great concerns worldwide, particularly in China. In 2013, a model of systematic reforms was developed in Sanming to address the inefficiency and waste in public hospitals. However, limited empirical studies have evaluated the effect of Sanming healthcare reform on antibiotic appropriate use. This study aims to evaluate the impact of the healthcare reform on the appropriate use of antibiotics in county-level public hospitals in Sanming, China. Methods: We conducted a retrospective observational study exploring trends in antibiotic use with an interrupted time series design. We selected three county-level hospitals in Sanming and extracted outpatient prescriptions of the Departments of Internal Medicine and the Department of Pediatrics between January 2011 and December 2017. Acute Upper Respiratory Tract Infection (AURI), Acute Bronchitis (AB) and Community Acquired Pneumonia (CAP) were selected as the sample diseases for our analysis. The primary outcome was the percentage of prescriptions conformed with standard treatment guidelines (STGs). Results: A total of 142,180 prescriptions were included in the analysis. During the study period, the percentage of antibiotics prescriptions conformed with STGs boosted from 32.4% in 2011 to 82.3% in 2017. Moreover, after the reform, the rate of prescriptions that conformed with STGs showed significant increasing trends in children with AURI (ß = 1.624, p < 0.001), children with AB (ß = 3.123, p < 0.001), adult with AB (ß = 1.665, p < 0.001), children with CAP (ß = 3.123, p < 0.001), adult with CAP (ß = 4.385, p < 0.001), but not in adult patients with AURI (ß = -0.360, p = 0.022). Conclusion: Our study confirmed that the Sanming healthcare reform helped to promote the appropriate use of antibiotics in county-level hospitals. This systematic approach to healthcare reform, characterized by an effective governance structure, dynamic financial compensation mechanisms, and specialized drug stewardship, is promising for future public hospital reforms.