Exosomal transfer of activated neutrophil-derived lncRNA CRNDE promotes proliferation and migration of airway smooth muscle cells in asthma.

Activated neutrophil-derived exosomes reportedly contribute to the proliferation of airway smooth muscle cells (ASMCs), thereby aggravating the airway wall remodeling during asthma; however, the specific mechanism remains unclear. Lipopolysaccharide (LPS)-EXO and si-CRNDE-EXO were extracted from the media of human neutrophils treated with LPS and LPS + si-CRNDE (a siRNA targets long non-coding RNA CRNDE), respectively. Human ASMCs were co-cultured with LPS-EXO or si-CRNDE-EXO, and cell viability, proliferation and migration were measured. The interplay of colorectal neoplasia differentially expressed (CRNDE), inhibitor of nuclear factor kappa B kinase subunit beta (IKKß) and nuclear receptor subfamily 2 group C member 2 (TAK1) was explored using RNA immunoprecipitation (RIP) and Co-IP assays. A mouse model of asthma was induced using ovalbumin. CRNDE was upregulated in LPS-EXO and successfully transferred from LPS-treated neutrophils to ASMCs through exosome. Mechanically, CRNDE loaded in LPS-EXO reinforced TAK1-mediated IKKß phosphorylation, thereby activating the nuclear factor kappa B (NF-κB) pathway. Functionally, silencing CRNDE in LPS-EXO, an IKKß inhibitor, and an NF-κB inhibitor all removed the upregulation of cell viability, proliferation and migration induced by LPS-EXO in ASMCs. In the end, the in vivo experiment demonstrated that CRNDE knockdown in neutrophils effectively reduced the thickness of bronchial smooth muscle in a mouse model for asthma. Activated neutrophils-derived CRNDE was transferred to ASMCs through exosomes and activated the NF-κB pathway by enhancing IKKß phosphorylation. The latter promoted the proliferation and migration of ASMCs and then contributed to airway remodeling in asthma.

Identification, expression analysis, and functional verification of three opsin genes related to the phototactic behaviour of Ostrinia furnacalis.

Ostrinia furnacalis is a disreputable herbivorous pest that poses a serious threat to corn crops. Phototaxis in nocturnal moths plays a crucial role in pest prediction and control. Insect opsins are the main component of insect visual system. However, the inherent molecular relationship between phototactic behaviour and vision of insects remains a mystery. Herein, three opsin genes were identified and cloned from O. furnacalis (OfLW, OfBL, and OfUV). Bioinformatics analysis revealed that all opsin genes had visual pigment (opsin) retinal binding sites and seven transmembrane domains. Opsin genes were distributed across different developmental stages and tissues, with the highest expression in adults and compound eyes. The photoperiod-induced assay elucidated that the expression of three opsin genes in females were higher during daytime, while their expression in males tended to increase at night. Under the sustained darkness, the expression of opsin genes increased circularly, although the increasing amplitude in males was lower when compared with females. Furthermore, the expression of OfLW, OfBL, and OfUV was upregulated under green, blue, and ultraviolet light, respectively. The results of RNA interference showed that the knockout of opsin genes decreased the phototaxis efficiency of female and male moths to green, blue, and ultraviolet light. Our results reveal that opsin genes are involved in the phototactic behaviour of moths, providing a potential target gene for pest control and a basis for further investigation on the phototactic behaviour of Lepidoptera insects.

Efficient and Selective Adsorption of cis-Diols via the Suzuki-Miyaura Cross-Coupling-Modified Phenylboronic-Acid Functionalized Covalent Organic Framework.

In this work, a functional group (boronic acid) was modified onto a covalent organic framework (COF) using the Suzuki-Miyaura cross-coupling reaction to obtain a phenylboronic acid-functionalized covalent organic framework (BrCOF-PBA). This product was used as a selective adsorbent and largely as an efficient solid-phase extractant of flavonoids containing cis-diol structures like quercetin (QUE). Five or six-membered cyclic esters generated from the COF were characterized, and some physicochemical studies were performed, resulting in excellent chemical stability and crystallinity, high specific surface area, stable pore structure, and regular pore size. Unique selectivity of BrCOF-PBA was observed toward QUE and exhibited a huge adsorption capacity (213.96 mg g-1) in a relatively short time (90 min). In contrast, the adsorption properties of morin (MOR) and kaempferol (KAE) with a certain degree of chemical similarity to QUE were only 27.62 and 21.76 mg g-1, respectively. BrCOF-PBA also demonstrated good reusability and robustness, making it an attractive composite material for further analytical applicability.

Preventive effects of caffeine on nicotine plus high-fat diet-induced hepatic steatosis and gain weight: a possible explanation for why obese smokers with high coffee consumption tend to be leaner.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder, affecting approximately 25 % of the population. Coffee-drinking obese smokers exhibit lower body weights and decreased NAFLD rates, but the reasons behind this remain unclear. Additionally, the effect of nicotine, the main component of tobacco, on the development of NAFLD is still controversial. Our study aimed to explore the possible reasons that drinking coffee could alleviate NAFLD and gain weight and identify the real role of nicotine in NAFLD of obese smokers. A NAFLD model in mice was induced by administering nicotine and a high-fat diet (HFD). We recorded changes in body weight and daily food intake, measured the weights of the liver and visceral fat, and observed liver and adipose tissue histopathology. Lipid levels, liver function, liver malondialdehyde (MDA), superoxide dismutase (SOD), serum inflammatory cytokine levels and the expression of hepatic genes involved in lipid metabolism were determined. Our results demonstrated that nicotine exacerbated the development of NAFLD and caffeine had a hepatoprotective effect on NAFLD. The administration of caffeine could ameliorate nicotine-plus-HFD-induced NAFLD by reducing lipid accumulation, regulating hepatic lipid metabolism, alleviating oxidative stress, attenuating inflammatory response and restoring hepatic functions. These results might explain why obese smokers with high coffee consumption exhibit the lower incidence rate of NAFLD and tend to be leaner. It is essential to emphasise that the detrimental impact of smoking on health is multifaceted. Smoking cessation remains the sole practical and effective strategy for averting the tobacco-related complications and reducing the risk of mortality.

An evaluation of different dilution modes on circuit lifespan during continuous veno-venous hemodiafiltration without anticoagulation.

BACKGROUND: Circuit clotting remains a major problem during continuous kidney replacement therapy (CKRT), particularly in patients with contraindications to anticoagulant use. We hypothesized that the different options of alternative replacement fluid infusion sites might affect circuit lifespan. However, research-based evidence supporting an optimal replacement fluid infusion strategy is limited. Therefore, we aimed to evaluate the effect of three dilution modes (pre-dilution, post-dilution, and pre- to post-dilution) on circuit lifespan during continuous veno-venous hemodiafiltration (CVVHDF). METHODS: This prospective cohort study was conducted between December 2019 and December 2020. Patients requiring CKRT were enrolled to receive pre-dilution, post-dilution, or pre- to post-dilution fluid infusion with CVVHDF. The primary endpoint was circuit lifespan, and the secondary outcomes included the clinical parameters of patients, such as changes in serum creatinine (Scr) and blood urea nitrogen (BUN) levels, 28-day all-cause mortality, and length of stay. For all patients included in this study, only the first circuit used was recorded. RESULTS: Among the 132 patients enrolled in this study, 40 were in the pre-dilution mode, 42 were in the post-dilution mode, and 50 were in the pre- to post-dilution mode. The mean circuit lifespan was significantly longer in the pre- to post-dilution group (45.72 h, 95% CI, 39.75-51.69 h) than in the pre-dilution group (31.58 h, 95% CI, 26.33-36.82 h) and the post-dilution group (35.20 h, 95% CI, 29.62-40.78 h). There was no significant difference between the pre- and post-dilution group circuit lifespan (p > 0.05). Kaplan-Meier survival analysis revealed a significant difference between the three dilution modes (p = 0.001). No significant differences were observed in terms of changes in the Scr and BUN levels, admission day, and 28-day all-cause mortality among the three dilution groups (p > 0.05). CONCLUSION: The pre- to post-dilution mode significantly prolonged circuit lifespan but did not reduce Scr and BUN levels, compared with the pre-dilution and post-dilution modes during CVVHDF when no anticoagulants were used.

Diagnostic significance of cerebrospinal fluid flow cytometry in Chinese children with B lineage acute lymphoblastic leukemia.

BACKGROUND: Central nervous system leukemia (CNSL) is one of the major causes of the poor prognosis of childhood leukemia. We aimed to compare the sensitivity of cytomorphology (CM) and flow cytometry (FCM) in diagnosing CNSL, emphasizing the importance of FCM in the diagnosis process. METHODS: One-hundred-sixty-five children with newly diagnosed B-cell Acute Lymphoblastic Leukemia (B-cell ALL) were included in this study. Cerebrospinal fluid (CSF) samples were taken for routine CSF analysis, CM analysis, and FCM examination. Computed tomography scans and/or magnetic resonance imaging were performed at diagnosis. Patients with CNS2, CNS3, and traumatic lumbar puncture (TLP) at diagnosis received two additional courses of triple intrathecal injections during induction treatment. We compared the sensitivity of FCM and CM in the diagnosis of children with CNSL. RESULTS: One hundred and twenty-eight (77.58%) CSF samples were negative by either CM or FCM (CM-/FCM-), four (2.42%) were positive by both CM and FCM (CM+/FCM+), and thirty-three (20%) displayed a single positive finding by FCM (CM-/FCM+) (p = 0.044). By adding two intrathecal injections in the induction treatment, ten children with TLP+ had no CNS relapse, like those with TLP-. However, compared to CNS1 and TLP, the event-free survival (EFS) did not significantly improve in patients with CNS2 and CNS3. Moreover, CNSL status was associated with worse 3-year EFS (p < 0.05). CONCLUSIONS: We have validated that FCM is more accurate in stratifying the status of the CNS compared to CM analysis. However, to improve the EFS rate of childhood leukemia, it is necessary to combine CM examination, FCM, and cranial imaging for the early diagnosis of CNSL.

Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy.

SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.

Portable paper-based probe for on-site ratiometric fluorescence determination of total flavonol glycosides in plant extract using smartphone imaging.

A smartphone-assisted, paper-based ratio fluorescence probe is presented for the rapid, low-cost and on-site quantification of total flavonol glycosides in Ginkgo biloba extracts (GBE). The Al3+/Eu-MOF/paper-based probe utilizes lanthanide metal-organic framework (Ln-MOF) nanoparticles immobilized on Whatman filter paper along with Al3+ for detecting flavonols, which are the hydrolyzed products of flavonol glycosides. The color change of the paper-based fluorescence image from red to orange depends on the concentration of the target analyte in the sample solution. The smartphone equipped with a red, green, blue (RGB) color detector measured the fluorescence signal intensity on the paper substrate after adding flavonol. The analytical variables affecting the performance of the probe, including the addition sequence of the aluminum nitrate solution, its concentration, that of the Ln-MOF solution, the drying time of the paper probe, the reaction time and the sensitivity parameters of the mobile phone camera (ISO), were optimized. Under optimal conditions, the Al3+/Eu-MOF/paper-based probe has good linear response in the concentration range 7 ~ 80 µg mL- 1 and a lower detection limit of 2.07 µg mL- 1. The results obtained with the paper-based ratio fluorescence probe and smartphone combination were validated by comparing them with high-performance liquid chromatography (HPLC) measurements. This study provides a potential strategy for fabricating Al3+/Eu-MOF/paper-based probe used for total flavonol glycosides determination.

The transcriptome of Icerya aegyptiaca (Hemiptera: Monophlebidae) and comparison with neococcoids reveal genetic clues of evolution in the scale insects.

BACKGROUND: Scale insects are worldwide sap-sucking parasites, which can be distinguished into neococcoids and non-neococcoids. Neococcoids are monophyletic with a peculiar reproductive system, paternal genome elimination (PGE). Different with neococcoids, Iceryini, a tribe in non-neococcoids including several damaging pests, has abdominal spiracles, compound eyes in males, relatively abundant wax, unique hermaphrodite system, and specific symbionts. However, the current studies on the gene resources and genomic mechanism of scale insects are mainly limited in the neococcoids, and lacked of comparison in an evolution frame. RESULT: We sequenced and de novo assembled a transcriptome of Icerya aegyptiaca (Douglas), a worldwide pest of Iceryini, and used it as representative of non-neococcoids to compare with the genomes or transcriptomes of other six species from different families of neococcoids. We found that the genes under positive selection or negative selection intensification (simplified as "selected genes" below) in I. aegyptiaca included those related to neurogenesis and development, especially eye development. Some genes related to fatty acid biosynthesis were unique in its transcriptome with relatively high expression and not detected in neococcoids. These results may indicate a potential link to the unique structures and abundant wax of I. aegyptiaca compared with neococcoids. Meanwhile, genes related to DNA repair, mitosis, spindle, cytokinesis and oogenesis, were included in the selected genes in I. aegyptiaca, which is possibly associated with cell division and germ cell formation of the hermaphrodite system. Chromatin-related process were enriched from selected genes in neococcoids, along with some mitosis-related genes also detected, which may be related to their unique PGE system. Moreover, in neococcoid species, male-biased genes tend to undergo negative selection relaxation under the PGE system. We also found that the candidate horizontally transferred genes (HTGs) in the scale insects mainly derived from bacteria and fungi. bioD and bioB, the two biotin-synthesizing HTGs were exclusively found in the scale insects and neococcoids, respectively, which possibly show potential demand changes in the symbiotic relationships. CONCLUSION: Our study reports the first I. aegyptiaca transcriptome and provides preliminary insights for the genetic change of structures, reproductive systems and symbiont relationships at an evolutionary aspect. This will provide a basis for further research and control of scale insects.

Whole exome sequencing with a focus on cardiac disease-associated genes in families of sudden unexplained deaths in Yunnan, southwest of China.

OBJECTIVES: To explore the causes of sudden unexpected death (SUD) and to search for high-risk people, whole exome sequencing (WES) was performed in families with SUDs.  METHODS: Whole exome sequencing of 25 people from 14 SUD families were screened based on cardiac disease-associated gene variants, and their echocardiograms and electrocardiograms (ECG) were also examined. The protein function of mutated genes was predicted by SIFT, PolyPhen2 and Mutation Assessor. RESULTS: In the group of 25 people from 14 SUD families, 49 single nucleotide variants (SNVs) of cardiac disease-associated genes were found and verified by Sanger sequencing. 29 SNVs of 14 cardiac disorder-related genes were predicted as pathogens by software. Among them, 7 SNVs carried by two or more members were found in 5 families, including SCN5A (c.3577C > T), IRX4 (c.230A > G), LDB3 (c.2104 T > G), MYH6 (c.3G > A), MYH6 (c.3928 T > C), TTN (c.80987C > T) and TTN (c.8069C > T). 25 ECGs were collected. In summary, 4 people had J-point elevation, 2 people had long QT syndrome (LQTS), 4 people had prolonged QT interval, 3 people had T-wave changes, 3 people had sinus tachycardia, 4 people had sinus bradycardia, 4 people had left side of QRS electrical axis, and 3 people had P wave broadening. Echocardiographic results showed that 1 person had atrial septal defect, 1 person had tricuspid regurgitation, and 2 people had left ventricular diastolic dysfunction. CONCLUSIONS: Of the 14 heart disease-associated genes in 14 SUDs families, there are 7 possible pathological SNVS may be associated with SUDs. Our results indicate that people with ECG abnormalities, such as prolonged QT interval, ST segment changes, T-wave change and carrying the above 7 SNVs, should be the focus of prevention of sudden death.

Application of real-time PCR-based multicolor melting curve with automatic analysis system in pregestational and prenatal thalassemia diagnoses.

BACKGROUND: To evaluate the value of the real-time PCR-based multicolor melting curve analysis (MMCA) with an automatic analysis system used in a mass thalassemia screening and prenatal diagnosis program. METHODS: A total of 18,912 peripheral blood samples from 9456 couples and 1150 prenatal samples were detected by MMCA assay. All prenatal samples were also tested by a conventional method. Samples with unknown melting peaks, unusual peak height ratios between a wild allele and a mutant allele, or a discordant phenotype-genotype match were further studied by using multiplex ligation-dependent probe amplification (MLPA) or Sanger sequencing. All MMCA results were automatically analyzed and manually checked. The consistency between MMCA assay and conventional methods among prenatal samples was investigated. RESULTS: Except for initiation codon (T > G) (HBB:c.2T > G), all genotypes of thalassemia inside the scope of conventional methods were detected by MMCA assay. Additionally, 27 carriers with 10 rare HBB variants, 13 with α fusion gene, 1 with a rare deletion in α globin gene, and 1 with rare HBA variant were detected by using MMCA assay. CONCLUSION: MMCA can be an alternative approach used in routine thalassemia carrier screening and prenatal diagnosis for its high throughput, sufficient stability, low cost, and easy operation.

A Cohort Study on Deficiency of ADA2 from China.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.

A highly sensitive sensor for carcinoembryonic antigen based on AlGaN/GaN high-electron-mobility transistors.

Carcinoembryonic antigen (CEA) is a well-known biomarker and validated serum biomarker for lung cancer. We introduce a simple label-free method for CEA detection. Specific recognition of CEA was made possible by immobilizing CEA antibodies in the sensing region of AlGaN/GaN high-electron-mobility transistors. The biosensors have a detection limit of 1 fg ml-1in phosphate buffer solution. This approach has advantages of integration, miniaturization, low cost, and rapid detection compared to other testing methods for lung cancer and could be used in future medical diagnostics.

Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy.

Heart aging is characterized by left ventricular hypertrophy and diastolic dysfunction, which in turn induces a variety of cardiovascular diseases. There is still no therapeutic drug to ameliorate cardiac abnormities in heart aging. In this study we investigated the protective effects of berberine (BBR) and its derivative tetrahydroberberrubine (THBru) against heart aging process. Heart aging was induced in mice by injection of D-galactose (D-gal, 120 mg · kg-1 · d-1, sc.) for 12 weeks. Meanwhile the mice were orally treated with berberine (50 mg · kg-1 · d-1) or THBru (25, 50 mg · kg-1 · d-1) for 12 weeks. We showed that BBR and THBru treatment significantly mitigated diastolic dysfunction and cardiac remodeling in D-gal-induced aging mice. Furthermore, treatment with BBR (40 µM) and THBru (20, 40 µM) inhibited D-gal-induced senescence in primary neonatal mouse cardiomyocytes in vitro. Overall, THBru exhibited higher efficacy than BBR at the same dose. We found that the levels of mitophagy were significantly decreased during the aging process in vivo and in vitro, THBru and BBR promoted mitophagy with different potencies. We demonstrated that the mitophagy-inducing effects of THBru resulted from increased mRNA stability of prohibitin 2 (PHB2), a pivotal factor during mitophagy, thereby upregulating PHB2 protein expression. Knockdown of PHB2 effectively reversed the antisenescence effects of THBru in D-gal-treated cardiomyocytes. On the contrary, overexpression of PHB2 promoted mitophagy and retarded cardiomyocyte senescence, as THBru did. In conclusion, this study identifies THBru as a potent antiaging medicine that induces PHB2-mediated mitophagy and suggests its clinical application prospects.

Regional distribution and migration potential of antibiotic resistance genes in croplands of Qinghai Tibet Plateau.

Agricultural activities have recently disturbed the ecosystem of the Qinghai-Tibet Plateau and the shift of antibiotic resistance genes (ARGs) in the different types of farmlands is not well understood, so more comprehensive ecological barrier management measures cannot be provided for the region. This research was performed to exploring ARG pollution in cropland soil on the Qinghai-Tibet Plateau to obtain information on the geographical and climatic factors shaping the ARG distribution. Based on high-throughput quantitative PCR (HT-qPCR) analysis, the ARG abundance in farmland ranged from 5.66 × 105 to 6.22 × 107 copies per gram of soil higher than previous research at soil and wetland in Qinghai-Tibet plateau, and it was higher in wheat and barley soils than in corn soil. The distribution of ARGs exhibited regional features as ARG abundance was adversely affected by mean annual precipitation and temperature with lower temperature and less rainfall at high altitude. According to network analysis and structural equation modeling (SEM), mobile genetic elements (MGEs) and heavy metals are the key drivers of ARG dissemination on the Qinghai-Tibet Plateau as they show negative relationship with ARGs, and selection copressure from heavy metals in cropland soil increases the horizontal gene transfer (HGT) potential of ARGs through synergistic selection effects, each contribution to the ARGs was 19% and 29% respectively. This research suggests the need to focus on controlling heavy metals and MGEs to constrain the dissemination of ARGs, as arable soil is already slightly contaminated by heavy metals.

Variations in the impact of the new case-based payment reform on medical costs, length of stay, and quality across different hospitals in China: an interrupted time series analysis.

BACKGROUND: In 2018, an innovative case-based payment scheme called Diagnosis-Intervention Packet (DIP) was piloted in a large developed city in southern China. This study aimed to investigate the impact of the new payment method on total medical expenditure per case, length of stay (LOS), and in-hospital mortality rate across different hospitals. METHODS: We used the de-identified patient-level discharge data of hospitalized patients from 2016 to 2019 in our study city. The interrupted time series model was used to examine the impact of the DIP payment reform on inflation-adjusted total expenditure per case, LOS, and in-hospital mortality rate across different hospitals, which were stratified into different hospital ownerships (public and private) and hospital levels (tertiary, secondary, and primary). RESULTS: We included 2.08 million and 2.98 million discharge cases of insured patients before and after the DIP payment reform, respectively. The DIP payment reform resulted in a significant increase of the monthly trend of adjusted total expenditure per case in public (1.1%, P = 0.000), tertiary (0.6%, P = 0.000), secondary (0.4%, P = 0.047) and primary hospitals (0.9%, P = 0.039). The monthly trend of LOS increased significantly in public (0.022 days, P = 0.041) and primary (0.235 days, P = 0.032) hospitals. The monthly trend of in-hospital mortality rate decreased significantly in private (0.083 percentage points, P = 0.002) and secondary (0.037 percentage points, P = 0.002) hospitals. CONCLUSIONS: We conclude that implementing the DIP payment reform yields inconsistent consequences across different hospitals. DIP reform encouraged public hospitals and high-level hospitals to treat patients with higher illness severities and requiring high treatment intensity, resulting in a significant increase in total expenditure per case. The inconsistencies between public and private hospitals may be attributed to their different baseline levels prior to the reform and their different responses to the incentives created by the reform.

How do inpatients' costs, length of stay, and quality of care vary across age groups after a new case-based payment reform in China? An interrupted time series analysis.

CONTEXT: A patient classification-based payment system called diagnosis-intervention packet (DIP) was piloted in a large city in southeast China in 2018. OBJECTIVE: This study evaluates the impact of DIP payment reform on total costs, out-of-pocket (OOP) payments, length of stay (LOS), and quality of care in hospitalised patients of different age. METHODS: An interrupted time series model was employed to examine the monthly trend changes of outcome variables before and after the DIP reform in adult patients, who were stratified into a younger (18-64 years) and an older group (≥ 65 years), further stratified into young-old (65-79 years) and oldest-old (≥ 80 years) groups. RESULTS: The adjusted monthly trend of costs per case significantly increased in the older adults (0.5%, P = 0.002) and oldest-old group (0.6%, P = 0.015). The adjusted monthly trend of average LOS decreased in the younger and young-old groups (monthly slope change: -0.058 days, P = 0.035; -0.025 days, P = 0.024, respectively), and increased in the oldest-old group (monthly slope change: 0.107 days, P = 0.030) significantly. The changes of adjusted monthly trends of in-hospital mortality rate were not significant in all age groups. CONCLUSION: Implementation of the DIP payment reform associated with increase in total costs per case in the older and oldest-old groups, and reduction in LOS in the younger and young-old groups without deteriorating quality of care.

[Manufacturing classification system for oral solid dosage forms of traditional Chinese medicines (â ¡): classification of tablets disintegration behavior].

In this paper, 50 batches of representative traditional Chinese medicine tablets were selected and the disintegration time was examined with the method in Chinese Pharmacopoeia. The disintegration time and disintegration phenomenon were recorded, and the dissolution behaviors of water-soluble and ultraviolet-absorbent components during the disintegration process of tablets were characterized by self-control method. The results revealed that coating type and raw material type influenced the disintegration time of tablets. It was found that only 4% of traditional Chinese medicine tablets had obvious fragmentation during the disintegration process, while 96% of traditional Chinese medicine tablets showed gradual dissolution or dispersion. Furthermore, according to the disintegration speed, disintegration phenomenon, and whether the cumulative dissolution of measured components was > 90% at complete disintegration, a disintegration behavior classification system(DBCS) was created for the regular-release traditional Chinese medicine tablets. As a result, the disintegration behaviors of 50 batches of traditional Chinese medicine tablets were classified into four categories, i.e. ⅠA_2, ⅠB_1, ⅡB_1, and ⅡB_2. traditional Chinese medicine tablets(Class I) with disintegration time ≤ 30 min were defined to be rapid in disintegration, which can be the objective of optimization or improvement of Chinese herbal extract(semi extract) tablets. Different drug release models were used to fit the dissolution curve of traditional Chinese medicine tablets with gradual dissolution or dispersion phenomenon(i.e. Type B tablets). The results showed that the dissolution curves of water-soluble components in the disintegration process conformed to the zero order kinetics and the Ritger-Peppas model. It could be inferred that the disintegration mechanisms of type B tablets were a combination of dissolution controlled and swelling controlled mechanisms. This study contributes to understanding the disintegration behavior of traditional Chinese medicine tablets, and provides a reference for the design and improvement of disintegration performance of traditional Chinese medicine tablets.

[Patent application of intelligent quality control technology in traditional Chinese medicine production process: a review].

In the new stage for intelligent manufacturing of traditional Chinese medicine(TCM) from pilot demonstration to in-depth application and comprehensive promotion, how to raise the degree of intelligence for the process quality control system has become the bottleneck of the development of TCM production process control technology. This article has sorted out 226 TCM intelligent manufacturing projects that have been approved by the national and provincial governments since the implementation of the "Made in China 2025" plan and 145 related pharmaceutical enterprises. Then, the patents applied by these pharmaceutical enterprises were thoroughly retrieved, and 135 patents in terms of intelligent quality control technology in the production process were found. The technical details about intelligent quality control at both the unit levels such as cultivation, processing of crude herbs, preparation pretreatment, pharmaceutical preparations, and the production workshop level were reviewed from three aspects, i.e., intelligent quality sensing, intelligent process cognition, and intelligent process control. The results showed that intelligent quality control technologies have been preliminarily applied to the whole process of TCM production. The intelligence control of the extraction and concentration processes and the intelligent sensing of critical quality attributes are currently the focus of pharmaceutical enterprises. However, there is a lack of process cognitive patent technology for the TCM manufacturing process, which fails to meet the requirements of closed-loop integration of intelligent sensing and intelligent control technologies. It is suggested that in the future, with the help of artificial intelligence and machine learning methods, the process cognitive bottleneck of TCM production can be overcome, and the holistic quality formation mechanisms of TCM products can be elucidated. Moreover, key technologies for system integration and intelligent equipment are expected to be innovated and accelerated to enhance the quality uniformity and manufacturing reliability of TCM.

[Discrete element simulation study of mixing process of Guizhi Fuling Capsules: parameter calibration].

The mixing process is a critical link in the formation of oral solid preparations of traditional Chinese medicine. This paper took the extract powder of Guizhi Fuling Capsules and Paeonol powder as research objects. The angle of repose, loose packing density, and particle size of the two powders were measured to calibrate discrete element simulation parameters for the mixing process. The discrete element method was used to calibrate the simulated solid density of Paeonol powder and extract powder of Guizhi Fuling Capsules based on the Hertz-Mindlin with JKR V2 contact model and particle scaling. The Plackett-Burman experimental design was used to screen out the critical contact parameters that had a significant effect on the simulation of the angle of repose. The regression model between the critical contact parameters and the simulated angle of repose was established by the Box-Behnken experimental design, and the critical contact parameters of each powder were optimized based on the regression model. The best combination of critical contact parameters of the extract powder of Guizhi Fuling Capsules was found to be 0.51 for particle-particle static friction coefficient, 0.31 for particle-particle rolling friction coefficient, and 0.64 for particle-stainless steel static friction coefficient. For Paeonol powder, the best combination of critical contact parameters was 0.4 for particle-particle static friction coefficient and 0.19 for particle-particle rolling friction coefficient. The best combination of contact parameters between Paeonol powder and extract powder of Guizhi Fuling Capsules was 0.27 for collision recovery coefficient, 0.49 for static friction coefficient, and 0.38 for rolling friction coefficient. The verification results show that the relative error between the simulated value and the measured value of the angle of repose of the two single powders is less than 1%, while the relative error between the simulated value and the measured value of the angle of repose of the mixed powder with a mass ratio of 1∶1 is less than 4%. These research results provide reliable physical property simulation data for the mixed simulation experiment of extract powder of Guizhi Fuling Capsules and Paeonol powder.