What, Where, and How to Collect Real-World Data and Generate Real-World Evidence to Support Drug Reimbursement Decision-Making in Asia: A reflection Into the Past and A Way Forward.

BACKGROUND: Globally, there is increasing interest in the use of real-world data (RWD) and real-world evidence (RWE) to inform health technology assessment (HTA) and reimbursement decision-making. Using current practices and case studies shared by eleven health systems in Asia, a non-binding guidance that seeks to align practices for generating and using RWD/RWE for decision-making in Asia was developed by the REAL World Data In ASia for HEalth Technology Assessment in Reimbursement (REALISE) Working Group, addressing a current gap and needs among HTA users and generators. METHODS: The guidance document was developed over two face-to-face workshops, in addition to an online survey, a face-to-face interview and pragmatic search of literature. The specific focus was on what, where and how to collect RWD/ RWE. RESULTS: All 11 REALISE member jurisdictions participated in the online survey and the first in-person workshop, 10 participated in the second in-person workshop, and 8 participated in the in-depth face-to-face interviews. The guidance document was iteratively reviewed by all working group members and the International Advisory Panel. There was substantial variation in: (a) sources and types of RWD being used in HTA, and (b) the relative importance and prioritization of RWE being used for policy-making. A list of national-level databases and other sources of RWD available in each country was compiled. A list of useful guidance on data collection, quality assurance and study design were also compiled. CONCLUSION: The REALISE guidance document serves to align the collection of better quality RWD and generation of reliable RWE to ultimately inform HTA in Asia.

[Arsenic speciation and valence].

As arsenic widely exists in nature and has been used in the pharmaceutical preparations, the traditional Chinese medicine(TCM) with arsenic include realgar(As_2S_2 or As_4S_4), orpiment(As_2S_3), and white arsenic(As_2O_3). Among the above representative medicine, the TCM compound formulas with realgar are utilized extensively. Just in Chinese Pharmacopoeia(2020 edition), there are 37 Chinese patent medicines including realgar. The traditional element analysis focuses on the detection of the total amount of elements, which neglects the study on the speciation and valence of elements. The activity, toxicity, bioavailability, and metabolic pathways of arsenic in vivo are closely related to the existence of its form, and different forms of arsenic have different effects on organisms. Therefore, the study on the speciation and valence of arsenic is of great importance for arsenic-containing TCMs and their compound formulas. This paper reviewed four aspects of the speciation and valence of arsenic, including property, absorption and metabolism, toxicity, and analytical assay.

[Monoterpenoids from Paeoniae Radix Rubra based on UPLC-Q-TOF-MS].

The ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was used to conduct the qualitative analysis of the monoterpene chemical components from Paeoniae Radix Rubra. Gradient elution was performed on C_(18) HD(2.1 mm×100 mm, 2.5 µm) column with a mobile phase of 0.1% formic acid(A) and acetonitrile(B). The flow rate was 0.4 mL·min~(-1) and the column temperature was 30 ℃. MS analysis was conducted in both positive and negative ionization modes using electrospray ionization(ESI) source. Qualitative Analysis 10.0 was used for data processing. The identification of chemical components was realized by the combination of standard compounds, fragmentation patterns, and mass spectra data reported in the literature. Forty-one monoterpenoids in Paeoniae Radix Rubra extract were identified. Among them, 8 compounds were reported in Paeoniae Radix Rubra for the first time and 1 was presumed to be the new compound 5″-O-methyl-galloylpaeoniflorin or its positional isomer. The method in this study realizes the rapid identification of monoterpenoids from Paeoniae Radix Rubra and provides a material and scientific basis for quality control and further study on the pharmaceutical effect of Paeoniae Radix Rubra.

[Investigation of the chemical components of Ciwujia injection using ultra-high performance liquid chromatography-quadrupole-electrostatic field orbitrap high-resolution mass spectrometry].

Ciwujia injection is commonly used to treat cerebrovascular and central nervous system diseases in clinical practice. It can significantly improve blood lipid levels and endothelial cell function in patients with acute cerebral infarction and promote the proliferation of neural stem cells in cerebral ischemic brain tissues. The injection has also been reported to have good curative effects on cerebrovascular diseases, such as hypertension and cerebral infarction. At present, the material basis of Ciwujia injection remains incompletely understood, and only two studies have reported dozens of components, which were determined using high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF MS). Unfortunately, the lack of research on this injection restricts the in-depth study of its therapeutic mechanism.In the present study, a qualitative method based on ultra-high performance liquid chromatography-quadrupole-electrostatic field orbitrap high-resolution mass spectrometry (UHPLC-Q/Orbitrap HRMS) was developed to analyze the chemical components of Ciwujia injection. Separation was performed on a BEH Shield RP18 column (100 mm×2.1 mm, 1.7 µm) using 0.1% formic acid aqueous solution (A) and acetonitrile (B) as the mobile phases, and gradient elution was performed as follows: 0-2 min, 0%B; 2-4 min, 0%B-5%B; 4-15 min, 5%B-20%B; 15-15.1 min, 20%B-90%B; 15.1-17 min, 90%B. The flow rate and column temperature were set to 0.4 mL/min and 30 ℃ respectively. MS1 and MS2 data were acquired in both positive- and negative-ion modes using a mass spectrometer equipped with an HESI source. For data post-processing, a self-built library including component names, molecular formulas, and chemical structures was established by collecting information on the isolated chemical compounds of Acanthopanax senticosus. The chemical components of the injection were identified by comparison with standard compounds or MS2 data in commercial databases or literature based on precise relative molecular mass and fragment ion information. The fragmentation patterns were also considered. For example, the MS2 data of 3-caffeoylquinic acid (chlorogenic acid), 4-caffeoylquinic acid (cryptochlorogenic acid), and 5-caffeoylquinic acid (neochlorogenic acid) were first analyzed. The results indicated that these compounds possessed similar fragmentation behaviors, yielding product ions at m/z 173 and m/z 179 simultaneously. However, the abundance of the product ion at m/z 173 was much higher in 4-caffeoylquinic acid than in 5-caffeoylquinic acid or 3-caffeoylquinic acid, and the fragment signal at m/z 179 was much stronger for 5-caffeoylquinic acid than for 3-caffeoylquinic acid. Four caffeoylquinic acids were identified using a combination of abundance information and retention times. MS2 data in commercial database and literature were also used to identify unknown constituents. For example, compound 88 was successfully identified as possessing a relative molecular mass and neutral losses similar to those of sinapaldehyde using the database, and compound 80 was identified as salvadoraside because its molecular and fragmentation behaviors were consistent with those reported in the literature. A total of 102 constituents, including 62 phenylpropanoids, 23 organic acids, 7 nucleosides, 1 iridoid, and 9 other compounds, were identified. The phenylpropanoids can be further classified as phenylpropionic acids, phenylpropanols, benzenepropanals, coumarins, and lignans. Among the detected compounds, 16 compounds were confirmed using reference compounds and 65 compounds were identified in Ciwujia injection for the first time. This study is the first to report the feasibility of using the UHPLC-Q/Orbitrap HRMS method to quickly and comprehensively analyze the chemical components of Ciwujia injection. The 27 newly discovered phenylpropanoids provide further material basis for the clinical treatment of neurological diseases and new research targets for the in-depth elucidation of the pharmacodynamic mechanism of Ciwujia injection and its related preparations.

New Insights into the Role of Oral Microbiota Dysbiosis in the Pathogenesis of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a group of chronic intestinal inflammatory disorders with a prolonged duration characterized by recurrent relapse and remission. The exact etiology of IBD remains poorly understood despite the identification of relevant risk factors, including individual genetic susceptibility, environmental triggers, and disruption of immune homeostasis. Dysbiosis of the gut microbiota is believed to exacerbate the progression of IBD. Recently, increasing evidence has also linked oral microbiota dysbiosis with the development of IBD. On the one hand, IBD patients show significantly unbalanced composition and function of the oral microbiota known as dysbiosis. On the other, overabundances of oral commensal bacteria with opportunistic pathogenicity have been found in the gut microbiota of IBD patients. Herein, we review the current information on the causative factors of IBD, especially recent evidence of IBD-associated oral microbiota dysbiosis, which has seldom been covered in the previous literature review, highlighting the pathogenic mechanisms of specific oral bacteria in the development of IBD. Ectopic colonization of several oral bacteria, including a subset of Porphyromonas gingivalis, Streptococcus mutans, Fusobacterium nucleatum, Campylobacter concisus, and Klebsiella pneumoniae, may lead to destruction of the intestinal epithelial barrier, excessive secretion of inflammatory cytokines, disruption of the host immune system, and dysbiosis of gut microbiota, consequently aggravating chronic intestinal inflammation. Studying oral microbiota dysbiosis may open future horizons for understanding IBD pathogenesis and provide novel biomarkers for IBD. This review also presents the current treatment and new perspectives for IBD treatment.

Latent profile analysis of self-perceptions of ageing among Chinese community-dwelling older adults.

BACKGROUND: Self-perceptions of ageing (SPA) is an important predictor for physical and mental health of older adults in successful ageing. SPA is mainly studied from negative or positive perspectives using variable-centred methodologies. The aim of the current study was to explore distinct profiles of SPA among Chinese community-dwelling older adults using a person-centred method and validate the SPA profiles by examining associations with psychological outcomes. METHODS: Participants aged 65 and over were randomly divided into test and validation samples (n = 451, respectively). SPA was measured by the Brief Ageing Perceptions Questionnaire using latent profile analysis. RESULTS: Three SPA profiles were identified. One adaptive subgroup was designated as 'Low ageing awareness and high positive control' (LAPC, 84.7% and 75% in both samples, respectively). Two maladaptive SPA subgroups were designated as 'Low positive consequences and control' (LPCC, 3.9% and 8.2% in both samples, respectively), and 'High ageing awareness and negative control' (HANC, 11.4% and 16.8% in both samples, respectively). Similar to negative/positive SPA, the HANC and LAPC subgroups showed the highest and lowest levels of depressive symptoms and cognitive decline. Low cognitive function was found in the LPCC subgroup. CONCLUSIONS: These findings highlight the heterogeneity of older adults' SPA. SPA profiles may aid community healthcare providers in China to identify individuals with high risk of maladaptive SPA and to tailor targeted interventions for psychological health in later life. Distinct SPA profiles require different interventions targeting negative or positive control or both aspects. More positive control strategies might be beneficial for cognitive functioning in older adults from the LPCC subgroup.

UPLC-MS/MS method for the determination of the herb composition of Tangshen formula and the in vivo pharmacokinetics of its metabolites in rat plasma.

INTRODUCTION: Tangshen formula (TSF) is a traditional Chinese medicine composed of seven medicinal herbs including Astragalus membranaceus, Rehmannia glutinosa Libosch, Citrus aurantium L., etc. which is used to treat diabetic nephropathy III, IV qi and yin deficiency and stasis syndrome. Most of the studies on TSF are pharmacological and pharmacodynamic experiments. There are few basic studies on its chemical substances, and the effective constituents are not clear. OBJECTIVE: To analyse the main chemical components of TSF and the absorbed components in rat plasma following oral administration based on liquid chromatography tandem mass spectrometry (LC-MS/MS). Moreover, providing a rapid and valid analytical strategy for simultaneous determination of six components in rat plasma and use it in pharmacokinetic studies. RESULTS: A total of 132 components were identified in TSF, and 44 components were identified in rat plasma after oral TSF, 35 of which were prototype components and nine were metabolic components. A sensitive and reliable LC-MS/MS method was developed for simultaneous determination of six components in rat plasma. The intra-day and inter-day precision relative standard deviation (RSD) was lower than 15%; the accuracy of low, medium and high concentrations ranged from 80% to 120%. The recovery met the requirements and the RSD of the recoveries was less than 15%. CONCLUSION: A total of 132 components were identified in TSF. The LC-MS/MS quantitative method for the simultaneous determination of morroniside, loganin, notoginsenoside R1 , ginsenoside Re, ginsenoside Rb1 and astragaloside IV in rat plasma was established for the first time. The pharmacokinetic parameters are clarified, which can guide the clinical medication of TSF.

Synergistic Cu/Pd-catalyzed asymmetric allylation: a facile access to α-quaternary cysteine derivatives.

An efficient synthetic methodology to access biologically important and synthetically useful α-quaternary cysteine derivatives via asymmetric catalytic α-allylation of readily available 2-thiazoline-4-carboxylates was successfully developed through a synergistic Cu/Pd catalytic system. A wide array of α-quaternary cysteine derivatives were obtained in moderate to high yields with good to excellent enantioselectivities (45-98% yields and 69->99% ee). Gram-scale asymmetric allylation was performed to obtain high yields maintaining the enantioselectivity. Moreover, some synthetic transformations to access chiral spirocyclic compounds proceeded smoothly, which exhibited the important utility of this methodology.

The micro-volume liquid focusing effect in Janus membrane and its biosensing application.

The micro-volume analysis and specific detection are both essential requirements in the field of chemical sensing and biological testing. Membrane prefiltration can be used to improve the selectivity and accuracy of detection. But for traditional porous membrane filtration, it is difficult to achieve the transmembrane transport of micro-volume liquid due to the influence of lateral diffusion on membrane surface. Herein, we studied the focused transmembrane transport of micro-volume liquid in the porous polyethersulfone membrane with asymmetric (Janus) surface wettability. The hydrophilic layer (polydopamine) and hydrophobic layer (fluoropolymer) were deposited with controllable thickness by dip-coating and roller-assisted liquid printing. The micro-volume liquid focusing effect was verified by experiments such as visual wetting circle and fluorescent tracer. The liquid focusing effect of as-prepared Janus membrane was integrated with glucose test strip in the application of micro-volume liquid biosensing. Compared with conventional porous membrane, detected signal amplitude and response time were improved 7.5× and 2.7×, respectively. In summary, this research studied the dynamics of liquid transport through Janus membrane and provides a new strategy for microfluidic detection applications through balancing detection volume, time and selectivity by the advantage of micro-volume liquid focusing effect.

Evaluation of controlled attenuation parameter in assessing hepatic steatosis in patients with autoimmune liver diseases.

BACKGROUND: Hepatic steatosis commonly occurs in some chronic liver diseases and may affect disease progression. AIM: To investigate the performance of controlled attenuation parameter (CAP) for the diagnosis of hepatic steatosis in patients with autoimmune liver diseases (AILDs). METHODS: Patients who were suspected of having AILDs and underwent liver biopsy were consistently enrolled. Liver stiffness measurement (LSM) and CAP were performed by transient elastography. The area under the receiver operating characteristic (AUROC) curve was used to evaluate the performance of CAP for diagnosing hepatic steatosis compared with biopsy. RESULTS: Among 190 patients with biopsy-proven hepatic steatosis, 69 were diagnosed with autoimmune hepatitis (AIH), 18 with primary biliary cholangitis (PBC), and 27 with AIH-PBC overlap syndrome. The AUROCs of CAP for the diagnosis of steatosis in AILDS were 0.878 (0.791-0.965) for S1, 0.764 (0.676-0.853) for S2, and 0.821 (0.716-0.926) for S3. The CAP value was significantly related to hepatic steatosis grade (P < 0.001). Among 69 patients with AIH, the median CAP score was 205.63 ± 47.36 dB/m for S0, 258.41 ± 42.83 dB/m for S1, 293.00 ± 37.18 dB/m for S2, and 313.60 ± 27.89 dB/m for S3. Compared with patients with nonalcoholic fatty liver disease (NAFLD) presenting with autoimmune markers, patients with AIH concomitant with NAFLD were much older and had higher serum IgG levels and LSM values. CONCLUSION: CAP can be used as a noninvasive diagnostic method to evaluate hepatic steatosis in patients with AILDs. Determination of LSM combined with CAP may help to identify patients with AIH concomitant with NAFLD from those with NAFLD with autoimmune phenomena.

High-throughput sequencing provides insights into oral microbiota dysbiosis in association with inflammatory bowel disease.

Although the prevalence of inflammatory bowel disease (IBD) has been increasing worldwide, the etiology remains elusive. Investigating oral microbiota dysbiosis is essential to understanding IBD pathogenesis. Our study evaluated variations in salivary microbiota and identified potential associations with IBD. The saliva microbiota of 22 IBD patients and 8 healthy controls (HCs) was determined using 16S ribosomal RNA (rRNA) gene sequencing and analyzed using QIIME2. A distinct saliva microbiota dysbiosis in IBD, characterized by alterations in microbiota biodiversity and composition, was identified. Saccharibacteria (TM7), Absconditabacteria (SR1), Leptotrichia, Prevotella, Bulleidia, and Atopobium, some of which are oral biofilm-forming bacteria, were significantly increased. Moreover, levels of inflammatory cytokines associated with IBD were elevated and positively correlated with TM7 and SR1. Functional variations include down-regulation of genetic information processing, while up-regulation of carbohydrate metabolism and protein processing in the endoplasmic reticulum in IBD. Our data implicate salivary microbiota dysbiosis involving in IBD pathogenesis.

Real-world data for health technology assessment for reimbursement decisions in Asia: current landscape and a way forward.

There is growing interest globally in using real-world data (RWD) and real-world evidence (RWE) for health technology assessment (HTA). Optimal collection, analysis, and use of RWD/RWE to inform HTA requires a conceptual framework to standardize processes and ensure consistency. However, such framework is currently lacking in Asia, a region that is likely to benefit from RWD/RWE for at least two reasons. First, there is often limited Asian representation in clinical trials unless specifically conducted in Asian populations, and RWD may help to fill the evidence gap. Second, in a few Asian health systems, reimbursement decisions are not made at market entry; thus, allowing RWD/RWE to be collected to give more certainty about the effectiveness of technologies in the local setting and inform their appropriate use. Furthermore, an alignment of RWD/RWE policies across Asia would equip decision makers with context-relevant evidence, and improve timely patient access to new technologies. Using data collected from eleven health systems in Asia, this paper provides a review of the current landscape of RWD/RWE in Asia to inform HTA and explores a way forward to align policies within the region. This paper concludes with a proposal to establish an international collaboration among academics and HTA agencies in the region: the REAL World Data In ASia for HEalth Technology Assessment in Reimbursement (REALISE) working group, which seeks to develop a non-binding guidance document on the use of RWD/RWE to inform HTA for decision making in Asia.

Stereodivergent Synthesis of α-Quaternary Serine and Cysteine Derivatives Containing Two Contiguous Stereogenic Centers via Synergistic Cu/Ir Catalysis.

A stereodivergent preparation of α-quaternary serine/cysteine derivatives incorporating two adjacent stereogenic centers has been developed through Cu/Ir-catalyzed asymmetric allylation of 2-oxazoline-4-carboxylates and 2-thiazoline-4-carboxylates. Tuning the electronic effect is the key to enhancing the reactivity of 2-oxazoline-4-carboxylates and suppressing the undesired ß-elimination. The salient feature of this protocol is that all four stereoisomers of α-quaternary serine and cysteine derivatives could be achieved from the identical starting materials through pairwise combination of two distinct chiral catalysts.

Regulation of lipid-induced macrophage polarization through modulating peroxisome proliferator-activated receptor-gamma activity affects hepatic lipid metabolism via a Toll-like receptor 4/NF-κB signaling pathway.

BACKGROUND AND AIM: Chronic inflammation links closely to insulin resistance and lipid metabolism in nonalcoholic fatty liver disease (NAFLD). Macrophage M1 activation plays an important role in the initiation and continuing of pro-inflammatory response of NAFLD. Our study was to investigate whether macrophage M1/M2 polarization switching would affect hepatic inflammation and lipid metabolism through modulation of peroxisome proliferator-activated receptor-gamma (PPAR-γ) activity in vivo and in vitro. METHODS: RAW264.7 macrophages were treated with different fatty acids, and cell culture supernatants were collected to prepare conditioned media (CM). Different co-culture systems between primary hepatocytes and CM from macrophages were established. A PPAR-γ agonist or antagonist was administered to regulate PPAR-γ activity and macrophage polarization. M1/M2 phenotype markers, inflammatory signaling pathway, and lipid-related genes expression were determined. Wild-type C57BL/6 mice were fed a high-fat diet to induce NAFLD and given rosiglitazone to regulate PPAR-γ activity in vivo. RESULTS: Saturated fatty acids induced M1-polarized macrophages while polyunsaturated fatty acids induced M2-polarized macrophages. M1-polarized macrophages significantly promoted lipid synthesis and accumulation in primary hepatocytes through upregulation of a toll-like receptor 4 (TLR4)/NF-κB signaling pathway. The PPAR-γ agonist made lipid-induced M1-polarized macrophages switch to an M2-predominant phenotype, while PPAR-γ antagonist had the opposite effect. Macrophage polarization shifting subsequently affected lipid metabolism in primary hepatocytes. Administration of rosiglitazone improved high-fat diet induced hepatic steatosis and lipid metabolism through reducing hepatic TLR4/NF-κB expression and M1-polarized Kupffer cells. CONCLUSIONS: Lipid-induced macrophage M1 polarization promoted hepatic lipid metabolism. Modulation of PPAR-γ activity could shift macrophage polarization and subsequently affect lipid metabolism. Upregulation of the TLR4/NF-κB signaling pathway is closely linked to dysregulated lipid metabolism in NAFLD.

Pd-Catalyzed Asymmetric Hydroalkylation of 1,3-Dienes: Access to Unnatural α-Amino Acid Derivatives Containing Vicinal Quaternary and Tertiary Stereogenic Centers.

Pd-phosphinooxazoline (Pd-PHOX)-catalyzed asymmetric hydroalkylation of 1,3-dienes with azlactones was successfully developed for the first time, affording various enantioenriched α-quaternary α-amino acid derivatives bearing contiguous quaternary and tertiary stereogenic centers in good yields with exclusive regioselectivity and excellent stereoselective control (up to 92% yield, >20:1 dr, and >99% ee). The scale-up catalytic asymmetric hydroalkylation was performed well without loss of reactivity and stereoselectivities, which exhibited great potential application. The synthetic utility of the current methodology was demonstrated through product transformations to access other biologically important compounds such as chiral ß-amino alcohol and α-quaternary cyclic α-amino acid derivatives.

Synthesis and Electrochemical Properties of CuC2O4·xH2O and CuC2O4·xH2O/Carbon Nanotubes (CNTs) Anodes for Lithium-Ion Batteries.

Pure CuC2O4·xH2O and CuC2O4·xH2O/carbon nanotubes (CNTs) composites are synthesized by a low-temperature hydrothermal process. The structure and morphology of the products are analyzed by X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetric analysis (TG) and Raman spectrum. The results demonstrate that the as-prepared CuC2O4·xH2O takes on a microsphere-like morphology, all CuC2O4·xH2O/CNTs nanocomposites are constructed by the intertwining of tabular CuC2O4·xH2O nanoparticles (NPs) and CNTs to form a tanglesome net. When evaluated as an anode materials for lithium ion batteries (LIBs), all CuC2O4·xH2O/CNTs electrodes possess higher reversible discharge capacities (more than 1000 mAh g-1) than the pure CuC2O4·xH2O, up to 200th cycle at a current density of 100 mA g-1. The results illustrate that the addition of CNTs can enhance the electrochemical performance of CuC2O4·xH2O. Overall, CuC2O4·xH2O/CNTs composite can be a promising candidate used as a promising anode for LIBs.

Impact of a pharmacist-led education and follow-up service on anticoagulation control and safety outcomes at a tertiary hospital in China: a randomised controlled trial.

OBJECTIVES: This study was designed to evaluate the impact of a pharmacist-led anticoagulation service on international normalised ratio (INR) control and other outcomes among patients receiving warfarin therapy at a tertiary hospital in Zhuhai, China. METHODS: In this randomised controlled trial, adult patients who were newly initiated on warfarin with intended treatment duration of at least 3 months were recruited. Participants were randomly allocated to receive the pharmacist-led education and follow-up service (PEFS) or usual care (UC). Anticoagulation control was calculated as the proportions of time within the target INR range (TTR) and time within the expanded target range (TER). KEY FINDINGS: A total of 152 participants (77 in the PEFS group and 75 in the UC group) were included. Within 180 days after hospital discharge, the PEFS group spent more TER than the UC group (54.4% versus 42.0%; P = 0.024), whereas the difference in TTR did not reach statistical significance (35.9% versus 29.5%; P = 0.203). No major bleeding events were observed, and the cumulative incidences of major thromboembolic events (6.5% versus 9.3%) and mortality (1.3% versus 1.3%) were similar between the two groups (P> 0.05). At 30 days postdischarge, the PEFS group had better warfarin knowledge by answering 57.5% of questions correctly, compared with the UC group (43.0%) (P = 0.003). CONCLUSIONS: The PEFS markedly enhanced anticoagulation control and warfarin knowledge but there was room for improvement. The expansion of pharmacists' clinical role and the development of more effective education and follow-up strategies are warranted to optimise anticoagulation management services in China.

The clinicopathologic features and prognosis of esophageal neuroendocrine carcinomas: a single-center study of 53 resection cases.

BACKGROUND: Esophageal neuroendocrine carcinomas (NECs) are exceedingly rare and poorly understood. The aims of the retrospective study were to delineate the clinicopathologic features and prognosis of patients with the disease. METHODS: We performed a retrospective study containing 53 patients of esophageal NECs in our center from 2002 through 2018. Patients were assigned to the pure esophageal NECs group and the esophageal NECs mixed with squamous carcinoma and/or esophageal adenocarcinoma (MiNECs) group. Demographic, clinical, pathologic and prognostic factors were recorded and analyzed. RESULTS: Of the 53 patients, elderly male patients were predominant. Dysphagia was the most common symptom (45/53, 84.9%). Most tumors were centered in the middle esophagus (36/53,67.9%).Ulcerated appearance was frequently seen in the pure NECs (56.8%), and the tumors in the MiNECs group mostly represented elevated types (57.9%). Synaptophysin (38/45, 84.4%), chromogranin A (21/38, 55.3%) and CD56(23/27, 85.2%) have been proven to be positive markers for NECs. Most patients (46/53, 86.8%) received surgery combined with chemotherapy. Though the pathologic stages were alike (P = 0.129), the median survival time was 3.53 years for the pure NECs group and 7 years for the MiNECs group. In multivariate analysis, pathologic stage (RR = 1.938, P = 0.045) and age (RR = 2.410, P = 0.028) were independent prognostic factors for patients with MiNECs. The prognosis of patients with pure NECs was independent from any factors. CONCLUSIONS: Careful endoscopic examination could help distinguish pure NECs from MiNECs. NECs were aggressive, but a relative better prognosis for patients with MiNECs. Surgery should be performed if applicable, and chemotherapy might be helpful.

Top-Down Strategy of Implantable Biosensor Using Adaptable, Porous Hollow Fibrous Membrane.

Fabrication of an outer membrane is crucial for an implantable biosensor to enhance the long-term stability and accuracy of sensors. Herein, an adaptable, controllable, porous outer membrane for an implantable biosensor was fabricated using a "top-down" method, allowing maximum retention of enzyme activity and fine control over membrane microstructure. Polysulfone hollow fibrous membranes with different pore sizes and porosities were used as a base membrane. Chitosan (CH) and sodium alginate (SA) were self-assembled on the inner surface of PSfHM to construct a biocompatible and conductive interface between PSfHM and the electrode. In vitro and in vivo experiments were used to evaluate the performance of implantable glucose biosensors with PSfHM and CH/SA modified PSfHM (PSfHM-CH/SA). The glucose biosensor with PSfHM-CH/SA exhibited a more stable output current than bare sensors and a quick response time (<50 s). The glucose biosensor with PSfHM-CH/SA linear sensing range was between 0 and 22 mM ( R2 = 0.9905), and relative sensitivity remained at >87% within 7 days and >76% within 15 days. Furthermore, response currents recorded by implanted sensors closely followed the blood glucose trend from the tail vein blood during in vivo experiments.

Bialternacins A-F, Aromatic Polyketide Dimers from an Endophytic Alternaria sp.

Six novel aromatic polyketide dimers, bialternacins A-F (1-6), were isolated from a plant endophytic Alternaria sp. The structures of compounds 1-6 were elucidated on the basis of extensive spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism analysis. Compounds 1, 2, 5, and 6 were characterized as four pairs of racemic mixtures. Compound (+)-5 was demonstrated to show acetylcholinesterase inhibitory activity with an IC50 value of 15.5 µM. A putative biosynthetic pathway for these compounds was proposed.