Use of metformin and insulin among pregnant women with gestation diabetes in the United Kingdom: A population-based cohort study.

AIMS: The contemporary prescription patterns of antidiabetic drugs following guideline changes recommending metformin as first-line gestational diabetes (GDM) pharmacotherapy is underexplored. We aimed to examined use of metformin and insulin during pregnancy among women with GDM over 20 years in the United Kingdom. METHODS: We conducted a population-based cohort study using linked data from the Clinical Practice Research Datalink, its pregnancy register and Hospital Episode Statistics from 1998 to 2017. We included pregnancies of women without prior diabetes history who received GDM diagnosis or initiated an antidiabetic drug after 20 weeks gestation. Patient-level and practice-level characteristics were compared between metformin initiators and insulin initiators. We described trends of initiating metformin as first-line treatment and described time to initiation of rescue insulin overall, and by body mass index among metformin initiators. RESULTS: Our cohort included 5633 pregnancies from 5393 women with GDM, of whom 38.9% initiated pharmacotherapy (41% insulin, 59% metformin). Metformin prescriptions (as opposed to insulin) increased substantially, from <5% of pregnancies before 2007 to 42.5% in 2008. Over 85% of pregnancies that were prescribed pharmacotherapy were prescribed metformin as first-line treatment in 2015. Among metformin initiators, 16% initiated rescue insulin, typically occurring within 40 days of metformin initiation. Choice of GDM pharmacotherapy varied by characteristics, including smoking, obesity, race/ethnicity and general practice regions. CONCLUSIONS: Metformin was the most prescribed medication for GDM, with large increases over the past 2 decades. The increasing use of oral-antidiabetic drugs during pregnancy, consistent with other regions, highlights the need for future studies examining effectiveness and safety of antidiabetic drug use during pregnancy.

Levothyroxine initiation and the risk of pregnancy loss among pregnant women with subclinical hypothyroidism: An observational study emulating a target trial.

BACKGROUND: While the benefits of levothyroxine are well-established for overt hypothyroidism, they are unclear for subclinical hypothyroidism (SCH) among pregnant women. OBJECTIVE: To estimate the effect of initiation of levothyroxine on pregnancy loss among women with SCH with an emulated target trial using observational data. METHODS: We emulated a target trial using the United Kingdom's Clinical Practice Research Datalink to account for the staggered timing of diagnosis and treatment of SCH and the time of entry of women into prenatal care. We emulated multiple nested trials (at each gestational week) and used an intention-to-treat approach to define levothyroxine use (≥1 prescription in the 7 days prior to trial entry), with eligible users matched to non-users (1:4) on time of diagnosis, gestational week of the first eligible trial and high-dimensional propensity score. Pregnancy losses included spontaneous abortion and stillbirth. A pooled logistic regression model with bootstrap resampling was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Based on 159,177 eligible person-trials (5781 women), the matched cohort included 181 initiators and 640 non-initiators of levothyroxine, with 57 pregnancy losses occurring during follow-up. Overall, the mean age of women was 32.2 years (SD 5.4), 25% were obese, 8% had type 2 diabetes and about 50% were nulliparous. After matching, women who initiated levothyroxine versus not had higher thyroid-stimulating levels during pregnancy and were more likely to have a history of hypothyroidism. The cumulative incidence of pregnancy loss was lower in initiators versus non-initiators of levothyroxine. The adjusted HR for pregnancy loss was 0.87 (95% CI 0.22, 1.56). CONCLUSIONS: Although our assessment of the effect of initiation of levothyroxine for SCH in pregnancy precludes any definitive conclusions due to wide confidence intervals, this study illustrates the feasibility of using the target trial emulation framework to examine the effectiveness of medication use in pregnancy.

Nasopharyngeal cancer cell-derived exosomal PD-L1 inhibits CD8+ T-cell activity and promotes immune escape.

Programmed cell death ligand 1 (PD-L1) is an immune surface protein that binds to programmed cell death 1 (PD-1) and allows tumors to evade T-cell immunity. This study aims to define the role of PD-L1 shuttled by tumor cell-derived exosomes in the immune escape of nasopharyngeal carcinoma (NPC). PD-L1 expression was determined in the exosomes isolated from the plasma of NPC patients or from NPC cells. It was found that PD-L1 was highly expressed in the exosomes from the plasma of NPC patients and also in the exosomes from NPC cells. PD-L1/PD-1 binding was identified in the presence or absence of interferon-gamma (IFN-γ) or anti-PD-L1 antibody. PD-L1 expression was elevated following IFN-γ treatment. Binding of PD-L1 to PD-1 was augmented by IFN-γ and blocked by anti-PD-L1 antibody. Following this, CD8+ T cells were sorted out from peripheral blood samples to assess the binding between exosomal PD-L1 and PD-1 on the CD8+ T-cell surface, and to measure the percentage of Ki-67-positive T cells. The results indicated that exosomal PD-L1 bound to the PD-1 on CD8+ T-cell surface, leading to a reduced percentage of Ki-67-positive CD8+ T cells and downregulated production of cytokines. In vivo data confirmed that exosomal PD-L1 promoted NPC tumor growth in mice by suppressing CD8+ T-cell activity. In conclusion, NPC cell-derived exosomes deliver PD-L1 to bind to PD-1 on the CD8+ T-cell surface, through which cytotoxic CD8+ T-cell function was attenuated and the immune escape was thus promoted in NPC.

Delayed callose degradation restores the fertility of multiple P/TGMS lines in Arabidopsis.

Photoperiod/temperature-sensitive genic male sterility (P/TGMS) is widely applied for improving crop production. Previous investigations using the reversible male sterile (rvms) mutant showed that slow development is a general mechanism for restoring fertility to P/TGMS lines in Arabidopsis. In this work, we isolated a restorer of rvms-2 (res3), as the male sterility of rvms-2 was rescued by res3. Phenotype analysis and molecular cloning show that a point mutation in UPEX1 l in res3 leads to delayed secretion of callase A6 from the tapetum to the locule and tetrad callose wall degradation. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis demonstrated that the tapetal transcription factor ABORTED MICROSPORES directly regulates UPEX1 expression, revealing a pathway for tapetum secretory function. Early degradation of the callose wall in the transgenic line eliminated the fertility restoration effect of res3. The fertility of multiple known P/TGMS lines with pollen wall defects was also restored by res3. We propose that the remnant callose wall may broadly compensate for the pollen wall defects of P/TGMS lines by providing protection for pollen formation. A cellular mechanism is proposed to explain how slow development restores the fertility of P/TGMS lines in Arabidopsis.

Invited Commentary: The Prevalent New-User Design in Pharmacoepidemiology-Challenges and Opportunities.

The prevalent new-user design includes a broader study population than the traditional new-user approach that is frequently used in pharmacoepidemiologic research. In an article appearing in this issue (Am J Epidemiol. 2021;190(7):1341-1348), Webster-Clark et al. describe the treatment initiator types included in the prevalent new-user design and contrast the causal questions assessed using a prevalent new-user design versus a new-user design. They further applied a series of simulation studies showing the importance of accounting for treatment history in addition to time since initiation of the comparator in the prevalent new-user design. In this commentary, we put their findings in the broader context with a discussion of the strengths and limitations of the prevalent new-user design and settings where it would be most useful. The prevalent new-user design and new-user design both address unique questions of clinical and public health importance. Real-world evidence generated by pharmacoepidemiologic research is increasingly being used by regulators and other knowledge users to inform their decision-making. Understanding the causal questions addressed by different designs is crucial in this process; the study by Webster-Clark et al. represents an important step in addressing this issue.

The Association Between the Risk of Hypertensive Disorders of Pregnancy and Folic Acid: A Systematic Review and Meta-Analysis.

PURPOSE: Although folic acid (FA) supplementation has been shown to reduce general cardiovascular risks, its impact on hypertensive disorders of pregnancy (HDP) is unclear. We performed a systematic review and meta-analysis to clarify the association between FA and the risk of HDP (pre-eclampsia (PE) and gestational hypertension (GH)). METHODS: PubMed, EmBase, and Cochrane Library were searched up to June 18, 2020, stratified by type of disease, initiation time of FA, form of FA and pre-conception Body Mass Index (BMI). The quality assessment of included studies was evaluated using Newcastle-Ottawa Scale (NOS) for cohort studies and Cochrane Collaboration's Risk of Bias Assessment Tool for randomized controlled trials (RCTs). Between-study heterogeneity was quantified using Cochran's Q-statistic and I2 statistics. Sensitivity analysis was performed by excluding the studies one by one, and publication bias was analyzed using funnel plots. RESULTS: Twenty studies with 359041 patients were identified for inclusion in the meta-analysis which included 3 RCTs and 17 cohort studies. Pooled estimates showed RR of 0.83 (95%CI 0.74-0.93, P=0.0008) for association between low dose FA (LD-FA) and the risk of PE, but LD-FA was not associated with GH (RR 1.05, 95% CI 0.97-1.13, P=0.20). In addition, the results of subgroup analysis showed that post-conception LD-FA had a 31% decreased risk of PE (RR 0.69, 95% CI 0.59-0.80, P<0.00001), and LD-FA in patients with pre-conception BMI<25 kg/m2 had a 32% decreased risk of PE (RR 0.68, 95% CI 0.56-0.81, P<0.0001) Conclusions: LD-FA significantly decreased the risk of PE but not GH, and post-conception LD-FA and pre-conception BMI<25 kg/m2 were considered as protective factors to reduce the risk of PE.

Association of preoperative medication with postoperative length of stay in elderly patients undergoing hip fracture surgery.

BACKGROUND: For elderly patients who are about to undergo surgery, research on the effects of preoperative medication on postoperative outcomes is rare, especially preoperative discontinuation-requiring medication (PDRM) which needed to be discontinued because of its increased risk of postoperative complications. AIM: To investigate whether preoperative medication (PDRM and polypharmacy) is associated with postoperative length of hospital stay (LOS) in elderly patients undergoing hip fracture surgery. METHODS: Patients aged ≥ 65 who were scheduled for hip (limited to femoral tuberosity) fracture surgery were included. Baseline characteristics, preoperative medication and postoperative LOS were collected from the electronic medical record. The primary outcome was postoperative LOS. RESULTS: A total of 369 hip fracture patients were included. There were 188 and 122 patients exposed to PDRM and polypharmacy, respectively. Multivariate analysis models were constructed using significant factors for prolonged postoperative hospital stay from univariate analysis: Model I (body mass index (BMI), Charlson comorbidity index (CCI) ≥ 7, creatinine clearance rate (Ccr) < 60 and PDRM) and Model II (BMI, Ccr ≥ 7, Ccr < 60 and polypharmacy). CCI was the most significant factor. Its adjusted odds ratio was as large as 2.7 and attributable risk was 63%. In preoperative medication use, both polypharmacy and PDRM showed significant association with postoperative LOS. CONCLUSION: The present study supported the impact of PDRM on postoperative LOS in geriatric hip fracture patients. The results added a further aspect to preoperative medication optimization in elderly patients undergoing hip fracture surgery.

Floridean Starch and Floridoside Metabolic Pathways of Neoporphyra haitanensis and Their Regulatory Mechanism under Continuous Darkness.

Floridean starch and floridoside are the main storage carbohydrates of red algae. However, their complete metabolic pathways and the origin, function, and regulatory mechanism of their pathway genes have not been fully elucidated. In this study, we identified their metabolic pathway genes and analyzed the changes in related gene expression and metabolite content in Neoporphyra haitanensis under continuous dark conditions. Our results showed that genes from different sources, including eukaryotic hosts, cyanobacteria, and bacteria, were combined to construct floridean starch and floridoside metabolic pathways in N. haitanensis. Moreover, compared with those in the control, under continuous dark conditions, floridean starch biosynthesis genes and some degradation genes were significantly upregulated with no significant change in floridean starch content, whereas floridoside degradation genes were significantly upregulated with a significant decrease in floridoside content. This implies that floridean starch content is maintained but floridoside is consumed in N. haitanensis under dark conditions. This study elucidates the "floridean starch-floridoside" metabolic network and its gene origins in N. haitanensis for the first time.

[Preparation and in vitro evaluation of forsythoside A-loaded exosomes].

A drug delivery system of forsythoside A-loaded exosomes(FTA-Exos) with high biocompatibility and low immunogenicity was established to investigate its impact on the migration of human lung epithelial adenocarcinoma A549 cells. The exosomes from A549 cells were extracted and purified by ultra-high speed centrifugation and ultrafiltration. FTA-Exos were prepared by ultrasonic incubation, and characterized by particle size analysis, transmission electron microscopy, and Western blot assay. The uptake of FTA-Exos by A549 cells was observed under the laser confocal microscope, and the impact of FTA-Exos on the migration of A549 cells was investigated by cell scratch assay. The results showed that the average particle size of the prepared FTA-Exos was(138.90±2.37) nm, which increased slightly after drug loading. The PDI was 0.291±0.013, and the average potential was(-10.1±0.66) mV. The FTA-Exos were spheroidal in appearance as observed by transmission electron microscope, with an obvious saucer-like double-layer membrane. Western blot assay indicated that the specific proteins CD63 and Alix were both expressed in exosomes. The laser confocal microscopy suggested that FTA-Exos were taken up by A549 cells and stably maintained in the cell for 4-8 h, and the fluorescence was significantly enhanced at 4 h. The scratch assay showed that the inhibitory effect of FTA-Exos on the migration of A549 cells was significantly stronger than that of forsythoside A(P < 0.05). In conclusion, the drug delivery system of FTA-Exos established in this study had good stability, reliable preparation process, and potent inhibitory effect on the migration of A549 cells in vitro, which can provide an important reference for subsequent in-depth research and application.

AUXIN RESPONSE FACTOR17 Directly Regulates MYB108 for Anther Dehiscence.

The timely release of mature pollen following anther dehiscence is essential for reproduction in flowering plants. AUXIN RESPONSE FACTOR17 (ARF17) plays a crucial role in pollen wall pattern formation, tapetum development, and auxin signal transduction in anthers. Here, we showed that ARF17 is also involved in anther dehiscence. The Arabidopsis (Arabidopsis thaliana) arf17 mutant exhibits defective endothecium lignification, which leads to defects in anther dehiscence. The expression of MYB108, which encodes a transcription factor important for anther dehiscence, was dramatically down-regulated in the flower buds of arf17 Chromatin immunoprecipitation assays and electrophoretic mobility shift assays showed ARF17 directly binds to the MYB108 promoter. In an ARF17-GFP transgenic line, in which ARF17-GFP fully complements the arf17 phenotype, ARF17-GFP was observed in the endothecia at anther stage 11. The GUS signal driven by the MYB108 promoter was also detected in endothecia at late anther stages in transgenic plants expressing promoterMYB108::GUS Thus, the expression pattern of both ARF17 and MYB108 is consistent with the function of these genes in anther dehiscence. Furthermore, the expression of MYB108 driven by the ARF17 promoter successfully restored the defects in anther dehiscence of arf17 These results demonstrated that ARF17 regulates the expression of MYB108 for anther dehiscence. Together with its function in microcytes and tapeta, ARF17 likely coordinates the development of different sporophytic cell layers in anthers. The ARF17-MYB108 pathway involved in regulating anther dehiscence is also discussed.

Critical appraisal of the quality and content of clinical practice guidelines for pneumocystis jiroveci pneumonia (PJP) prophylaxis using the AGREE II instrument.

WHAT IS KNOWN AND OBJECTIVE: Pneumocystis jiroveci (P jiroveci) is an important opportunistic fungus and causes pneumocystis jiroveci pneumonia (PJP) in kidney transplant recipients (KTRs). By using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, the objective of this study was to evaluate the quality of PJP prophylaxis clinical practice guidelines (CPGs), and to help develop, update or improve guideline. METHODS: A search was conducted for PJP prophylaxis CPGs using PubMed, Embase, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), WanFang data, VIP Database, Google and guideline websites (until 18 January 2020). Data extraction and quality assessment were independently assessed by two appraisers, and the intra-class correlation coefficient (ICC) was used to assess interrater reliability. The specific recommendations were evaluated based on the quality results. RESULTS AND DISCUSSION: A total of 6 CPGs were included. The highest median scores were in the clarity of presentation domain (92%), and the lowest median scores were in the applicability domain (25%). The Kidney Disease Improving Global Outcome (KDIGO) and Renal Association (RA)/British Transplantation Society (BTS) CPGs were strongly recommended. The specific recommendations were inconsistent, such as the dose, frequency and duration. WHAT IS NEW AND CONCLUSION: The KDIGO and RA/BTS CPGs were strongly recommended. Not only the quality of the PJP prophylaxis CPGs needs to be improved during the development progress, but also the specific recommendations should be further refined.

Genome Sequence and QTL Analyses Using Backcross Recombinant Inbred Lines (BILs) and BILF1 Lines Uncover Multiple Heterosis-related Loci.

: Heterosis is an interesting topic for both breeders and biologists due to its practical importance and scientific significance. Cultivated rice (Oryza sativa L.) consists of two subspecies, indica and japonica, and hybrid rice is the predominant form of indica rice in China. However, the molecular mechanism underlying heterosis in japonica remains unclear. The present study determined the genome sequence and conducted quantitative trait locus (QTL) analysis using backcross recombinant inbred lines (BILs) and BILF1 lines to uncover the heterosis-related loci for rice yield increase under a japonica genetic background. The BIL population was derived from an admixture variety Habataki and japonica variety Sasanishiki cross to improve the genetic diversity but maintain the genetic background close to japonica. The results showed that heterosis in F1 mainly involved grain number per panicle. The BILF1s showed an increase in grain number per panicle but a decrease in plant height compared with the BILs. Genetic analysis then identified eight QTLs for heterosis in the BILF1s; four QTLs were detected exclusively in the BILF1 population only, presenting a mode of dominance or super-dominance in the heterozygotes. An additional four loci overlapped with QTLs detected in the BIL population, and we found that Grains Height Date 7 (Ghd7) was correlated in days to heading in both BILs and BILF1s. The admixture genetic background of Habataki was also determined by subspecies-specific single nucleotide polymorphisms (SNPs). This investigation highlights the importance of high-throughput sequencing to elucidate the molecular mechanism of heterosis and provides useful germplasms for the application of heterosis in japonica rice production.

Comparison of Parametric and Nonparametric Estimators for the Association Between Incident Prepregnancy Obesity and Stillbirth in a Population-Based Cohort Study.

While prepregnancy obesity increases risk of stillbirth, few studies have evaluated the role of newly developed obesity independent of long-standing obesity. Additionally, researchers have relied almost exclusively on parametric models, which require correct specification of an unknown function for consistent estimation. We estimated the association between incident obesity and stillbirth in a cohort constructed from linked birth and death records in Pennsylvania (2003-2013). Incident obesity was defined as body mass index (weight (kg)/height (m)2) greater than or equal to 30. We used parametric G-computation, semiparametric inverse-probability weighting, and parametric/nonparametric targeted minimum loss-based estimation (TMLE) to estimate the association between incident prepregnancy obesity and stillbirth. Compared with pregnancies from women who stayed nonobese, women who became obese prior to their next pregnancy were estimated to have 2.0 (95% confidence interval (CI): 0.5, 3.5) more stillbirths per 1,000 pregnancies using parametric G-computation. However, despite well-behaved stabilized inverse probability weights, risk differences estimated from inverse-probability weighting, nonparametric TMLE, and parametric TMLE represented 6.9 (95% CI: 3.7, 10.0), 0.4 (95% CI: 0.1, 0.7), and 2.9 (95% CI: 1.5, 4.2) excess stillbirths per 1,000 pregnancies, respectively. These results, particularly those derived from nonparametric TMLE, were highly sensitive to covariates included in the propensity score models. Our results suggest that caution is warranted when using nonparametric estimators to quantify exposure effects.

Accelerating Photogenerated Charge Kinetics via the Synergetic Utilization of 2D Semiconducting Structural Advantages and Noble-Metal-Free Schottky Junction Effect.

Although photocatalysis is one of the most promising technologies for environmental and energy issues, the irreconcilable contradiction between the absorption of the visible light and the strong redox capability of the photocatalyst and the low photocatalytic reaction kinetics result in the poor efficiency. Here, a composite photocatalyst is reported with high redox capability and accelerated reaction kinetics synergistically utilizing 2D semiconducting structural advantages and the noble-metal-free Schottky junction effect. The 2D structure can not only increase the bandgap of the photocatalyst but also improve the transfer and separation of the photogenerated charge carriers. Furthermore, the introduction of the noble-metal-free Schottky junction effect accelerates the photocatalytic reaction kinetics. The Schottky barrier can also prevent the photogenerated charges trapped by the electron acceptor from flowing back to the semiconductor, which can further boost the photocatalytic performance. The transfer process of the photogenerated charge carriers is also researched in detail by the comprehensive characterization methods, which enable the photocatalytic mechanism to be revealed.

E-Cigarette Use in a Country With Prevalent Tobacco Smoking: A Population-Based Study in Taiwan.

BACKGROUND: The different profiles of e-cigarette users in different age groups have seldom been investigated, particularly in populations facing a high prevalence of cigarette smoking. This study aims to examine the prevalence and correlates of e-cigarette use separately for adolescents and adults in nationally representative samples in Taiwan. METHODS: Among 17,837 participants in the 2014 National Survey of Substance Use in Taiwan, 4445 were aged 12 to 17 years and 13,392 were aged 18 to 64 years. Individuals' lifetime tobacco use was divided into four groups: non-use, exclusive e-cigarette use, exclusive cigarette use, and dual use. Questions on sociodemographic features, use and problematic use of tobacco, alcohol, and other drugs, and psychosocial distress, among others, were administered using a computer-assisted self-interview on tablet computers. RESULTS: Among lifetime users of e-cigarette (2.2% for adults and 0.8% for adolescents), 4.5% for adults and 36.6% for adolescents were exclusive e-cigarette users. From use of exclusive e-cigarettes to use of exclusive cigarettes to dual use, those usage groups were related to an increasing trend of adjusted odds ratios for use of other psychoactive substances, particularly problematic use of alcohol or drugs, and with more depressive symptoms. Two correlates were specific to e-cigarette use: alcohol use had stronger relationships with e-cigarette use among adolescents, and younger adults (18-34) were more likely to try e-cigarettes compared to older adults. CONCLUSIONS: These results provide essential information regarding e-cigarette use in the general population, and future prevention strategies should account for its specific correlates in young people.

Fine regulation of ARF17 for anther development and pollen formation.

BACKGROUND: In Arabidopsis, the tapetum and microsporocytes are critical for pollen formation. Previous studies have shown that ARF17 is expressed in microsporocytes and tetrads and directly regulates tetrad wall synthesis for pollen formation. ARF17 is the direct target of miR160, and promoterARF17::5mARF17 (5mARF17/WT) transgenic plants, which have five silent mutations within the miR160-complementary domain, are sterile. RESULTS: Here, we found that ARF17 is also expressed in the tapetum, which was defective in arf17 mutants. Compared with arf17 mutants, 5mARF17/WT plants had abnormal tapetal cells and tetrads but were less vacuolated in the tapetum. Immunocytochemical assays showed that the ARF17 protein over-accumulated in tapetum, microsporocytes and tetrads of 5mARF17/WT plants at early anther stages, but its expression pattern was not affected during anther development. 5mARF17 driven by its native promoter did not rescue the arf17 male-sterile phenotype. The expression of 5mARF17 driven by the tapetum-specific promoter A9 led to a defective tapetum and male sterility in transgenic plants. These results suggest that the overexpression of ARF17 in the tapetum and microsporocytes of 5mARF17/WT plants leads to male sterility. Microarray data revealed that an abundance of genes involved in transcription and translation are ectopically expressed in 5mARF17/WT plants. CONCLUSIONS: Our work shows that ARF17 plays an essential role in anther development and pollen formation, and ARF17 expression under miR160 regulation is critical for its function during anther development.

Safety and efficacy of lobaplatin combined with 5-fluorouracil as first-line induction chemotherapy followed by lobaplatin-radiotherapy in locally advanced nasopharyngeal carcinoma: preliminary results of a prospective phase II trial.

BACKGROUND: Due to improvements in imaging and radiological techniques as well as the use of chemotherapy, distant metastasis has become the predominant mode of treatment failure in patients with locally advanced nasopharyngeal carcinoma (LA-NPC). Platinum-based systemic chemotherapy has shown survival benefits and is now the standard strategy for systemic therapy in patients with LA-NPC. Notably, the third-generation platinum reagent lobaplatin has shown anti-tumor effects in several solid tumors with lower incidences of gastrointestinal, hepatic and renal toxicity relative to other platinum drugs. However, the safety and efficacy of lobaplatin as a first-line regimen in patients with LA-NPC are undetermined. METHODS: Patients with stage III-IVa-b NPC received lobaplatin at a dose of 30 mg/m2 on days 1 and 22 combined with a continuous 120-h intravenous injection of 5-fluorouracil at a dose of 4 g/m2 followed by lobaplatin at a dose of 50 mg/m2 on days 43 and 64 concomitant with intensity-modulated radiation therapy. Objective response rates and acute toxicity were assessed based on RECIST (1.1) and CTCAE v.3.0, respectively. Kaplan-Meier analysis was used to calculate survival rates. RESULTS: Fifty-nine patients were enrolled, and 44 patients (74.6%) received allocated cycles of chemotherapy. The objective response rates were 88.1% (95% confidence interval [CI], 0.77 to 0.95) and 100% after induction chemotherapy (ICT) and concurrent chemoradiotherapy (CRT), respectively. With a median follow-up period of 44 months, the 3-year estimated progression-free survival and overall survival were 86.4% (95% CI, 69.8 to 98.8) and 94.9% (95% CI, 89.5 to 100), respectively. The most common grade 3-4 toxicities were neutropenia (8.5%) and thrombocytopenia (40.7%) after ICT and CRT, respectively. CONCLUSION: Lobaplatin combined with 5-fluorouracil followed by lobaplatin-RT treatment showed encouraging anti-tumor effects with tolerable toxicities in patients with LA-NPC. Randomized controlled trials of lobaplatin in patients with LA-NPC are warranted. TRIAL REGISTRATION: This trial was registered with the Chinese Clinical Trials Registry and approved on March 31st, 2012, number ChiCTR-ONC-12002060 .

A prognostic model predicts the risk of distant metastasis and death for patients with nasopharyngeal carcinoma based on pre-treatment interleukin 6 and clinical stage.

Because inflammation plays a critical role in nasopharyngeal carcinoma (NPC), this study aims to investigate the correlation between the pro-inflammation cytokine interleukin-6 (IL6) and the prognosis of NPC and develop a new prognostic model. IL6 levels were measured in the serum of 290 NPC patients by ELISA and the correlation between IL6 and prognosis of NPC was evaluated by Kaplan-Meier analysis and multivariate analysis. The results showed that elevated IL6 levels were positively correlated with poorer 9-year overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and lung metastasis-free survival (lung-MFS). IL6 level was an independent prognostic factor for OS, DFS, DMFS and lung-MFS. The CI-model based on TNM stage and IL6 level could better predict the OS, DFS, DMFS and lung-MFS of NPC patients. Here, the newly developed prognostic CI-model for predicting distant metastasis and death of NPC patients could facilitate patients consulting and individualized immunotherapy.

Heart transplantation in endstage rheumatic heart disease-experience of an endemic area.

BACKGROUND: Rheumatic heart disease (RHD) remains a significant cause of cardiovascular disease in developing countries. The nonsuppurative cardiovascular sequel of group A streptococcal infection is sustained inflammatory and immune reactions toward the myocardium and valves. This study attempted to determine the long-term outcome of heart transplantation in endstage RHD patients.Methods and Results:The 23 patients with endstage RHD at National Taiwan University Hospital between June 1987 and March 2012 were enrolled. In the same period, 226 dilated cardiomyopathy (DCM) patients were enrolled as the control group. The RHD group experienced more right ventricular failure and higher central venous pressure than the control group, which resulted in impaired liver and kidney function. The RHD patients had a lower 15-year survival rate than the DCM patients after transplantation (22.7% vs. 45.7%, P=0.038) and higher incidence of tricuspid regurgitation than the control group (32.2% vs. 11.4%). No differences existed between the groups for the mitral regurgitation rate (RHD 37.7% vs. DCM 29.4%, P=0.562). CONCLUSIONS: Preoperatively, the RHD patients suffered more tricuspid regurgitation than the control group. The aortic and mitral valves in both groups functioned well over the long term. Heart transplantation for endstage RHD had a long-term survival rate that was inferior to that for DCM patients.