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.

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.

[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.

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.

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 .

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.

In vitro simulated digestion and fermentation characteristics of pectic polysaccharides from fresh passion fruit (Passiflora edulis f. flavicarpa L.) peel.

In this study, two pectic polysaccharides (PFP-T and PFP-UM) were extracted from fresh passion fruit peels using three-phase partitioning (TPP) and sequential ultrasound-microwave-assisted TPP methods, respectively, and their effects on the in vitro gastrointestinal digestion and fecal fermentation characteristics were examined. The results indicate that gastrointestinal digestion has a minimal effect on the physicochemical and structural characteristics of PFP-T and PFP-UM. However, during in vitro fecal fermentation, both undigested PFP-T and PFP-UM are significantly degraded and utilized by intestinal microorganisms, showing increased the total relative abundance of Firmicutes and Bacteroidota in the intestinal flora. Notably, compared with PFP-UM, PFP-T better promoted the reproduction of beneficial bacteria such as Prevotella, Megasphaera and Dialister, while suppressed the growth of harmful genera including Escherichia-Shigella, producing higher content of short-chain fatty acids. Therefore, our findings suggest that PFP-T derived from passion fruit peel has potential as a dietary supplement for promoting intestinal health.

Longan Polysaccharides with Covalent Selenylation Combat the Fumonisin B1-Induced Cell Toxicity and Barrier Disruption in Intestinal Epithelial (IEC-6) Cells.

In this study, the soluble, but non-digestible, longan (Dimocarpus longan Lour.) polysaccharides (LP) were extracted from dried longan fruits and then chemically selenylated to produce two selenylated products, namely SeLP1 and SeLP2, with different selenylation extents. The aim was to investigate their protective effects on rat intestinal epithelial (IEC-6) cells exposed to the food toxin fumonisin B1 (FB1). LP only contained total Se content of less than 0.01 g/kg, while SeLP1 and SeLP2 were measured with respective total Se content of up to 1.46 and 4.79 g/kg. The cell viability results showed that these two selenylated products were more efficient than LP in the IEC-6 cells in alleviating FB1-induced cell toxicity, suppressing lactate dehydrogenase (LDH) release, and decreasing the generation of intracellular reactive oxygen species (ROS). These two selenylated products were also more effective than LP in combating FB1-induced barrier disruption via increasing the transepithelial electric resistance (TEER), reducing the paracellular permeability, decreasing the mitochondrial membrane potential (MMP) loss, and maintaining cell barrier integrity by upregulating the tight-junction-related genes and proteins. FB1 caused cell oxidative stress and barrier dysfunction by activating the MAPK and mitochondrial apoptosis signaling pathways, while SeLP1 and SeLP2 could regulate the tMAPK- and apoptosis-related proteins to suppress the FB1-mediated activation of the two pathways. Overall, SeLP2 was observed to be more active than SeLP1 in the IEC-6 cells. In conclusion, the chemical selenylation of LP caused an activity enhancement to ameliorate the FB1-induced cell cytotoxicity and intestinal barrier disruption. Meanwhile, the increased selenylation of LP would endow the selenylated product SeLP2 with more activity.

Activities of the soluble and non-digestible longan (Dimocarpus longan Lour.) polysaccharides against HCT-116 cells as affected by a chemical selenylation.

The soluble and non-digestible longan (Dimocarpus longan Lour.) polysaccharides (LP) with Se content less than 0.01 g/kg were extracted and selenylated chemically with the HNO3-Na2SeO3 system, to prepare two selenylated products namely SeLP1 and SeLP2 with enhanced Se contents of 1.46 and 4.79 g/kg, respectively. LP, SeLP1, and SeLP2 were then measured and compared for their saccharide features and bioactivity in human colon carcinoma HCT-116 cells. Compared with LP, both SeLP1 and SeLP2 contained more neutral saccharides, but showed reduced uronic acid content and undetectable sulfate. Moreover, SeLP1 and especially SeLP2 in the cells showed higher activities than LP, reflected by their enhanced capacity to inhibit cell growth, alter cell morphology, and suppress cell colony formation. Compared with LP, SeLP1 and especially SeLP2 were also more capable of promoting intracellular reactive oxygen species and Ca2+ levels, causing mitochondrial membrane potential loss, or inducing cell apoptosis via up- and down-regulating the eight apoptosis-related genes and proteins. Overall, the performed chemical selenylation of LP resulted in obvious changes in these saccharide features and simultaneously enhanced the anti-cancer activity of the selenylated products against the cells clearly, while a higher selenylation extent of the selenylated products consistently caused higher activity towards the cells. The results of this study thus highlighted that this chemical selenylation is applicable when aiming to enhance the bioactivities of natural polysaccharides.

Enhanced Growth Inhibition and Apoptosis Induction in Human Colon Carcinoma HT-29 Cells of Soluble Longan Polysaccharides with a Covalent Chemical Selenylation.

The selenylated polysaccharides chemically belong to the organic Se-conjugated macromolecules and have recently been attracting more and more attention due to their potential to promote body health or prevent cancers. Longan (Dimocarpus longan L.), as a subtropical fruit, contains soluble and non-digestible polysaccharides that are regarded with health care functions in the body. In this study, the longan polysaccharides (LP) were obtained via enzyme-assisted water extraction, and then chemically selenylated using a reaction system composed of HNO3-Na2SeO3 to yield two selenylated products, namely, SeLP1 and SeLP2, with Se contents of 1.46 and 4.79 g/kg, respectively. The anti-cancer effects of the three polysaccharide samples (LP, SeLP1, and SeLP2) were thus investigated using the human colon cancer HT-29 cells as the cell model. The results showed that SeLP1 and SeLP2 were more able than LP to inhibit cell growth, alter cell morphology, cause mitochondrial membrane potential loss, increase intracellular reactive oxygen and [Ca2+]i levels, and induce apoptosis via regulating the eight apoptosis-related genes and proteins including Bax, caspases-3/-8/-9, CHOP, cytochrome c, DR5, and Bcl-2. It was thereby proven that the selenylated polysaccharides could induce cell apoptosis via activating the death receptor, mitochondrial-dependent, and ER stress pathways. Collectively, both SeLP1 and SeLP2 showed higher activities than LP in HT-29 cells, while SeLP2 was consistently more active than SeLP1 in exerting these assessed anti-cancer effects on the cells. In conclusion, this chemical selenylation covalently introduced Se into the polysaccharide molecules and caused an enhancement in their anti-cancer functions in the cells, while higher selenylation extent was beneficial to the activity enhancement of the selenylated products.

Challenges in evaluating treatments for COVID-19: The case of in-hospital anticoagulant use and the risk of adverse outcomes.

Anticoagulants are a potential treatment for the thrombotic complications resulting from COVID-19. We aimed to determine the association between anticoagulant use and adverse outcomes among hospitalized patients with COVID-19. We used data from the COVID-19 International Collaborative Research Project in South Korea from January to June 2020. We defined exposure using an intention-to-treat approach, with person-time classified as use or non-use of anticoagulants at cohort entry, and a time-varying approach. The primary outcome was all-cause, in-hospital mortality; the secondary outcome was a composite including respiratory outcomes, cardiovascular outcomes, venous thromboembolism, major bleeding, and intensive care unit admission. Cox proportional hazards models estimated adjusted hazard ratios (HRs) of the outcomes comparing use versus non-use of anticoagulants. Our cohort included 2,677 hospitalized COVID-19 patients, of whom 24 received anticoagulants at cohort entry. Users were older and had more comorbidities. The crude incidence rate (per 1,000 person-days) of mortality was 5.83 (95% CI: 2.80, 10.72) among anticoagulant users and 1.36 (95% CI: 1.14, 1.59) for non-users. Crude rates of the composite outcome were 3.20 (95% CI: 1.04, 7.47) and 1.80 (95% CI: 1.54, 2.08), respectively. Adjusted HRs for mortality (HR: 1.12, 95% CI: 0.48, 2.64) and the composite outcome (HR: 0.79, 95% CI: 0.28, 2.18) were inconclusive. Although our study was not able to draw conclusions on anticoagulant effectiveness for COVID-19 outcomes, these results can contribute to future knowledge syntheses of this important question. Our study demonstrated that the dynamic pandemic environment may have important implications for observational studies of COVID-19 treatment effectiveness.

Niacin skin flush and membrane polyunsaturated fatty acids in schizophrenia from the acute state to partial remission: a dynamic relationship.

Despite the consistent finding of an attenuated niacin-induced flush response in schizophrenia, its long-term stability and relationship to the membrane polyunsaturated fatty acid (PUFA) levels remain unknown. We conducted niacin skin tests and measured the membrane PUFAs using gas chromatography among 46 schizophrenia inpatients and 37 healthy controls at the baseline and the 2-month follow-up. Attenuated flush responses were persistently observed in schizophrenia patients in both acute and partial remission states, whereas an increased flush response was found in the controls. A persistent decrease in both dihomo-gamma-linolenic acid and docosahexaenoic acid and an increased turnover of arachidonic acid (ARA) via endogenous biosynthesis were found in schizophrenia patients. A composite niacin flush score by combining those with a control-to-case ratio of >1.4 (i.e., scores at 5 min of 0.1 M, 0.01 M, and 0.001 M + 10 min of 0.01 M and 0.001 M + 15 min of 0.001 M) at the baseline was correlated positively with ARA levels among controls but not among schizophrenia patients, whereas the flush score at the 2-month follow-up was correlated positively with ARA levels among patients. The 2-month persistence of attenuated niacin-induced flush response in schizophrenia patients implies that the niacin skin test might tap a long-term vulnerability to schizophrenia beyond acute exacerbation.

Use of levothyroxine among pregnant women with subclinical hypothyroidism in the United Kingdom: A population-based assessment.

Our study aimed to describe levothyroxine prescription patterns and trends over time among pregnant women with subclinical hypothyroidism (SCH) in the United Kingdom. We used data from the Clinical Practice Research Datalink linked to its Pregnancy Register and the Hospital Episode Statistics database from 1998 to 2017. The study population included women with a diagnosis of SCH or an abnormal thyroid-simulated hormone (TSH) level one year prior to or during pregnancy. We compared characteristics between women who received a prescription for levothyroxine during pregnancy and those who did not. We further described the timing, dose, duration, and temporal trends of levothyroxine prescriptions. Our cohort included 6,757 pregnancies from 6,287 women with SCH, of whom 10% received levothyroxine during pregnancy. Among women who received levothyroxine, most received their first prescription during the first trimester (median gestational age: 7 weeks; interquartile range [IQR]: 0, 16) with a median daily dosage of 50 mcg (IQR: 50, 73). Levothyroxine prescription varied over time, decreasing from 23% of pregnant women in 1998 to 7.5% in 2003, remaining stable until 2014, and increasing to 12.5% in 2016. Smoking, diabetes, polycystic ovary syndrome, infertility, timing of SCH diagnosis, age, TSH level at diagnosis, and general practice regions were associated with prescription. Few women with SCH received levothyroxine during pregnancy, and treatment varied by patient characteristics and geographical regions. These results highlight the need to increase awareness among healthcare providers and will guide future studies that explore barriers to initiating levothyroxine treatment for women with SCH during pregnancy.

A Randomized Controlled Trial Comparing Two Different Schedules for Cisplatin Treatment in Patients with Locoregionally Advanced Nasopharyngeal Cancer.

PURPOSE: Previous studies suggest that a cumulative cisplatin dose of 200 mg/m2 might be adequate in the intensity-modulated radiation therapy (IMRT) era for locoregionally advanced nasopharyngeal carcinoma (LANPC). However, two cycles of once-every-3-weeks cisplatin at 100 mg/m2 has never been prospectively compared with standard once-a-week cisplatin regimen. PATIENTS AND METHODS: This trial was conducted at three hospitals from 2011 to 2016. Patients who met the eligibility criteria were recruited (ChiCTR-TRC-12001979) and randomly assigned (1:1) via a computer-generated sequence to receive once-every-3-weeks cisplatin at 100 mg/m2 for two cycles or once-a-week cisplatin at 40 mg/m2 for six cycles concurrently with IMRT. Primary endpoint was failure-free survival and between-group absolute difference of 10% as the noninferiority margin. RESULTS: A total of 510 patients were enrolled. Median follow-up time was 58.3 months with 85.4% of 3-year failure-free survival in the once-every-3-weeks group and 85.6% in the once-a-week group. An absolute difference of -0.2% (95% confidence interval, -6.3 to 5.9; P noninferiority = 0.0016). Acute toxicities of grade 3 or higher occurred in 55.8% in the once-every-3-weeks group and 66.3% in the once-a-week group (P = 0.015). The most common acute toxicities were hematologic abnormalities, including leukopenia (16% vs. 27%; P = 0.0022) and thrombocytopenia (1% vs. 5%; P = 0.015). The late grade 3-4 auditory loss rate was significantly lower in the once-every-3-weeks group than the once-a-week group (6% vs. 13%; P = 0.0039). CONCLUSIONS: Once-every-3-weeks cisplatin as concurrent chemoradiotherapy is noninferior to once-a-week cisplatin in the treatment efficacy in the LANPC. Although both regimens are well tolerated, severe acute toxicities and late-onset auditory loss are higher in the once-a-week group.