Changing Clinical Epidemiology of Plasmodium vivax Malaria as Transmission Decreases: Population-Based Prospective Panel Survey in the Brazilian Amazon.

BACKGROUND: Malarial infections are often missed by microscopy, and most parasite carriers are asymptomatic in low-endemicity settings. Whether parasite detectability and its ability to elicit symptoms change as transmission declines remains unclear. METHODS: We performed a prospective panel survey with repeated measurements on the same participants over 12 months to investigate whether Plasmodium vivax detectability by microscopy and risk of symptoms upon infection varied during a community-wide larviciding intervention in the Amazon basin of Brazil that markedly reduced vector density. We screened 1096 to 1400 residents in the intervention site for malaria by microscopy and quantitative TaqMan assays at baseline and twice during intervention. RESULTS: We found that more P vivax infections than expected from their parasite densities measured by TaqMan assays were missed by microscopy as transmission decreased. At lower transmission, study participants appeared to tolerate higher P vivax loads without developing symptoms. We hypothesize that changes in the ratio between circulating parasites and those that accumulate in the bone marrow and spleen, by avoiding peripheral blood microscopy detection, account for decreased parasite detectability and lower risk of symptoms under low transmission. CONCLUSIONS: P vivax infections are more likely to be subpatent and remain asymptomatic as malaria transmission decreases.

Pedunculagin and tellimagrandin-I stimulate inflammation and angiogenesis and upregulate vascular endothelial growth factor and tumor necrosis factor-alpha in vivo.

Pedunculagin (PD) and tellimagrandin-I (TL), isolated from Myrciaria cauliflora seeds and Eucaliptus microcorys leaves, respectively, have attracted great attention owing to their relevant biological activities, such as antitumor, antioxidant, and hepatoprotective activities. This study investigated the angiogenic potential of PD and TL using a chick embryo chorioallantoic membrane (CAM) assay. Using the CAM assay, our results showed that both PD and TL promoted a significant increase in the number and caliber of blood vessels, the thickness of the CAM, and the presence of fibroblasts and inflammatory cells. Moreover, an increase of tumor necrosis factor-α and vascular endothelial growth factor was observed in the CAM treated with PD and TL, indicating the induction of angiogenic factors. Thus, the remarkable profile of PD and TL in inducing angiogenesis opens up new perspectives for their potential utilization in different therapeutic approaches involving neovascularization.

Tellimagrandin-I and camptothin a exhibit chemopreventive effects in Salmonella enterica serovar Typhimurium strains and human lymphocytes.

Tellimagrandin-I (TL) and camptothin A (CA) are ellagitannins widely found in diverse plant species. Numerous studies demonstrated their significant biological activities, which include antitumor, antioxidant, and hepatoprotective properties. Despite this protective profile, the effects of TL and CA on DNA have not been comprehensively investigated. Thus, the aim of this study was to determine the mutagenic and antimutagenic effects attributed to TL and CA exposure on Salmonella enterica serovar Typhimurium strains using the Ames test. In addition, the cytotoxic and genotoxic effects were examined on human lymphocytes, employing both trypan blue exclusion and CometChip assay. The antigenotoxic effect was determined following TL and CA exposure in the presence of co-treatment with doxorubicin (DXR). Our results from the Ames test indicated that TL or CA did not display marked mutagenic activity. However, TL or CA demonstrated an ability to protect DNA against the damaging effects of the mutagens 4-nitroquinoline-1-oxide and sodium azide, thereby exhibiting antimutagenic properties. In relation to human lymphocytes, TL or CA did not induce significant cytotoxic or genotoxic actions on these cells. Further, these ellagitannins exhibited an ability to protect DNA from damage induced by DOX during co-treatment, indicating their potential beneficial usefulness as antigenotoxic agents. In conclusion, the protective effects of TL or CA against mutagens, coupled with their absence of genotoxic and cytotoxic effects on human lymphocytes, emphasize their potential therapeutic value in chemopreventive strategies.

Clinical Trajectories and Long-Term Outcomes of Alcoholic Versus Other Forms of Dilated Cardiomyopathy.

BACKGROUND: Alcoholic cardiomyopathy (ACM) is a form of dilated cardiomyopathy (DCM) occurring secondary to long-standing heavy alcohol use and is associated with poor outcomes, but the cause-specific risks are insufficiently understood. METHOD: Between 1997 and 2018, we identified all patients with a first diagnosis of ACM or DCM. The cumulative incidence of different causes of hospitalisation and mortality in the two groups was calculated using the Fine-Gray and Kaplan-Meier methods. RESULTS: A Total of 1,237 patients with ACM (mean age 56.3±10.1 years, 89% men) and 17,211 individuals with DCM (mean age 63.6±13.8 years, 71% men) were identified. Diabetes (10% vs 15%), hypertension (22% vs 31%), and stroke (8% vs 10%) were less common in ACM than DCM, whereas obstructive lung disease (15% vs 12%) and liver disease (17% vs 2%) were more prevalent (p<0.05). Cumulative 5-year mortality was 49% in ACM vs 33% in DCM, p<0.0001, multivariable adjusted hazards ratio 2.11 (95% confidence interval 1.97-2.26). The distribution of causes of death was similar in ACM and DCM, with the predominance of cardiovascular causes in both groups (42% in ACM vs 44% in DCM). 5-year cumulative incidence of heart failure hospitalisations (48% vs 54%) and any somatic cause (59% vs 65%) were also similar in ACM vs DCM. At 1 year, the use of beta blockers (55% vs 80%) and implantable cardioverter defibrillators (3% vs 14%) were significantly less often used in ACM vs DCM. CONCLUSIONS: Patients with ACM had similar cardiovascular risks and hospitalisation patterns as other forms of DCM, but lower use of guideline-directed cardiovascular therapies and greater mortality.

Associations of Maternal Educational Level, Proximity to Greenspace During Pregnancy, and Gestational Diabetes With Body Mass Index From Infancy to Early Adulthood: A Proof-of-Concept Federated Analysis in 18 Birth Cohorts.

International sharing of cohort data for research is important and challenging. We explored the feasibility of multi-cohort federated analyses by examining associations between three pregnancy exposures (maternal education, exposure to green vegetation and gestational diabetes) with offspring BMI from infancy to 17 years. We used data from 18 cohorts (n=206,180 mother-child pairs) from the EU Child Cohort Network and derived BMI at ages 0-1, 2-3, 4-7, 8-13 and 14-17 years. Associations were estimated using linear regression via one-stage IPD meta-analysis using DataSHIELD. Associations between lower maternal education and higher child BMI emerged from age 4 and increased with age (difference in BMI z-score comparing low with high education age 2-3 years = 0.03 [95% CI 0.00, 0.05], 4-7 years = 0.16 [95% CI 0.14, 0.17], 8-13 years = 0.24 [95% CI 0.22, 0.26]). Gestational diabetes was positively associated with BMI from 8 years (BMI z-score difference = 0.18 [CI 0.12, 0.25]) but not at younger ages; however associations attenuated towards the null when restricted to cohorts which measured GDM via universal screening. Exposure to green vegetation was weakly associated with higher BMI up to age one but not at older ages. Opportunities of cross-cohort federated analyses are discussed.

Environmental opportunities facilitating cognitive development in preschoolers: development of a multicriteria index.

Access to environmental opportunities can favor children's learning and cognitive development. The objectives is to construct an index that synthesizes environmental learning opportunities for preschoolers considering the home environment and verify whether the index can predict preschoolers' cognitive development. A quantitative, cross-sectional, exploratory study was conducted with 51 preschoolers using a multi-attribute utility theory (MAUT). The criteria used for drawing up the index were supported by the literature and subdivided in Group A "Resources from the house" extracted from HOME Inventory including: (1) to have three or more puzzles; (2) have at least ten children's books; (3) be encouraged to learn the alphabet; (4) take the family out at least every 2 weeks. Group B "Screens" (5) caution with using television; (6) total screen time in day/minutes. Group C "Parental Schooling" (7) maternal and paternal education. Pearson correlation analyses and univariate linear regression were performed to verify the relationship between the established index with cognitive test results. The index correlated with the total score of the mini-mental state exam (MMC) and verbal fluency test (VF) in the category of total word production and word production without errors. Multicriteria index explained 18% of the VF (total word production), 19% of the VF (total production of words without errors) and 17% of the MMC. The present multicriteria index has potential application as it synthesizes the preschooler's environmental learning opportunities and predicts domains of child cognitive development.

Association between biomarkers of redox status and cytokines with different patterns of habitual physical activity in eutrophic and overweight/obese preschoolers: multivariate analysis of a cross-sectional study.

BACKGROUND: Although it is well known that obesity is frequently associated with reduced levels of habitual physical activity (HPA), which contributes to determining severe oxidative stress and inflammatory state, this association is however unknown in preschoolers so far. This study aimed to investigate the association between biomarkers of redox status and cytokines with different patterns of HPA according to the adiposity of preschoolers. METHODS: A cross-sectional study was conducted in 50 preschoolers (25 overweight/obese, OW/OB and 25 eutrophic, EU), matched for age, sex, economic level, and maternal education. Total antioxidant capacity (TAC), superoxide dismutase (SOD) and catalase (CAT) activities, substances reactive to thiobarbituric acid (TBARS), soluble tumor necrosis factor receptors (sTNFRs), and leptin levels were evaluated. HPA levels were evaluated by accelerometry (ActiGraph GT9X accelerometer). Correlation, multiple linear regression, and partial least squares regression analysis were used to determine the association between redox status biomarkers and cytokines with different patterns of HPA (HPA level, bouts of moderate to vigorous physical activity [MVPA], and multivariate pattern of HPA) in EU and OW/OB preschoolers. RESULTS: OW/OB preschoolers had lower CAT activity, higher levels of TAC, TBARS, and cytokines, and similar levels of HPA to EU preschoolers. In EU preschoolers, SOD activity exhibited a stronger negative association with moderate intensity ranges of HPA (R2 = 0.18), and negative correlation with sTNFRs (r = -0.40 to -0.46). TBARS had a stronger positive association with ranges of light intensity in the multivariate pattern of HPA (R2 = 0.10). In OW/OB preschoolers, the HPA multivariate associative pattern was predominantly from vigorous intensity ranges. Thus, SOD activity had a positive association with the multivariate pattern of HPA (R2 = 0.38) and MVPA bouts (ß [95% CI] = 0.457 [0.0026. 0.0576]). TAC had a negative association with the multivariate pattern of HPA (R2 = 0.38) and MVPA bouts (ß [95% CI] = -0.718 [-0.0025. -0.0003]). Additionally, leptin levels were lower in OW/OB preschoolers engaged in vigorous physical activity (VPA) (8000-9999 counts/min) for longer periods of time. CONCLUSION: The results of this study indicate that OW/OB preschoolers have higher levels of oxidative stress biomarkers and pro-inflammatory cytokines compared to EU preschoolers. Moreover, VPA may exert antioxidative and anti-inflammatory effects in OW/OB preschoolers.

Novel sulfonamide-chalcone hybrid stimulates inflammation, angiogenesis and upregulates vascular endothelial growth factor (VEGF) in vivo.

Chalcones and sulfonamides are well-known chemical groups associated with several biological activities such as antibiotic, anti-inflammatory, and antitumor activities. Over the past few decades, a series of sulfonamide-chalcone hybrids have been synthesized and assessed to develop compounds with interesting biological properties for application in disease therapy. In the present study, a new sulfonamide-chalcone hybrid µ - (2,5-dichloro-N-{4-[(3E)-4-(3-nitrophenyl) buta-1,3-dien-2-yl] phenyl} benzene sulfonamide), or simply CL185, was synthesized, and its angiogenic activity was assessed using the chick embryo chorioallantoic membrane (CAM) assay at different concentrations (12.5, 25, and 50 µg/µL). To further investigate the role of CL185 in the angiogenic process, we evaluated the levels of vascular endothelial growth factor (VEGF) in all treated CAMs. The results showed that all concentrations of CL185 significantly increased tissue vascularization (p < 0.05) as well as the parameters associated with angiogenesis, in which inflammation was the most marked phenomenon observed. In all CAMs treated with CL185, VEGF levels were significantly higher than those in the negative control (p < 0.05), and at the highest concentration, VEGF levels were even higher than in the positive control (p < 0.05). The pronounced angiogenic activity displayed by CL185 may be related to the increase in VEGF levels that were stimulated by inflammatory processes observed in our study. Therefore, CL185 presents a favorable profile for the development of drugs that can be used in pro-angiogenic and tissue repair therapies.

Pedunculagin isolated from Plinia cauliflora seeds exhibits genotoxic, antigenotoxic and cytotoxic effects in bacteria and human lymphocytes.

Pedunculagin (PD), an ellagitannin found in different plant species, possesses several pharmaceutical properties, including antitumor, antioxidant, gastroprotective, hepatoprotective, and anti-inflammatory properties. However, the effects of PD alone on DNA remain to be determined. The aim of this study was to investigate the potential cytotoxic, genotoxic, and antigenotoxic activities of PD isolated from Plinia cauliflora seeds using in silico and in vitro assays. To elucidate the biological activities of PD, in silico tools indicative of antioxidant, antineoplastic, and chemopreventive activities of PD were used. Subsequently, the mutagenic/antimutagenic effects of PD were later assessed using bacteria with the Ames test, and the cytotoxic, genotoxic, and antigenotoxic effects utilizing human lymphocytes as evidenced by trypan blue exclusion test and CometChip assay. In silico analysis indicated potential antioxidant, chemopreventive, free radical scavenger, and cytostatic activities of PD. In the Ames test, PD was found to be not mutagenic; however, this plant component protected DNA against damage-mediated by mutagens 4-nitroquinoline-1-oxide and sodium azide. Regarding human lymphocytes, PD alone was cytotoxic and genotoxic; however, it also reduced DNA damage induced by doxorubicin at co- and post-treatment. In conclusion, PD showed genotoxic, antigenotoxic and cytotoxic effects in human lymphocytes and antimutagenic effects in bacteria.

Physical environmental opportunities for active play and physical activity level in preschoolers: a multicriteria analysis.

BACKGROUND: Active play opportunities seems to influence the level of physical activity during childhood. However, a gap remains about which environmental opportunities including the daycare physical environment could have a positive impact on the level of physical activity in preschoolers. OBJECTIVES: (1) To develop an index to measure the environmental opportunities of free active play for preschoolers of middle-income countries; (2) to check the relationship and contribution of the index to explain objectively the level of physical activity. METHODS: A quantitative, cross-sectional, exploratory study with 51 preschool children. The established criteria for the index according to the literature were: (1) Outdoor time on typical days of the week. (2) Outdoor time on a typical weekend day. (3) The presence of internal space and external environment in the child's home that allows playing. (4) Presence of patio with space for games at the school. (5) Presence of a playground with a toy at the school. We applied multi-attribute utility theory for the determination of the multicriteria index of physical environmental opportunities. Pearson's correlation analysis and simple linear regression were used to verify the association between the index and the physical activity level. RESULTS: The index showed a positive correlation with the level of physical activity, e.g., the average time of MVPA (r = 0.408, p = 0.003). The univariate linear regression demonstrated that the quality of physical environmental opportunities for physical activity explained 20% of the preschooler's classification as active and 16% of the time in moderate to vigorous physical activity (p < 0.001). CONCLUSION: Physical environmental opportunities for active play have a positive effect on physical activity in preschoolers and should be encouraged in different social segments.

Association between executive functions and gross motor skills in overweight/obese and eutrophic preschoolers: cross-sectional study.

BACKGROUND: Preschool age (3-5 years old) is a crucial period for children to acquire gross motor skills and develop executive functions (EFs). However, the association between the qualitative gross motor skills and EFs remains unknown in preschoolers, especially among overweight and obese children. METHODS: This was a cross-sectional, exploratory, and quantitative study carried out on 49 preschool children, divided into two subgroups according to their body mass index (overweight/obese: 24; eutrophic [normal weight]: 25). The mean age was 4.59 years. More than half of the sample were boys (55%) and most of the mothers had completed high school (67%) and were class C socioeconomic level (63%). Gross motor skills were assessed using the Test of Gross Motor Development-2, while EFs were evaluated using Semantic verbal fluency (SVF), Tower of Hanoi (TH), Day/Night Stroop, and Delayed Gratification tests. Multiple linear regression models adjusted for sex, age, maternal education, socioeconomic status, quality of the home environment, and quality of the school environment using the stepwise method were executed, considering the cognitive tasks as independent variables and gross motor skills as dependent variable. RESULTS: The overweight/obese preschoolers showed worse locomotor skills than their eutrophic peers and below average gross motor quotient (GMQ). Overweight/obese girls performed worse in OC skills than boys with excess weight. SVF (number of errors) and TH (rule breaks) explained 57.8% of the variance in object control (OC) skills and 40.5% of the variance in GMQ (p < .05) in the overweight/obese children. Surprisingly, there was no significant association between any of the EF tasks and gross motor skills in the eutrophic children. CONCLUSION: A relationship between EF tasks (number of errors in SVF and rule breaks in TH) and gross motor skills (OC and GMQ) was demonstrated in the overweight/obese preschoolers, indicating that worse cognitive flexibility, working memory, planning, and problem solving are associated with worse gross motor skills in this population when compared to eutrophic children.

In vitro hematotoxicity of Vernonanthura polyanthes leaf aqueous extract and its fractions.

Vernonanthura polyanthes, popularly known as 'assa-peixe', is widely used in Brazil for therapeutic purpose mainly to treat respiratory tract problems. However, few studies investigated its chemical safety. In this way, we first obtained the V. polyanthes leaf aqueous extract (VpLAE) and three fractions (aqueous; n-butanol, n-BF; and ethyl acetate), and we chemically characterized this material. Then, the cytogenotoxic potential of the VpLAE and its fractions was investigated against human erythrocytes and lymphocytes using Trypan blue exclusion test of cell viability and CometChip. The phytochemical screening of V. polyanthes leaf revealed the presence of total phenolic compounds, flavonoids, tannins, coumarins, terpenic compounds, and cardioactive heterosides. n-BF presented the highest total phenolic, flavonoids, and tannins contents and, consequently, the highest antioxidant activity, according to the DPPH free radical scavenging method. Although the VpLAE and its fractions did not cause death of erythrocytes, the cells acquired an echinocytic form. Regarding lymphocytes, VpLAE and its fractions presented cytotoxicity and genotoxicity. When VpLAE or its fractions were co-treated with doxorubicin (DXR), a recognized cytotoxic drug, we observed an enhancement of DXR cytotoxicity against lymphocytes, but the DXR genotoxicity decreased around 15%. Since the VpLAE and its fractions increased the DXR cytotoxicity and decreased its genotoxicity, further studies should be conducted for the development of an adjuvant drug from this extract to reduce the side effects of chemotherapy. Moreover, the indiscriminate use of 'assa-peixe' by local people should be discouraged.

Toxic Potential of Cerrado Plants on Different Organisms.

Cerrado has many compounds that have been used as biopesticides, herbicides, medicines, and others due to their highly toxic potential. Thus, this review aims to present information about the toxicity of Cerrado plants. For this purpose, a review was performed using PubMed, Science Direct, and Web Of Science databases. After applying exclusion criteria, 187 articles published in the last 20 years were selected and analyzed. Detailed information about the extract preparation, part of the plant used, dose/concentration tested, model system, and employed assay was provided for different toxic activities described in the literature, namely cytotoxic, genotoxic, mutagenic, antibacterial, antifungal, antiviral, insecticidal, antiparasitic, and molluscicidal activities. In addition, the steps to execute research on plant toxicity and the more common methods employed were discussed. This review synthesized and organized the available research on the toxic effects of Cerrado plants, which could contribute to the future design of new environmentally safe products.

Anti-angiogenic activity of azathioprine.

Azathioprine (AZA) is the main drug used in immunomodulatory therapy in post-transplant patients or with autoimmune diseases. However, no study has evaluated the AZA angiogenic response. Therefore, this study investigated the effects of AZA on the angiogenic process through macroscopic, histological, and immunohistochemical analyses in chick embryo chorioallantoic membrane (CAM). Our results showed potent anti-angiogenic activity of AZA at the higher concentrations tested in the CAM assay. The histological analysis of CAM confirmed this effect, since AZA induced a significant reduction in all parameters evaluated. In addition, immunohistochemical evaluation of CAM revealed that AZA decreased TGF-ß and VEGF levels, important cytokines involved in the angiogenic process. Therefore, the AZA anti-angiogenic effect identified in our study provides new information for the possible application of this drug in anticancer treatment.

[Evaluation of the Filaria Detect™ IgG4 kit employing recombinant Wb123 antigen for diagnosis of lymphatic filariasis in BrazilEvaluación del estuche Detect™ para pruebas de anticuerpos antifiláricos IgG4, fabricado con el antígeno recombinante Wb123, para el diagnóstico de la filariasis linfática en Brasil]. / Avaliação do kit Filaria Detect™ IgG4 produzido com o antígeno recombinante Wb123 para diagnóstico da filariose linfática no Brasil.

The Global Programme to Eliminate Lymphatic Filariasis, launched by the World Health Organization in the year 2000, proposes the use of circulating filarial antigen tests as a diagnostic tool to assess and monitor initiatives to control filarial infection. However, despite a high sensitivity, these tests are not efficient to detect infection at early stages, before worms have reached the adult stage. Considering this limitation, anti-filarial antibody testing has been suggested as an alternative, given that the antibodies produced against the larvae are detectable before the presence of circulating filarial antigen. The objective of the present study was to determine the diagnostic cut-off and the accuracy of the Filaria Detect™ IgG4 kit employing recombinant Wb123 antigen for diagnosis of lymphatic filariasis in Brazil. For that, we performed a diagnostic evaluation study in which 256 serum samples were analyzed: 79 (30.9%) obtained from microfilaremic individuals and 177 (60.1%) from amicrofilaremic individuals who tested negative with the Bm14 CELISA and Og4C3 ELISA immunologic tests. The ideal cutoff as well as the Filaria Detect™ IgG4 kit accuracy were determined based on ROC curve analyses, with an optical density of 0.239 identified as the cutoff with the best performance, with 81.0% sensitivity and 96.6% specificity. The results show that the Filaria Detect™ IgG4 kit is a promising tool for investigation and monitoring of areas undergoing mass drug administration for lymphatic filariasis.

En el programa mundial de eliminación de la filariasis linfática, puesto en marcha por la Organización Mundial de la Salud en el año 2000, se propone el uso de pruebas de detección del antígeno filárico circulante como instrumento de diagnóstico para la evaluación y el seguimiento de las medidas de control de la parasitosis. Sin embargo, esas pruebas, a pesar de tener un alto grado de sensibilidad, no permiten detectar con eficiencia la infección en su fase inicial, cuando todavía no existen helmintos adultos. En vista de esa limitación, se ha señalado como una opción el estudio de anticuerpos antifiláricos, puesto que los anticuerpos producidos contra las larvas infectantes del parásito se detectan antes de la existencia de antígeno filárico circulante. El objetivo de este estudio fue definir el punto de corte y evaluar la exactitud del estuche Detect™ para pruebas de anticuerpos antifiláricos IgG4, fabricado con el antígeno recombinante Wb123, para el diagnóstico de la filariasis linfática en Brasil. Para ello, se realizó un estudio de evaluación de la prueba diagnóstica, en el cual se utilizaron 256 muestras de suero, a saber, 79 (30,9%) obtenidas de personas microfilarémicas y 177 (60,1%) de personas amicrofilarémicas, que arrojaron resultados seronegativos en las pruebas inmunológicas CELISA Bm14 y ELISA Og4C3. La definición del punto de corte ideal y de la exactitud del estuche Detect™ se obtuvo con la construcción de curvas de la característica operativa del receptor (ROC); una densidad óptica de 0,239 marcó el mejor nivel de desempeño de la prueba, con una sensibilidad de 81,0% y una especificidad de 96,6%. Los resultados obtenidos demostraron que el estuche Detect™ es un instrumento prometedor para la investigación y el seguimiento de las regiones donde se realiza un tratamiento masivo de la filariasis linfática.

Network meta-analysis of His bundle, biventricular, or right ventricular pacing as a primary strategy for advanced atrioventricular conduction disease with normal or mildly reduced ejection fraction.

INTRODUCTION: Although right ventricular pacing (RVP) may impair ventricular function, it is commonly used for advanced atrioventricular block (AVB) and normal or mildly reduced ejection fraction (EF). We aimed to compare His bundle pacing (HBP), biventricular pacing (BiVP), and RVP for advanced AVB in patients with normal or mildly reduced EF. METHODS AND RESULTS: MEDLINE, Embase, Cochrane CENTRAL, ClinicalTrials.gov, Scopus, and Web of Science were searched. Outcomes were all-cause death, heart failure hospitalizations (HFH), EF, left ventricular volumes, 6-minute walk test, and QRS duration. HBP or BiVP was compared with RVP. Subsequently, network meta-analysis compared the three pacing options. Our protocol was registered in PROSPERO (CRD42018094132). Six studies compared BiVP and RVP (704 vs 614 patients) and four compared HBP and RVP (463 vs 568 patients). Follow-up was 6 months to 5 years. There was significantly lower mortality and HFH with HBP or BiVP as compared with RVP (odds ratio [OR], 0.66, [0.51-0.85], P = .002; OR, 0.61 [0.45-0.82], P < .001, respectively]. HBP or BiVP also showed significant increase in EF and decrease in QRS duration (mean difference [MD], 5.27 [3.86-6.69], P < .001; MD -42.2 [-51.2 to -33.3], P < .001, respectively). In network meta-analysis, HBP and BiVP were associated with significantly improved survival compared to RVP, with surface under the cumulative ranking curve (SUCRA) probability of 79.4%, 69.4%, and 1.2% for HBP, BiVP, and RVP, respectively. For HFH, SUCRA probability was 91.5%, 57.2%, and 1.3%, respectively. CONCLUSION: HBP or BiVP were the superior strategies to reduce all-cause death and HFH for advanced AVB with normal or mildly reduced EF, with no significant difference between BiVP and HBP.

Prevention of Stroke in Atrial Fibrillation After Coronary Stenting.

Background and Purpose- The optimal antithrombotic strategy to balance thromboembolic and bleeding events, especially acute stroke, for patients with atrial fibrillation following coronary stenting remains a matter of debate. We conducted a network meta-analysis to identify the antithrombotic regimen associated with the lowest rate of bleeding and thromboembolic events in atrial fibrillation after coronary stenting. Methods- PubMed, Scopus, and Cochrane Central were searched for randomized controlled trials and observational studies of patients with atrial fibrillation after coronary stenting. The outcomes of interest were stroke, myocardial infarction, major adverse cardiac events, mortality, and major bleeding. A network meta-analysis was performed comparing the available antithrombotic regimens in the literature. Results- Three randomized and 15 observational studies were included, with a total of 23 478 participants. Median follow-up was 2 years. Network meta-analysis demonstrated that vitamin K antagonist plus single antiplatelet therapy or direct-acting oral anticoagulant plus single antiplatelet therapy were the most effective regimens in preventing stroke. Direct-acting oral anticoagulant regimens were associated with lower major bleeding rates than vitamin K antagonist regimens. Regimens with dual antiplatelet therapy were associated with lower rates of myocardial infarction. Vitamin K antagonist plus dual antiplatelet therapy was associated with a lower mortality and low-dose direct-acting oral anticoagulants with decreased major cardiovascular adverse events. Conclusions- Direct-acting oral anticoagulant regimens were associated with less major bleeding and major cardiovascular adverse events, but vitamin K antagonists were associated with decreased mortality and stroke. These results suggest that the decision of antithrombotic therapy in patients with atrial fibrillation after percutaneous coronary intervention needs to be individualized.

A meta-analysis of arrhythmia endpoints in randomized controlled trials of transendocardial stem cell injections for chronic ischemic heart disease.

INTRODUCTION: The electrophysiologic impact of cell-based therapy on the injured myocardium remains highly controversial. We aimed to perform a meta-analysis of studies comparing arrhythmia burden following transendocardial stem cell therapy vs placebo in patients with chronic ischemic heart disease (CIHD). METHODS AND RESULTS: PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched. No restriction of stem cell type was specified. The outcomes included sustained supraventricular or ventricular arrhythmias (VAs), sudden cardiac death (SCD), and resuscitated sudden cardiac arrest (SCA). Effect sizes were reported as odds ratio (OR) and 95% CI. Poisson regression was used to account for zero-events data. Twelve randomized trials that included 736 patients (384 in the cell therapy group and 352 in the placebo group) were analyzed. Six different cell types were used. Follow-up ranged from 6 to 12 months. There was a significant decrease in risk of SCD in the cell therapy group, (FE OR, 0.19 [0.04, 0.93]; P = .04). In subgroup analysis, there was a significantly lower risk of SCD or resuscitated SCA in the cell therapy group limited to studies that did not use skeletal myoblasts, (FE OR, 0.23 [0.06, 0.83]; P = .03). There was no significant difference in the incidence of sustained VA between groups (FE OR, 0.91 [0.47, 1.77]; P = .8), even after stratifying by cell type. There was no difference in supraventricular arrhythmias between groups. CONCLUSION: Nonskeletal myoblast transendocardial cell therapy was associated with a significantly lower risk of SCD or resuscitated SCA compared to control, with no proarrhythmic effects.

Leaf heteroblasty in Passiflora edulis as revealed by metabolic profiling and expression analyses of the microRNAs miR156 and miR172.

BACKGROUND AND AIMS: Juvenile-to-adult phase transition is marked by changes in leaf morphology, mostly due to the temporal development of the shoot apical meristem, a phenomenon known as heteroblasty. Sugars and microRNA-controlled modules are components of the heteroblastic process in Arabidopsis thaliana leaves. However, our understanding about their roles during phase-changing in other species, such as Passiflora edulis, remains limited. Unlike Arabidopsis, P. edulis (a semi-woody perennial climbing vine) undergoes remarkable changes in leaf morphology throughout juvenile-to-adult transition. Nonetheless, the underlying molecular mechanisms are unknown. METHODS: Here we evaluated the molecular mechanisms underlying the heteroblastic process by analysing the temporal expression of microRNAs and targets in leaves as well as the leaf metabolome during P. edulis development. KEY RESULTS: Metabolic profiling revealed a unique composition of metabolites associated with leaf heteroblasty. Increasing levels of glucose and α-trehalose were observed during juvenile-to-adult phase transition. Accumulation of microRNA156 (miR156) correlated with juvenile leaf traits, whilst miR172 transcript accumulation was associated with leaf adult traits. Importantly, glucose may mediate adult leaf characteristics during de novo shoot organogenesis by modulating miR156-targeted PeSPL9 expression levels at early stages of shoot development. CONCLUSIONS: Altogether, our results suggest that specific sugars may act as co-regulators, along with two microRNAs, leading to leaf morphological modifications throughout juvenile-to-adult phase transition in P. edulis.