Displaying publications 1 - 20 of 30 in total

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  1. Berki DM, Liu L, Choon SE, David Burden A, Griffiths CEM, Navarini AA, et al.
    J. Invest. Dermatol., 2015 Dec;135(12):2964-2970.
    PMID: 26203641 DOI: 10.1038/jid.2015.288
    Caspase recruitment family member 14 (CARD14, also known as CARMA2), is a scaffold protein that mediates NF-κB signal transduction in skin keratinocytes. Gain-of-function CARD14 mutations have been documented in familial forms of psoriasis vulgaris (PV) and pityriasis rubra pilaris (PRP). More recent investigations have also implicated CARD14 in the pathogenesis of pustular psoriasis. Follow-up studies, however, have been limited, so that it is not clear to what extent CARD14 alleles account for the above conditions. Here, we sought to address this question by carrying out a systematic CARD14 analysis in an extended patient cohort (n=416). We observed no disease alleles in subjects with familial PV (n=159), erythrodermic psoriasis (n=23), acral pustular psoriasis (n=100), or sporadic PRP (n=29). Conversely, our analysis of 105 individuals with generalized pustular psoriasis (GPP) identified a low-frequency variant (p.Asp176His) that causes constitutive CARD14 oligomerization and shows a significant association with GPP in Asian populations (P=8.4×10(-5); odds ratio=6.4). These data indicate that the analysis of CARD14 mutations could help stratify pustular psoriasis cohorts but would be mostly uninformative in the context of psoriasis and sporadic PRP.
  2. Bosch J, Eikelboom JW, Connolly SJ, Bruns NC, Lanius V, Yuan F, et al.
    Can J Cardiol, 2017 08;33(8):1027-1035.
    PMID: 28754388 DOI: 10.1016/j.cjca.2017.06.001
    BACKGROUND: Long-term aspirin prevents vascular events but is only modestly effective. Rivaroxaban alone or in combination with aspirin might be more effective than aspirin alone for vascular prevention in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD). Rivaroxaban as well as aspirin increase upper gastrointestinal (GI) bleeding and this might be prevented by proton pump inhibitor therapy.

    METHODS: Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) is a double-blind superiority trial comparing rivaroxaban 2.5 mg twice daily combined with aspirin 100 mg once daily or rivaroxaban 5 mg twice daily vs aspirin 100 mg once daily for prevention of myocardial infarction, stroke, or cardiovascular death in patients with stable CAD or PAD. Patients not taking a proton pump inhibitor were also randomized, using a partial factorial design, to pantoprazole 40 mg once daily or placebo. The trial was designed to have at least 90% power to detect a 20% reduction in each of the rivaroxaban treatment arms compared with aspirin and to detect a 50% reduction in upper GI complications with pantoprazole compared with placebo.

    RESULTS: Between February 2013 and May 2016, we recruited 27,395 participants from 602 centres in 33 countries; 17,598 participants were included in the pantoprazole vs placebo comparison. At baseline, the mean age was 68.2 years, 22.0% were female, 90.6% had CAD, and 27.3% had PAD.

    CONCLUSIONS: COMPASS will provide information on the efficacy and safety of rivaroxaban, alone or in combination with aspirin, in the long-term management of patients with stable CAD or PAD, and on the efficacy and safety of pantoprazole in preventing upper GI complications in patients receiving antithrombotic therapy.

  3. Cai L, Xi Z, Amorim AM, Sugumaran M, Rest JS, Liu L, et al.
    New Phytol., 2019 01;221(1):565-576.
    PMID: 30030969 DOI: 10.1111/nph.15357
    Whole-genome duplications (WGDs) are widespread and prevalent in vascular plants and frequently coincide with major episodes of global and climatic upheaval, including the mass extinction at the Cretaceous-Tertiary boundary (c. 65 Ma) and during more recent periods of global aridification in the Miocene (c. 10-5 Ma). Here, we explore WGDs in the diverse flowering plant clade Malpighiales. Using transcriptomes and complete genomes from 42 species, we applied a multipronged phylogenomic pipeline to identify, locate, and determine the age of WGDs in Malpighiales using three means of inference: distributions of synonymous substitutions per synonymous site (Ks ) among paralogs, phylogenomic (gene tree) reconciliation, and a likelihood-based gene-count method. We conservatively identify 22 ancient WGDs, widely distributed across Malpighiales subclades. Importantly, these events are clustered around the Eocene-Paleocene transition (c. 54 Ma), during which time the planet was warmer and wetter than any period in the Cenozoic. These results establish that the Eocene Climatic Optimum likely represents a previously unrecognized period of prolific WGDs in plants, and lends further support to the hypothesis that polyploidization promotes adaptation and enhances plant survival during episodes of global change, especially for tropical organisms like Malpighiales, which have tight thermal tolerances.
  4. Chen JH, Liu L, Lim PE, Wei D
    Bioprocess Biosyst Eng, 2019 Jul;42(7):1129-1142.
    PMID: 30919105 DOI: 10.1007/s00449-019-02110-z
    Microalgal lipid production by Chlorella protothecoides using sugarcane bagasse hydrolysate was investigated in this study. First, maximum glucose and reducing sugar concentrations of 15.2 and 27.0 g/L were obtained in sugarcane bagasse hydrolysate (SCBH), and the effects of different percentages of glucose and xylose on algal cultivation were investigated. Afterwards, SCBH was used as a carbon source for the cultivation of C. protothecoides and higher biomass concentration of 10.7 g/L was achieved. Additionally, a large amount of fatty acids, accounting up to 16.8% of dry weight, were accumulated in C. protothecoides in the nitrogen-limited (0.1-1 mmol/L) culture. Although SCBH inhibited fatty acid accumulation to a certain degree and the inhibition was aggravated by nitrogen starvation, SCBH favored microalgal cell growth and fatty acid production. The present study is of significance for the integration of cost-effective feedstocks production for biodiesel with low-cost SCBH as well as environmentally friendly disposal of lignocellulosic wastes.
  5. Chen L, Wang Z, Zhang B, Ge M, Ng H, Niu Y, et al.
    Carbohydr Polym, 2019 Feb 01;205:271-278.
    PMID: 30446105 DOI: 10.1016/j.carbpol.2018.10.070
    Carbon and nitrogen sources in culture medium of Antrodia cinnamomea were optimized to eliminate the interference of exterior macromolecules on exopolysaccharide (EPS) yield by submerged fermentation. The results suggested that culture medium containing 50 g/L of glucose and 20 g/L of yeast extract as the optimal carbon and nitrogen sources could produce 1.03 g/L of exopolysaccharides. After purification, two heteropolysaccharides (AC-EPS1 and AC-EPS2) were obtained and characterized to provide the basic structure information. As the main component of the produced EPS, AC-EPS2 (accounting for 89.63%) was mainly composed of galactose (87.42%) with Mw (molecular weight) and R.M.S. (root-mean-square) radius of 1.18 × 105 g/mol and 25.3 nm, respectively. Furthermore, the spherical and flexible chain morphologies of EPS were observed in different solvents by TEM. The structural and morphological information of purified EPS were significant for further study on their structure-activity relationship and related applications.
  6. Cui X, Wang R, Bian P, Wu Q, Seshadri VDD, Liu L
    Artif Cells Nanomed Biotechnol, 2019 Dec;47(1):3391-3398.
    PMID: 31394949 DOI: 10.1080/21691401.2019.1649269
    Nimbolide, a triterpenoid isolated from flower of neem tree possess various therapeutic properties. The objective of the study was to assess the anti-arthritic activity of nimbolide in arthritis induced rats. Nimbolide (20 mg/kg per day) was given orally to arthritic rats induced with Complete Freund's Adjuvant and changes in paw volume, body weight, organ indices (thymus and spleen), arthritic score, biochemical parameters and proinflammatory cytokines levels were determined. Histopathological analysis was also performed. Western blot analysis was also performed. Rats treated with nimbolide displayed marked reduction in arthritic score, organ indices, volume of paw, edema formation, along with substantial enhancement in body weight. Histopathological findings showed significant reduction in destruction of joints and inflammation following nimbolide treatment. The protective action of arthritic rats treated with nimbolide was also substantiated by molecular and biochemical studies. The results of the study show that nimbolide treatment has markedly enhanced health and reduced inflammation via lessening the proinflammatory cytokines expression in arthritic rats. Hence, nimbolide may be used as a potent therapeutic drug in treating rheumatoid arthritis.
  7. Duong M, Islam S, Rangarajan S, Teo K, O'Byrne PM, Schünemann HJ, et al.
    Lancet Respir Med, 2013 Oct;1(8):599-609.
    PMID: 24461663 DOI: 10.1016/S2213-2600(13)70164-4
    BACKGROUND: Despite the rising burden of chronic respiratory diseases, global data for lung function are not available. We investigated global variation in lung function in healthy populations by region to establish whether regional factors contribute to lung function.

    METHODS: In an international, community-based prospective study, we enrolled individuals from communities in 17 countries between Jan 1, 2005, and Dec 31, 2009 (except for in Karnataka, India, where enrolment began on Jan 1, 2003). Trained local staff obtained data from participants with interview-based questionnaires, measured weight and height, and recorded forced expiratory volume in 1 s (FEV₁) and forced vital capacity (FVC). We analysed data from participants 130-190 cm tall and aged 34-80 years who had a 5 pack-year smoking history or less, who were not affected by specified disorders and were not pregnant, and for whom we had at least two FEV₁ and FVC measurements that did not vary by more than 200 mL. We divided the countries into seven socioeconomic and geographical regions: south Asia (India, Bangladesh, and Pakistan), east Asia (China), southeast Asia (Malaysia), sub-Saharan Africa (South Africa and Zimbabwe), South America (Argentina, Brazil, Colombia, and Chile), the Middle East (Iran, United Arab Emirates, and Turkey), and North America or Europe (Canada, Sweden, and Poland). Data were analysed with non-linear regression to model height, age, sex, and region.

    FINDINGS: 153,996 individuals were enrolled from 628 communities. Data from 38,517 asymptomatic, healthy non-smokers (25,614 women; 12,903 men) were analysed. For all regions, lung function increased with height non-linearly, decreased with age, and was proportionately higher in men than women. The quantitative effect of height, age, and sex on lung function differed by region. Compared with North America or Europe, FEV1 adjusted for height, age, and sex was 31·3% (95% CI 30·8-31·8%) lower in south Asia, 24·2% (23·5-24·9%) lower in southeast Asia, 12·8% (12·4-13·4%) lower in east Asia, 20·9% (19·9-22·0%) lower in sub-Saharan Africa, 5·7% (5·1-6·4%) lower in South America, and 11·2% (10·6-11·8%) lower in the Middle East. We recorded similar but larger differences in FVC. The differences were not accounted for by variation in weight, urban versus rural location, and education level between regions.

    INTERPRETATION: Lung function differs substantially between regions of the world. These large differences are not explained by factors investigated in this study; the contribution of socioeconomic, genetic, and environmental factors and their interactions with lung function and lung health need further clarification.

    FUNDING: Full funding sources listed at end of the paper (see Acknowledgments).

  8. Kamei KI, Mashimo Y, Yoshioka M, Tokunaga Y, Fockenberg C, Terada S, et al.
    Small, 2017 05;13(18).
    PMID: 28272774 DOI: 10.1002/smll.201603104
    Cellular microenvironments are generally sophisticated, but crucial for regulating the functions of human pluripotent stem cells (hPSCs). Despite tremendous effort in this field, the correlation between the environmental factors-especially the extracellular matrix and soluble cell factors-and the desired cellular functions remains largely unknown because of the lack of appropriate tools to recapitulate in vivo conditions and/or simultaneously evaluate the interplay of different environment factors. Here, a combinatorial platform is developed with integrated microfluidic channels and nanofibers, associated with a method of high-content single-cell analysis, to study the effects of environmental factors on stem cell phenotype. Particular attention is paid to the dependence of hPSC short-term self-renewal on the density and composition of extracellular matrices and initial cell seeding densities. Thus, this combinatorial approach provides insights into the underlying chemical and physical mechanisms that govern stem cell fate decisions.
  9. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al.
    Autophagy, 2016;12(1):1-222.
    PMID: 26799652 DOI: 10.1080/15548627.2015.1100356
  10. Law ZK, Meretoja A, Engelter ST, Christensen H, Muresan EM, Glad SB, et al.
    Eur Stroke J, 2017 Mar;2(1):13-22.
    PMID: 31008298 DOI: 10.1177/2396987316676610
    Purpose: Haematoma expansion is a devastating complication of intracerebral haemorrhage (ICH) with no established treatment. Tranexamic acid had been an effective haemostatic agent in reducing post-operative and traumatic bleeding. We review current evidence examining the efficacy of tranexamic acid in improving clinical outcome after ICH.

    Method: We searched MEDLINE, EMBASE, CENTRAL and clinical trial registers for studies using search strategies incorporating the terms 'intracerebral haemorrhage', 'tranexamic acid' and 'antifibrinolytic'. Authors of ongoing clinical trials were contacted for further details.

    Findings: We screened 268 publications and retrieved 17 articles after screening. Unpublished information from three ongoing clinical trials was obtained. We found five completed studies. Of these, two randomised controlled trials (RCTs) comparing intravenous tranexamic acid to placebo (n = 54) reported no significant difference in death or dependency. Three observational studies (n = 281) suggested less haematoma growth with rapid tranexamic acid infusion. There are six ongoing RCTs (n = 3089) with different clinical exclusions, imaging selection criteria (spot sign and haematoma volume), time window for recruitment and dosing of tranexamic acid.

    Discussion: Despite their heterogeneity, the ongoing trials will provide key evidence on the effects of tranexamic acid on ICH. There are uncertainties of whether patients with negative spot sign, large haematoma, intraventricular haemorrhage, or poor Glasgow Coma Scale should be recruited. The time window for optimal effect of haemostatic therapy in ICH is yet to be established.

    Conclusion: Tranexamic acid is a promising haemostatic agent for ICH. We await the results of the trials before definite conclusions can be drawn.

  11. Lee CH, Ko AM, Warnakulasuriya S, Ling TY, Sunarjo, Rajapakse PS, et al.
    Am J Public Health, 2012 Mar;102(3):e17-24.
    PMID: 22390524 DOI: 10.2105/AJPH.2011.300521
    We investigated the population burden of betel quid abuse and its related impact on oral premalignant disorders (OPDs) in South, Southeast, and East Asia.
  12. Li H, Liu L, Dang M, Zhang W, Liu J
    Int. J. Neurosci., 2019 Sep 13.
    PMID: 31516045 DOI: 10.1080/00207454.2019.1667797
    The present study was designed to explore the relative susceptibility of in vitro fertilization (IVF)-conceived mice to global cerebral ischemic injury with the possible role of hydrogen sulfide and enzymes responsible for its production. IVF was carried to obtain pups, which were allowed to grow to the age of eight weeks. Thereafter, male mice were subjected to 20 minutes of global ischemia and 24 hours of reperfusion. The mice obtained from other groups including normal mating; superovulation, but normal mating and normal mating, but embryo implantation were also subjected to global ischemia-reperfusion (I/R) injury. IVF-derived mice exhibited significant more injury in response to I/R injury in comparison to other groups assessed in terms of impairment in locomotor activity, development of motor in coordination, neurological severity score, cerebral infarction, apoptosis markers (caspase-3 activity and Bcl-2 expression). Moreover, there was a relative decrease in the brain levels of hydrogen sulfide (H2S) and its biosynthetic enzymes viz. cystathionine-β-synthase and cystathionine-γ-lyase. Interestingly, the levels of H2S and cystathionine-γ-lyase were significantly low in IVF-derived mice in basal conditions also i.e. before subjecting to I/R injury and these biochemical alterations were associated with the behavioral deficits in mice, even before subjecting to I/R injury. It is concluded that in vitro fertilization-derived mice are more susceptible to global cerebral ischemia reperfusion injury, which may be possibly due to decreased levels of hydrogen sulfide and its biosynthetic enzymes viz., cystathionine-β-synthase and cystathionine-γ-lyase.
  13. Li X, Xu A, Sheng H, Ting TH, Mao X, Huang X, et al.
    Pediatr Diabetes, 2018 03;19(2):251-258.
    PMID: 28791793 DOI: 10.1111/pedi.12560
    BACKGROUND: Sulfonylurea therapy can improve glycemic control and ameliorate neurodevelopmental outcomes in patients suffering from neonatal diabetes mellitus (NDM) with KCNJ11 or ABCC8 mutations. As genetic testing results are often delayed, it remains controversial whether sulfonylurea treatment should be attempted immediately at diagnosis or doctors should await genetic confirmation.

    OBJECTIVE: This study aimed to investigate the effectiveness and safety of sulfonylurea therapy in Chinese NDM patients during infancy before genetic testing results were available.

    METHODS: The medical records of NDM patients with their follow-up details were reviewed and molecular genetic analysis was performed. Sulfonylurea transfer regimens were applied in patients diagnosed after May 2010, and glycemic status and side effects were evaluated in each patient.

    RESULTS: There were 23 NDM patients from 22 unrelated families, 10 had KCNJ11 mutations, 3 harbored ABCC8 mutations, 1 had INS mutations, 4 had chromosome 6q24 abnormalities, 1 had a deletion at chromosome 1p36.23p36.12, and 4 had no genetic abnormality identified. Sixteen NDM infants were treated with glyburide at an average age of 49 days (range 14-120 days) before genetic confirmation. A total of 11 of 16 (69%) were able to successfully switch to glyburide with a more stable glucose profile. The responsive glyburide dose was 0.51 ± 0.16 mg/kg/d (0.3-0.8 mg/kg/d), while the maintenance dose was 0.30 ± 0.07 mg/kg/d (0.2-0.4 mg/kg/d). No serious adverse events were reported.

    CONCLUSIONS: Molecular genetic diagnosis is recommended in all patients with NDM. However, if genetic testing results are delayed, sulfonylurea therapy should be considered before such results are received, even in infants with newly diagnosed NDM.

  14. Li X, Ting TH, Sheng H, Liang CL, Shao Y, Jiang M, et al.
    BMC Pediatr, 2018 03 06;18(1):101.
    PMID: 29510678 DOI: 10.1186/s12887-018-1060-8
    BACKGROUND: There is scarcity of information on the clinical features and genetics of glucokinase-maturity-onset diabetes of the young (GCK-MODY) in China. The aim of the study was to investigate the clinical and molecular characteristics of Chinese children with GCK-MODY.

    METHODS: Eleven children with asymptomatic hyperglycemia and clinically suspected GCK-MODY were identified from the database of children with diabetes in the biggest children's hospital in South China. Clinical data were obtained from medical records. Blood was collected from the patients and their parents for glucokinase (GCK) gene analysis. Parents without diabetes were tested for fasting glucose and HbA1c. Clinical information and blood for GCK gene analysis were obtained from grandparents with diabetes. GCK gene mutational analysis was performed by polymerase chain reaction and direct sequencing. Patients without a GCK gene mutation were screened by targeted next-generation sequencing (NGS) technology for other MODY genes.

    RESULTS: Nine children tested positive for GCK gene mutations while two were negative. The nine GCK-MODY patients were from unrelated families, aged 1 month to 9 years and 1 month at first detection of hyperglycaemia. Fasting glucose was elevated (6.1-8.5 mmol/L), HbA1c 5.2-6.7% (33.3-49.7 mmol/mol), both remained stable on follow-up over 9 months to 5 years. Five detected mutations had been previously reported: p.Val182Met, c.679 + 1G > A, p.Gly295Ser, p.Arg191Gln and p.Met41Thr. Four mutations were novel: c.483 + 2 T > A, p.Ser151del, p.Met57GlyfsX29 and p.Val374_Ala377del. No mutations were identified in the other two patients, who were also tested by NGS.

    CONCLUSIONS: GCK gene mutations are detected in Chinese children and their family members with typical clinical features of GCK-MODY. Four novel mutations are detected.
  15. Liu L, Han ZB, Wang SM, Yuan DQ, Ng SW
    Inorg Chem, 2015 Apr 20;54(8):3719-21.
    PMID: 25849722 DOI: 10.1021/acs.inorgchem.5b00185
    Herein, two stable lead(II) molecular-bowl-based metal-organic frameworks and their micro- and nanosized forms with open metal sites were presented. These materials could act as Lewis acid catalysts to cyanosilylation reaction. Moreover, the catalytic performances are size-dependent, with the catalyst with nanosized form being 1 order of magnitude more efficient than those with micro- and millisized forms.
  16. Liu L, Mo Z, Liang Z, Zhang Y, Li R, Ong KC, et al.
    BMC Med, 2015;13:226.
    PMID: 26381232 DOI: 10.1186/s12916-015-0448-7
    To investigate the long-term effects on immunity of an inactivated enterovirus 71 (EV71) vaccine and its protective efficacy.
  17. Liu L, Mi J, Wang Y, Zou Y, Ma B, Liao X, et al.
    Sci. Total Environ., 2018 Apr 01;619-620:1673-1681.
    PMID: 29056384 DOI: 10.1016/j.scitotenv.2017.10.133
    Antibiotic residues in swine manure when entered the soil would most likely affect the complex composition and functions of the soil microbiome, which is also responsible for degrading these antibiotics. Three different methods of adding ciprofloxacin (CIP), a common antibiotic used in the swine industry, to the soil were used to investigate the effects of CIP on the soil microbiome and the degradation of CIP. Results of the study showed that the microbiome could promote the degradation of CIP in the soil when CIP was incorporated into the soil together with manure. However, the CIP degradation time was prolonged when adding the manure of swine fed with diet containing CIP in the soil. All treatments did not affect the copy number of the resistance genes, except for aac(6')-Ib-cr, as compared with the initial numbers of each treatment. MiSeq Illumina sequencing and Biolog-ECO microplates results showed that CIP had a significant effect on the abundance, structure, and function of the soil microbiome, but different addition methods resulted in distinct effects. Results of the present study demonstrated that the microbiome and fate of CIP responded differently to the different methods of adding CIP to the soil.
  18. Liu L, Chen J, Lim PE, Wei D
    Bioresour. Technol., 2018 May;255:140-148.
    PMID: 29414159 DOI: 10.1016/j.biortech.2018.01.114
    The single cell oil (SCO) production by the mono and mixed culture of microalgae Chlorella pyrenoidosa and red yeast Rhodotorula glutinis was investigated using non-detoxified cassava bagasse hydrolysate (CBH) as carbon source. The results suggested that the two strains were able to tolerate and even degrade some byproducts presented in the CBH, and the mixed culture approach enhanced the degradation of certain byproducts. Biomass (20.37 ± 0.38 g/L) and lipid yield (10.42 ± 1.21 g/L) of the mixed culture achieved in the batch culture were significantly higher than that of the mono-cultures (p L and 18.47 ± 3.25 g/L, respectively. The lipids mainly composed of oleic acid and palmitic acid, suggesting the potential applications such as biofuel feedstock, cosmetics, food additives and lubricant. This study provided new insights for the integration of the economical SCO production with agro-industrial waste disposal.
  19. Lonn E, Bosch J, Pogue J, Avezum A, Chazova I, Dans A, et al.
    Can J Cardiol, 2016 Mar;32(3):311-8.
    PMID: 26481083 DOI: 10.1016/j.cjca.2015.07.001
    Cholesterol and blood pressure (BP) can be effectively and safely lowered with statin drugs and BP-lowering drugs, reducing major cardiovascular (CV) events by 20%-30% within 5 years in high-risk individuals. However, there are limited data in lower-risk populations. The Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial is evaluating whether cholesterol lowering with a statin drug, BP lowering with low doses of 2 antihypertensive agents, and their combination safely reduce major CV events in individuals at intermediate risk who have had no previous vascular events and have average cholesterol and BP levels.
  20. Lonn EM, Bosch J, López-Jaramillo P, Zhu J, Liu L, Pais P, et al.
    N. Engl. J. Med., 2016 May 26;374(21):2009-20.
    PMID: 27041480 DOI: 10.1056/NEJMoa1600175
    BACKGROUND: Antihypertensive therapy reduces the risk of cardiovascular events among high-risk persons and among those with a systolic blood pressure of 160 mm Hg or higher, but its role in persons at intermediate risk and with lower blood pressure is unclear.
    METHODS: In one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to receive either candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; the second coprimary outcome additionally included resuscitated cardiac arrest, heart failure, and revascularization. The median follow-up was 5.6 years.
    RESULTS: The mean blood pressure of the participants at baseline was 138.1/81.9 mm Hg; the decrease in blood pressure was 6.0/3.0 mm Hg greater in the active-treatment group than in the placebo group. The first coprimary outcome occurred in 260 participants (4.1%) in the active-treatment group and in 279 (4.4%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P=0.40); the second coprimary outcome occurred in 312 participants (4.9%) and 328 participants (5.2%), respectively (hazard ratio, 0.95; 95% CI, 0.81 to 1.11; P=0.51). In one of the three prespecified hypothesis-based subgroups, participants in the subgroup for the upper third of systolic blood pressure (>143.5 mm Hg) who were in the active-treatment group had significantly lower rates of the first and second coprimary outcomes than those in the placebo group; effects were neutral in the middle and lower thirds (P=0.02 and P=0.009, respectively, for trend in the two outcomes).
    CONCLUSIONS: Therapy with candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day was not associated with a lower rate of major cardiovascular events than placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.).
    Note: Malaysia is a study site (Author: Yusoff K)
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