| 1. |
- Adjuik, Martin A., et al.
(författare)
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The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria : a meta-analysis of individual patient data
- 2015
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Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. Methods: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. Results: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. Conclusions: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.
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| 2. |
- Mansoor, Rashid, et al.
(författare)
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Haematological consequences of acute uncomplicated falciparum malaria : a WorldWide Antimalarial Resistance Network pooled analysis of individual patient data
- 2022
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Ingår i: BMC Medicine. - : Springer Nature. - 1741-7015. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPlasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia.MethodsIndividual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall >= 25% at day 3 and day 7.ResultsA total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0-19.7 g/dL) in Africa, 11.6 g/dL (range 5.0-20.0 g/dL) in Asia and 12.3 g/dL (range 6.9-17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to >= 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39-3.05], p < 0.001).ConclusionsIn patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery.
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| 3. |
- Mewton, Nathan, et al.
(författare)
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Rationale and design of the Cyclosporine to ImpRove Clinical oUtcome in ST-elevation myocardial infarction patients (the CIRCUS trial)
- 2015
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Ingår i: American Heart Journal. - : Elsevier BV. - 1097-6744 .- 0002-8703. ; 169:6, s. 6-766
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Tidskriftsartikel (refereegranskat)abstract
- Background Both acute myocardial ischemia and reperfusion contribute to cardiomyocyte death in ST-elevation myocardial infarction (STEMI). The final infarct size is the principal determinant of subsequent clinical outcome in STEMI patients. In a proof-of-concept phase II trial, the administration of cyclosporine prior to primary percutaneous coronary intervention (PPCI) has been associated with a reduction of infarct size in STEMI patients. Methods CIRCUS is an international, prospective, multicenter, randomized, double-blinded, placebo-controlled trial. The study is designed to compare the efficacy and safety of cyclosporine versus placebo, in addition to revascularization by PPCI, in patients presenting with acute anterior myocardial infarction within 12 hours of symptoms onset and initial TIMI flow <= 1 in the culprit left anterior descending coronary artery. Patients are randomized in a 1: 1 fashion to 2.5 mg/kg intravenous infusion of cyclosporine or matching placebo performed in theminutes preceding PCI. The primary efficacy end point of CIRCUS is a composite of 1-year all-cause mortality, rehospitalization for heart failure or heart failure worsening during initial hospitalization, and left ventricular adverse remodeling as determined by sequential transthoracic echochardiography. Secondary outcomes will be tested using a hierarchical sequence of left ventricular (LV) ejection fraction and absolute measurements of LV volumes. The composite of death and rehospitalization for heart failure or heart failure worsening during initial hospitalization will be further assessed at three years after the initial infarction. Results Recruitment lasted from April 2011 to February 2014. The CIRCUS trial has recruited 975 patients with acute anterior myocardial infarction. The 12-months results are expected to be available in 2015. Conclusions The CIRCUS trial is testing the hypothesis that cyclosporine in addition to early revascularization with PPCI compared to placebo in patients with acute anterior myocardial infarction reduces the incidence of death, heart failure and adverse LV remodeling at one-year follow-up.
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| 4. |
- Probst, Anne, et al.
(författare)
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Evaluation of Plant Responses to Atmospheric Nitrogen Deposition in France Using Integrated Soil-Vegetation Models
- 2015
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Ingår i: Critical Loads and Dynamic Risk Assessments : Nitrogen, Acidity and Metals in Terrestrial and Aquatic Ecosystems - Nitrogen, Acidity and Metals in Terrestrial and Aquatic Ecosystems. - Dordrecht : Springer Netherlands. - 1566-0745. - 9789401795074 - 9789401795081 ; 25, s. 359-379
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Bokkapitel (refereegranskat)abstract
- The aim of this chapter is to give an overview of plant responses to nitrogen (N) deposition by using two dynamic biogeochemical models coupled with a vegetation module: VSD+-VEG and ForSAFE-VEG. The biogeochemical models were first validated on some French forest sites from the ICP-Forests network. A French vegetation table (which is now part of a European database) containing 230 species with their appropriate ecological environmental parameters, was set up. The outputs of each model in terms of plant response to atmospheric nitrogen deposition were compared to measured values for one forest stand. The two models underestimated the occurrence of certain herbs and grasses and overestimated (ForSAFE-VEG) or underestimated (VSD+-VEG) the presence of certain mosses. This allowed us to improve the validation and thus the calibration of some parameters. For the simulated period ForSAFE-VEG indicated some variations in the occurrence of the plant groups, the mosses group showing the highest increase and indicating a high sensitivity to atmospheric N deposition. No significant changes in the occurrence percentage of plant groups were observed by running the VSD+-VEG model, this model being less sensitive than ForSAFE-VEG to simulate tenuous vegetation changes. The observed changes over time in the dominant ground plant groups using ForSAFE-VEG could be related to changes in site environmental conditions, but only the influence of the maximum N deposition was obvious. Further investigations are needed to compare the performance of the two models on other sites, but these tests of the ForSAFE-VEG and VSD+-VEG models showed promise for simulating the link between N deposition and vegetation diversity.
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| 5. |
- Thorning, Tanja Kongerslev, et al.
(författare)
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Whole dairy matrix or single nutrients in assessment of health effects : current evidence and knowledge gaps
- 2017
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 105:5, s. 1033-1045
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Tidskriftsartikel (refereegranskat)abstract
- Foods consist of a large number of different nutrients that are contained in a complex structure. The nature of the food structure and the nutrients therein (i.e., the food matrix) will determine the nutrient digestion and absorption, thereby altering the overall nutritional properties of the food. Thus, the food matrix may exhibit a different relation with health indicators compared to single nutrients studied in isolation. The evidence for a dairy matrix effect was presented and discussed by an expert panel at a closed workshop, and the following consensus was reached: 1) Current evidence does not support a positive association between intake of dairy products and risk of cardiovascular disease (i.e., stroke and coronary heart disease) and type 2 diabetes. In contrast, fermented dairy products, such as cheese and yogurt, generally show inverse associations. 2) Intervention studies have indicated that the metabolic effects of whole dairy may be different than those of single dairy constituents when considering the effects on body weight, cardiometabolic disease risk, and bone health. 3) Different dairy products seem to be distinctly linked to health effects and disease risk markers. 4) Different dairy structures and common processing methods may enhance interactions between nutrients in the dairy matrix, which may modify the metabolic effects of dairy consumption. 5) In conclusion, the nutritional values of dairy products should not be considered equivalent to their nutrient contents but, rather, be considered on the basis of the biofunctionality of the nutrients within dairy food structures. 6) Further research on the health effects of whole dairy foods is warranted alongside the more traditional approach of studying the health effects of single nutrients. Future diet assessments and recommendations should carefully consider the evidence of the effects of whole foods alongside the evidence of the effects of individual nutrients. Current knowledge gaps and recommendations for priorities in future research on dairy were identified and presented.
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| 6. |
- Venkatesan, Meera, et al.
(författare)
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Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes : parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.
- 2014
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Ingår i: The American journal of tropical medicine and hygiene. - : American Society of Tropical Medicine and Hygiene. - 1476-1645 .- 0002-9637. ; 91:4, s. 833-43
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Tidskriftsartikel (refereegranskat)abstract
- Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.
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| 7. |
- Barra, Sérgio, et al.
(författare)
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Sex-specific outcomes with addition of defibrillation to resynchronisation therapy in patients with heart failure
- 2017
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 103:10, s. 753-760
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Tidskriftsartikel (refereegranskat)abstract
- Objective Among primary prevention patients with heart failure receiving cardiac resynchronisation therapy (CRT), the impact of additional implantable cardioverter defibrillator (ICD) treatment on outcomes and its interaction with sex remains uncertain. We aim to assess whether the addition of the ICD functionality to CRT devices offers a more pronounced survival benefit in men compared with women, as previous research has suggested. Methods Observational multicentre cohort study of 5307 consecutive patients with ischaemic or nonischaemic dilated cardiomyopathy and no history of sustained ventricular arrhythmias having CRT implantation with (cardiac resynchronisation therapy defibrillator (CRT-D), n=4037) or without (cardiac resynchronisation therapy pacemaker (CRT-P), n=1270) defibrillator functionality. Using propensity score (PS) matching and weighting and cause-of-death data, we assessed and compared the outcome of patients with CRT-D versus CRT-P. This analysis was stratified according to sex. Results After a median follow-up of 34 months (interquartile range 22-60 months) no survival advantage, of CRT-D versus CRT-P was observed in both men and women after PS matching (HR=0.95, 95% CI 0.77 to 1.16, p=0.61, and HR=1.30, 95% CI 0.83 to 2.04, p=0.25, respectively). With inverse-probability weighting, a benefit of CRT-D was seen in male patients (HR 0.78, 95% CI 0.65 to 0.94, p=0.012) but not in women (HR 0.87, 95% CI 0.63 to 1.19, p=0.43). The excess unadjusted mortality of patients with CRT-P compared with CRT-D was related to sudden cardiac death in 7.4% of cases in men but only 2.2% in women. Conclusions In primary prevention patients with CRT indication, the addition of a defibrillator might convey additional benefit only in well-selected male patients.
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| 8. |
- Bousquet, Jean, et al.
(författare)
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Allergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018) : Change management in allergic rhinitis and asthma multimorbidity using mobile technology
- 2019
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 143:3, s. 864-879
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Tidskriftsartikel (refereegranskat)abstract
- Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional.
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| 9. |
- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 10. |
- Hägglund, Sara, et al.
(författare)
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Characterization of an Experimental Vaccine for Bovine Respiratory Syncytial Virus
- 2014
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Ingår i: Clinical and Vaccine Immunology. - 1556-6811 .- 1556-679X. ; 21:7, s. 997-1004
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Tidskriftsartikel (refereegranskat)abstract
- Bovine respiratory syncytial virus (BRSV) and human respiratory syncytial virus (HRSV) are major causes of respiratory disease in calves and children, respectively, and are priorities for vaccine development. We previously demonstrated that an experimental vaccine, BRSV-immunostimulating complex (ISCOM), is effective in calves with maternal antibodies. The present study focuses on the antigenic characterization of this vaccine for the design of new-generation subunit vaccines. The results of our study confirmed the presence of membrane glycoprotein (G), fusion glycoprotein (F), and nucleoprotein (N) proteins in the ISCOMs, and this knowledge was extended by the identification of matrix (M), M2-1, phosphoprotein (P), small hydrophobic protein (SH) and of cellular membrane proteins, such as the integrins alpha(V)beta(1), alpha(V)beta(3), and alpha(3)beta(1). The quantity of the major protein F was 4- to 5-fold greater than that of N (similar to 77 mu g versus similar to 17 mu g/calf dose), whereas G, M, M2-1, P, and SH were likely present in smaller amounts. The polymerase (L), M2-2, nonstructural 1 (NS1), and NS2 proteins were not detected, suggesting that they are not essential for protection. Sera from the BRSV-ISCOM-immunized calves contained high titers of IgG antibody specific for F, G, N, and SH. Antibody responses against M and P were not detected; however, this does not exclude their role in protective T-cell responses. The absence of immunopathological effects of the cellular proteins, such as integrins, needs to be further confirmed, and their possible contribution to adjuvant functions requires elucidation. This work suggests that a combination of several surface and internal proteins should be included in subunit RSV vaccines and identifies absent proteins as potential candidates for differentiating infected from vaccinated animals.
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