| 1. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
- 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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| 3. |
- Kisa, Phyllis, et al.
(författare)
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Unifying Children's Surgery and Anesthesia Stakeholders Across Institutions and Clinical Disciplines : Challenges and Solutions from Uganda
- 2019
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Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 43:6, s. 1435-1449
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThere is a significant unmet need for children's surgical care in low- and middle-income countries (LMICs). Multidisciplinary collaboration is required to advance the surgical and anesthesia care of children's surgical conditions such as congenital conditions, cancer and injuries. Nonetheless, there are limited examples of this process from LMICs. We describe the development and 3-year outcomes following a 2015 stakeholders' meeting in Uganda to catalyze multidisciplinary and multi-institutional collaboration.MethodsThe stakeholders' meeting was a daylong conference held in Kampala with local, regional and international collaborators in attendance. Multiple clinical specialties including surgical subspecialists, pediatric anesthesia, perioperative nursing, pediatric oncology and neonatology were represented. Key thematic areas including infrastructure, training and workforce retention, service delivery, and research and advocacy were addressed, and short-term objectives were agreed upon. We reported the 3-year outcomes following the meeting by thematic area.ResultsThe Pediatric Surgical Foundation was developed following the meeting to formalize coordination between institutions. Through international collaborations, operating room capacity has increased. A pediatric general surgery fellowship has expanded at Mulago and Mbarara hospitals supplemented by an international fellowship in multiple disciplines. Coordinated outreach camps have continued to assist with training and service delivery in rural regional hospitals.ConclusionCollaborations between disciplines, both within LMICs and with international partners, are required to advance children's surgery. The unification of stakeholders across clinical disciplines and institutional partnerships can facilitate increased children's surgical capacity. Such a process may prove useful in other LMICs with a wide range of children's surgery stakeholders.
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| 4. |
- Plomion, Christophe, et al.
(författare)
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Oak genome reveals facets of long lifespan
- 2018
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Ingår i: NATURE PLANTS. - : Springer Science and Business Media LLC. - 2055-026X .- 2055-0278. ; 4:7, s. 440-452
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Tidskriftsartikel (refereegranskat)abstract
- Oaks are an important part of our natural and cultural heritage. Not only are they ubiquitous in our most common landscapes' but they have also supplied human societies with invaluable services, including food and shelter, since prehistoric times(2). With 450 species spread throughout Asia, Europe and America(3), oaks constitute a critical global renewable resource. The longevity of oaks (several hundred years) probably underlies their emblematic cultural and historical importance. Such long-lived sessile organisms must persist in the face of a wide range of abiotic and biotic threats over their lifespans. We investigated the genomic features associated with such a long lifespan by sequencing, assembling and annotating the oak genome. We then used the growing number of whole-genome sequences for plants (including tree and herbaceous species) to investigate the parallel evolution of genomic characteristics potentially underpinning tree longevity. A further consequence of the long lifespan of trees is their accumulation of somatic mutations during mitotic divisions of stem cells present in the shoot apical meristems. Empirical(4) and modelling(5) approaches have shown that intra-organismal genetic heterogeneity can be selected for(6) and provides direct fitness benefits in the arms race with short-lived pests and pathogens through a patchwork of intra-organismal phenotypes(7). However, there is no clear proof that large-statured trees consist of a genetic mosaic of clonally distinct cell lineages within and between branches. Through this case study of oak, we demonstrate the accumulation and transmission of somatic mutations and the expansion of disease-resistance gene families in trees.
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| 5. |
- Reddy, Prashanth, et al.
(författare)
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Intrajejunal Levodopa Versus Conventional Therapy in Parkinson Disease: Motor and Nonmotor Effects.
- 2012
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Ingår i: Clinical neuropharmacology. - 1537-162X. ; 35:5, s. 205-207
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: Seventeen patients with advanced Parkinson disease (PD) were treated with intrajejunal L-dopa infusion (IJL) and compared with a matched group of 9 patients (termed comparator [C]) not given IJL because of funding restriction by primary care trusts (PCTs) in the UK, although considered to be clinically eligible for IJL. Assessments were baseline and follow-up (6 months) with Hoehn and Yahr staging, unified PD rating scale (UPDRS-III and UPDRS-IV), Parkinson disease questionnaire (PDQ-8, quality of life [QoL]) and nonmotor symptom scale (NMSS).Baseline characteristics were comparable between the groups. The IJL-treated group showed highly significant improvements in UPDRS-III (P = 0.005), UPDRS-IV (P = 0.0004), total NMSS score (P = 0.004), and QoL (P = 0.01), whereas the C group showed no change in these parameters. A large effect size of IJL was seen in treated patients for UPDRS-III (1.13), UPDRS-IV (1.52), NMSS score (0.82), and QoL (1.12), whereas continuing conventional treatment registered no effect in C.This study confirms the robust effect of IJL on motor and, in particular, nonmotor symptoms and QoL in advanced PD as described in open-label studies but additionally points to the need for such treatment in those denied this therapy because of centrally dictated funding policies leading to inequalities in health care.
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| 6. |
- Archambault, Alexi N., et al.
(författare)
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Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer
- 2020
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1274-1286.e12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 x 10(-5)). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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| 7. |
- Datry, T., et al.
(författare)
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A global analysis of terrestrial plant litter dynamics in non-perennial waterways
- 2018
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Ingår i: Nature Geoscience. - : Nature Publishing Group. - 1752-0894 .- 1752-0908. ; 11:7, s. 497-503
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Tidskriftsartikel (refereegranskat)abstract
- Perennial rivers and streams make a disproportionate contribution to global carbon (C) cycling. However, the contribution of intermittent rivers and ephemeral streams (IRES), which sometimes cease to flow and can dry completely, is largely ignored although they represent over half the global river network. Substantial amounts of terrestrial plant litter (TPL) accumulate in dry riverbeds and, upon rewetting, this material can undergo rapid microbial processing. We present the results of a global research collaboration that collected and analysed TPL from 212 dry riverbeds across major environmental gradients and climate zones. We assessed litter decomposability by quantifying the litter carbon-to-nitrogen ratio and oxygen (O2) consumption in standardized assays and estimated the potential short-term CO2 emissions during rewetting events. Aridity, cover of riparian vegetation, channel width and dry-phase duration explained most variability in the quantity and decomposability of plant litter in IRES. Our estimates indicate that a single pulse of CO2 emission upon litter rewetting contributes up to 10% of the daily CO2 emission from perennial rivers and stream, particularly in temperate climates. This indicates that the contributions of IRES should be included in global C-cycling assessments.
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| 8. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 9. |
- Kaempfer, Peter, et al.
(författare)
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Elizabethkingia anophelis sp nov., isolated from the midgut of the mosquito Anopheles gambiae
- 2011
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Ingår i: International Journal of Systematic and Evolutionary Microbiology. - : Microbiology Society. - 1466-5026 .- 1466-5034. ; 61, s. 2670-2675
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Tidskriftsartikel (refereegranskat)abstract
- The taxonomic position, growth characteristics and antibiotic resistance properties of a slightly yellow-pigmented bacterial strain, designated R26(T), isolated from the midgut of the mosquito Anopheles gambiae, were studied. The isolate produced rod-shaped cells, which stained Gram-negative. The bacterium had two growth optima at 30-31 degrees C and 37 degrees C. Strain R26(T) demonstrated natural antibiotic resistance to ampicillin, chloramphenicol, kanamycin, streptomycin and tetracycline. 16S rRNA gene sequence analysis revealed that the isolate showed 98.6% sequence similarity to that of Elizabethkingia meningoseptica ATCC 13253(T) and 98.2 % similarity to that of Elizabethkingia miricola GTC 862(T). The major fatty acids of strain R26(T) were iso-C(15:0), iso-C(17:0) 3-OH and summed feature 4 (iso-C(15:0) 2-OH and/or C(16:1)omega 7c/t. Strain R26(T) contained only menaquinone MK-6 and showed a complex polar lipid profile consisting of diphosphatidylglycerol, phosphatidylinositol, an unknown phospholipid and unknown polar lipids and glycolipids. DNA-DNA hybridization experiments with E. meningoseptica CCUG 214(T) (=ATCC 13253(T)) and E. miricola KCTC 12492(T) (=GTC 862(T)) gave relatedness values of 34.5 % (reciprocal 41.5 %) and 35.0 % (reciprocal 25.7 %), respectively. DNA-DNA hybridization results and some differentiating biochemical properties indicate that strain R26T represents a novel species, for which the name Elizabethkingia anophelis sp. nov. is proposed. The type strain is R26(T) (=CCUG 60038(T) =CCM 7804(T)).
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