| 1. |
- Dahal, Prabin, et al.
(författare)
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Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy : an individual participant data meta-analysis
- 2022
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Ingår i: Malaria Journal. - : Springer Nature. - 1475-2875. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- Background: The duration of trial follow-up affects the ability to detect recrudescent infections following anti-malarial treatment. The aim of this study was to explore the proportions of recrudescent parasitaemia as ascribed by genotyping captured at various follow-up time-points in treatment efficacy trials for uncomplicated Plasmodium falciparum malaria.Methods: Individual patient data from 83 anti-malarial efficacy studies collated in the WorldWide Antimalarial Resistance Network (WWARN) repository with at least 28 days follow-up were available. The temporal and cumulative distributions of recrudescence were characterized using a Cox regression model with shared frailty on study-sites. Fractional polynomials were used to capture non-linear instantaneous hazard. The area under the density curve (AUC) of the constructed distribution was used to estimate the optimal follow-up period for capturing a P. falciparum malaria recrudescence. Simulation studies were conducted based on the constructed distributions to quantify the absolute overestimation in efficacy due to sub-optimal follow-up.Results: Overall, 3703 recurrent infections were detected in 60 studies conducted in Africa (15,512 children aged < 5 years) and 23 studies conducted in Asia and South America (5272 patients of all ages). Using molecular genotyping, 519 (14.0%) recurrences were ascribed as recrudescent infections. A 28 day artemether-lumefantrine (AL) efficacy trial would not have detected 58% [95% confidence interval (CI) 47-74%] of recrudescences in African children and 32% [95% CI 15-45%] in patients of all ages in Asia/South America. The corresponding estimate following a 42 day dihydroartemisinin-piperaquine (DP) efficacy trial in Africa was 47% [95% CI 19-90%] in children under 5 years old treated with > 48 mg/kg total piperaquine (PIP) dose and 9% [95% CI 0-22%] in those treated with <= 48 mg/kg PIP dose. In absolute terms, the simulation study found that trials limited to 28 days follow-up following AL underestimated the risk of recrudescence by a median of 2.8 percentage points compared to day 63 estimates and those limited to 42 days following DP underestimated the risk of recrudescence by a median of 2.0 percentage points compared to day 42 estimates. The analysis was limited by few clinical trials following patients for longer than 42 days (9 out of 83 trials) and the imprecision of PCR genotyping which overcalls recrudescence in areas of higher transmission biasing the later distribution.Conclusions: Restricting follow-up of clinical efficacy trials to day 28 for AL and day 42 for DP will miss a proportion of late recrudescent treatment failures but will have a modest impact in derived efficacy. The results highlight that as genotyping methods improve consideration should be given for trials with longer duration of follow-up to detect early indications of emerging drug resistance.
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| 2. |
- Flechard, Chris R., et al.
(författare)
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Carbon-nitrogen interactions in European forests and semi-natural vegetation - Part 1: Fluxes and budgets of carbon, nitrogen and greenhouse gases from ecosystem monitoring and modelling
- 2020
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Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189. ; 17:6, s. 1583-1620
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Tidskriftsartikel (refereegranskat)abstract
- The impact of atmospheric reactive nitrogen (N-r) deposition on carbon (C) sequestration in soils and biomass of unfertilized, natural, semi-natural and forest ecosystems has been much debated. Many previous results of this dC/dN response were based on changes in carbon stocks from periodical soil and ecosystem inventories, associated with estimates of N-r deposition obtained from large-scale chemical transport models. This study and a companion paper (Flechard et al., 2020) strive to reduce uncertainties of N effects on C sequestration by linking multi-annual gross and net ecosystem productivity estimates from 40 eddy covariance flux towers across Europe to local measurement-based estimates of dry and wet N-r deposition from a dedicated collocated monitoring network. To identify possible ecological drivers and processes affecting the interplay between C and N-r inputs and losses, these data were also combined with in situ flux measurements of NO, N2O and CH4 fluxes; soil NO3- leaching sampling; and results of soil incubation experiments for N and greenhouse gas (GHG) emissions, as well as surveys of available data from online databases and from the literature, together with forest ecosystem (BAS-FOR) modelling. Multi-year averages of net ecosystem productivity (NEP) in forests ranged from -70 to 826 gCm(-2) yr(-1) at total wet + dry inorganic N-r deposition rates (N-dep) of 0.3 to 4.3 gNm(-2) yr(-1) and from -4 to 361 g Cm-2 yr(-1) at N-dep rates of 0.1 to 3.1 gNm(-2) yr(-1) in short semi-natural vegetation (moorlands, wetlands and unfertilized extensively managed grasslands). The GHG budgets of the forests were strongly dominated by CO2 exchange, while CH4 and N2O exchange comprised a larger proportion of the GHG balance in short semi-natural vegetation. Uncertainties in elemental budgets were much larger for nitrogen than carbon, especially at sites with elevated N-dep where N-r leaching losses were also very large, and compounded by the lack of reliable data on organic nitrogen and N-2 losses by denitrification. Nitrogen losses in the form of NO, N2O and especially NO3- were on average 27%(range 6 %-54 %) of N-dep at sites with N-dep < 1 gNm(-2) yr(-1) versus 65% (range 35 %-85 %) for N-dep > 3 gNm(-2) yr(-1). Such large levels of N-r loss likely indicate that different stages of N saturation occurred at a number of sites. The joint analysis of the C and N budgets provided further hints that N saturation could be detected in altered patterns of forest growth. Net ecosystem productivity increased with N-r deposition up to 2-2.5 gNm(-2) yr(-1), with large scatter associated with a wide range in carbon sequestration efficiency (CSE, defined as the NEP/GPP ratio). At elevated N-dep levels (> 2.5 gNm(-2) yr(-1)), where inorganic N-r losses were also increasingly large, NEP levelled off and then decreased. The apparent increase in NEP at low to intermediate N-dep levels was partly the result of geographical cross-correlations between N-dep and climate, indicating that the actual mean dC/dN response at individual sites was significantly lower than would be suggested by a simple, straightforward regression of NEP vs. N-dep.
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| 3. |
- Palmer, Elizabeth E., et al.
(författare)
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Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition
- 2023
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Ingår i: Molecular Psychiatry. - : SPRINGERNATURE. - 1359-4184 .- 1476-5578. ; 28:2, s. 668-697
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Tidskriftsartikel (refereegranskat)abstract
- Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
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