| 1. |
- Kampmann, Christian, 1975-
(författare)
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Go with your gut : The human intestinal microbiota, international travel, Campylobacter and ESBL-producing Enterobacteriaceae
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Up to 100 million people travel annually from industrialized countries to resource-limited ones. Each traveller contains an internal ecosystem composed of tens of trillions of microbes, known as the intestinal microbiota, which has a large effect on health. The microbiota seems to be highly individual and mostly stable but can be significantly affected by several factors. Many international travellers are at high risk of getting infected by Campylobacter, the most common cause of bacterial enteritis worldwide. Campylobacter infection can cause a wide range of symptoms, with varying severity, for reasons largely unknown. Travel also radically increases the risk of colonization by antibiotic-resistant intestinal bacteria, notably Extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (EPE). To date, there are no therapies available for EPE-decolonization. In this thesis, it was investigated whether the bacterial intestinal microbiota affected susceptibility to Campylobacter and if international travel as such had an impact on the microbiota. In a prospective, observational study, 67 healthy Swedes, travelling in groups to countries with a high risk of Campylobacter infection, were followed. The travellers answered questionnaires and delivered two faecal samples before and three samples after the trip. These samples were cultured for enteropathogens and analysed for the microbiota composition. Low diversity of microbiota seemed to increase the risk of Campylobacter jejuni infection, whereas a high relative abundance of Lachnospiraceae might decrease the risk (Paper I). Furthermore, the overall bacterial diversity did not seem to change in connection with travelling. However, the bacterial family Enterobacteriaceae (otherwise connected with inflammation, infection and antibiotic-resistance) was shown to be dramatically increased in abundance immediately after travel, and the family Christensenellaceae (otherwise connected with beneficial health conditions) simultaneously decreased (Paper II). Eight travellers, from two different destinations, were infected with closely related C. jejuni isolates (ST353CC). The bacterial analysis of genomic and phenotypic characteristics revealed that the C. jejuni isolates of the travellers returning from one of the destinations and with more severe symptoms actually showed less pathogenic potential, compared to the isolates of travellers from the other destination and with milder symptoms. However, the travellers with more severe symptoms had much higher relative abundances of Bacteroidetes in their intestinal microbiota and, in contrast to the other travellers, excluded meat from their diet. (Paper III) Finally, we investigated in a randomized, placebo-controlled clinical trial of 80 established intestinal carriers of EPE, whether the oral probiotic product Vivomixx® could eradicate EPE. Vivomixx® was not superior to placebo (Paper IV).
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| 2. |
- Anderberg, Eva, et al.
(författare)
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Prevalence of impaired glucose tolerance and diabetes after gestational diabetes mellitus comparing different cut-off criteria for abnormal glucose tolerance during pregnancy.
- 2011
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Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 90, s. 1252-1258
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To determine the prevalence of diabetes and impaired glucose tolerance after gestational diabetes mellitus in relation to different categories of glucose tolerance during pregnancy. Design. Prospective study. Setting. Four delivery departments and three hospitals in southern Sweden took part in recruitment and follow-up. Population. Women undergoing a 75 g oral glucose tolerance test during pregnancy delivering in 2003-2005. Methods. At first follow-up, 1-2 years after delivery, 29% of eligible women with abnormal glucose tolerance during pregnancy had an oral glucose tolerance test; 160 with gestational diabetes, 309 with gestational impaired glucose tolerance, in addition to 167 control women. Cut-off levels defining gestational diabetes and impaired glucose tolerance were 2-hour capillary blood glucose levels 9.0 and 7.8 mmol/l or plasma glucose 10.0 and 8.6 mmol/l, respectively. Main outcome measures. Frequency of abnormal test results at follow-up. Results: Diabetes was diagnosed in 11% and impaired glucose tolerance in 24% of women with gestational diabetes vs. 4% and 23% in those with gestational impaired glucose tolerance. Combining women with abnormal test results during pregnancy revealed diabetes or impaired glucose tolerance in 29% as compared to 10% among controls; the odds ratio (95% confidence interval) for having abnormal test results was 3.3 (1.8-5.9) in a multivariate logistic regression analysis. Conclusions: Lowering the cut-off level for gestational diabetes to also include the category of impaired glucose tolerance would identify a high percentage of women with diabetes and impaired glucose tolerance postpartum, they constitute target groups for intervention and/or diabetes prevention.
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| 3. |
- Dahal, Prabin, et al.
(författare)
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Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria : a WorldWide Antimalarial Resistance Network individual participant data meta-analysis
- 2019
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Ingår i: Malaria Journal. - : BMC. - 1475-2875 .- 1475-2875. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections.Methods: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.Results: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (rho): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [rho: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold.Conclusions: The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.
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| 4. |
- 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 .- 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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| 5. |
- Henriksson, Jens, et al.
(författare)
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Out-of-Distribution Detection as Support for Autonomous Driving Safety Lifecycle
- 2023
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Ingår i: <em>Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatic. )</em>Volume 13975 LNCS, Pages 233 - 242. - : Springer Science and Business Media Deutschland GmbH. - 9783031297854 ; , s. 233-242
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Konferensbidrag (refereegranskat)abstract
- The automotive industry is moving towards increased automation, where features such as automated driving systems typically include machine learning (ML), e.g. in the perception system. [Question/Problem] Ensuring safety for systems partly relying on ML is challenging. Different approaches and frameworks have been proposed, typically where the developer must define quantitative and/or qualitative acceptance criteria, and ensure the criteria are fulfilled using different methods to improve e.g., design, robustness and error detection. However, there is still a knowledge gap between quality methods and metrics employed in the ML domain and how such methods can contribute to satisfying the vehicle level safety requirements. In this paper, we argue the need for connecting available ML quality methods and metrics to the safety lifecycle and explicitly show their contribution to safety. In particular, we analyse Out-of-Distribution (OoD) detection, e.g., the frequency of novelty detection, and show its potential for multiple safety-related purposes. I.e., as (a) an acceptance criterion contributing to the decision if the software fulfills the safety requirements and hence is ready-for-release, (b) in operational design domain selection and expansion by including novelty samples into the training/development loop, and (c) as a run-time measure, e.g., if there is a sequence of novel samples, the vehicle should consider reaching a minimal risk condition. [Contribution] This paper describes the possibility to use OoD detection as a safety measure, and the potential contributions in different stages of the safety lifecycle. © 2023, The Author(s)
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| 6. |
- Jovel, Irina Tatiana, et al.
(författare)
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Temporal and Seasonal Changes of Genetic Polymorphisms Associated with Altered Drug Susceptibility to Chloroquine, Lumefantrine, and Quinine in Guinea-Bissau between 2003 and 2012.
- 2015
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Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 59:2, s. 872-9
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Tidskriftsartikel (refereegranskat)abstract
- In 2008, artemether-lumefantrine was introduced in Guinea-Bissau, West Africa, but quinine has also been commonly prescribed for the treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine have been described. P. falciparum chloroquine resistance transporter (pfcrt) K76T, pfmdr1 gene copy numbers, pfmdr1 polymorphisms N86Y and Y184F, and pfmdr1 sequences 1034 to 1246 were determined using PCR-based methods. Blood samples came from virtually all (n = 1,806) children <15 years of age who had uncomplicated P. falciparum monoinfection and presented at a health center in suburban Bissau (from 2003 to 2012). The pfcrt K76T and pfmdr1 N86Y frequencies were stable, and seasonal changes were not seen from 2003 to 2007. Since 2007, the mean annual frequencies increased (P < 0.001) for pfcrt 76T (24% to 57%), pfmdr1 N86 (72% to 83%), and pfcrt 76 + pfmdr1 86 TN (10% to 27%), and pfcrt 76T accumulated during the high transmission season (P = 0.001). The pfmdr1 86 + 184 NF frequency increased from 39% to 66% (from 2003 to 2011; P = 0.004). One sample had two pfmdr1 gene copies. pfcrt 76T was associated with a lower parasite density (P < 0.001). Following the discontinuation of an effective chloroquine regimen, probably highly artemether-lumefantrine-susceptible P. falciparum (with pfcrt 76T) accumulated, possibly due to suboptimal use of quinine and despite a fitness cost linked to pfcrt 76T. (The studies reported here were registered at ClinicalTrials.gov under registration no. NCT00137514 [PSB-2001-chl-amo], NCT00137566 [PSB-2004-paracetamol], NCT00426439 [PSB-2006-coartem], NCT01157689 [AL-eff 2010], and NCT01704508 [Eurartesim 2012].).
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| 7. |
- Jovel, Irina T., et al.
(författare)
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Unexpected selections of Plasmodium falciparum polymorphisms in previously treatment-naive areas after monthly presumptive administration of three different anti-malarial drugs in Liberia 1976-78
- 2017
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875 .- 1475-2875. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: To assess the effect on malaria prevalence, village specific monthly administrations of pyrimethamine, chlorproguanil, chloroquine or placebo were given to children in four previously treatment-naive Liberian villages, 1976-78. Plasmodium falciparum in vivo resistance developed to pyrimethamine only. Selection of molecular markers of P.falciparum resistance after 2 years of treatment are reported. Methods: Blood samples were collected from 191 study children in a survey in 1978. Polymorphisms in pfcrt, pfmdr1, pfdhfr, pfdhps, pfmrp1 and pfnhe1 genes were determined using PCR-based methods. Results: Pfcrt 72-76 CVIET was found in one chloroquine village sample, all remaining samples had pfcrt CVMNK. Pfmdr1 N86 prevalence was 100%. A pfmdr1 T1069(ACT -> ACG) synonymous polymorphism was found in 30% of chloroquine village samples and 3% of other samples (P = 0.008). Variations in pfnhe1 block I were found in all except the chloroquine treated village (P < 0.001). Resistance associated pfdhfr 108N prevalence was 2% in the pyrimethamine village compared to 45-65% elsewhere, including the placebo village (P = 0.001). Conclusions: Chloroquine treatment possibly resulted in the development of pfcrt 72-76 CVIET. Selection of pfmdr1 T1069(ACG) and a pfnhe1 block 1 genotypes indicates that chloroquine treatment exerted a selective pressure on P. falciparum. Pyrimethamine resistance associated pfdhfr 108N was present prior to the introduction of any drug. Decreased pfdhfr 108N frequency concurrent with development of pyrimethamine resistance suggests a non-pfdhfr polymorphisms mediated resistance mechanism.
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| 8. |
- Kofoed, Poul-Erik, et al.
(författare)
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Paracetamol versus placebo in treatment of non-severe malaria in children in Guinea-Bissau : a randomized controlled trial
- 2011
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875 .- 1475-2875. ; 10, s. 148-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:The current guidelines for treatment of malaria include paracetamol to children with fever. No convincing evidence for the beneficial effects of this practice exists. Studies show that time to parasite clearance is significantly longer in children treated with paracetamol, which questions the policy. Whether this is of clinical importance has not been investigated.METHODS:Children with Plasmodium falciparum monoinfection and ≥20 parasites per 200 leucocytes at the Bandim Health Centre, Guinea-Bissau were randomized to receive paracetamol or placebo together with chloroquine for three days in a double blind randomized study. Temperature and symptoms were recorded twice daily during treatment and on day 3. The participants were interviewed and a malaria film taken once weekly until day 35. The data is in the form of grouped failure-times, the outcome of interest being time until parasitaemia during follow-up. Mantel-Haenszel weighted odds ratios are given. Other differences between and within the two groups have been tested using the Chi-square test and Mann-Whitney U test.RESULTS:In the evening of the day of inclusion, the temperature was slightly, but statistically insignificant, higher in the placebo group and significantly more children complained of headache. At no other time was a significant difference in temperature or symptoms detected. However, 6 children from the placebo-group as compared to two children from the paracetamol-group were admitted to hospital with high fever and convulsions by day 3. No differences in the cumulative percentages of children with adequate clinical and parasitological response were found in the intention-to-treat analysis or in the per-protocol analysis.CONCLUSION:Fewer children had early treatment failure and the mean temperature was slightly lower in the afternoon on day 0 in the paracetamol group. However, the cumulative adequate clinical and parasitological cure rates were not significantly different during the period of study. It is doubtful whether adding paracetamol to the treatment of uncomplicated malaria in children is beneficial.TRIAL REGISTRATION:NCT00137566
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| 9. |
- 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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| 10. |
- Mero, Sointu, et al.
(författare)
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Multiplex PCR detection of Cryptosporidium sp, Giardia lamblia and Entamoeba histolytica directly from dried stool samples from Guinea-Bissauan children with diarrhoea
- 2017
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Ingår i: Infectious Diseases. - : Taylor & Francis. - 2374-4235 .- 2374-4243. ; 49:9, s. 655-663
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Tidskriftsartikel (refereegranskat)abstract
- Background: In developing countries, diarrhoea is the most common cause of death for children under five years of age, with Giardia lamblia, Cryptosporidium and Entamoeba histolytica as the most frequent pathogenic parasites. Traditional microscopy for stool parasites has poor sensitivity and specificity, while new molecular methods may provide more accurate diagnostics. In poor regions with sample storage hampered by uncertain electricity supply, research would benefit from a method capable of analysing dried stools. Methods: A real-time multiplex PCR method with internal inhibition control was developed for detecting Giardia lamblia, Cryptosporidium hominis/parvum and Entamoeba histolytica directly from stool specimens. Applicability to dried samples was checked by comparing with fresh ones in a small test material. Finally, the assay was applied to dried specimens collected from Guinea-Bissauan children with diarrhoea. Results: The PCR's analytical sensitivity limit was 0.1 ng/ml for G. lamblia DNA, 0.01 ng/ml for E. histolytica DNA and 0.1 ng/ml for Cryptosporidium sp. In the test material, the assay performed similarly with fresh and dried stools. Of the 52 Guinea-Bissauan samples, local microscopy revealed a parasite in 15%, while PCR detected 62% positive for at least one parasite: 44% of the dried samples had Giardia, 23% Cryptosporidium and 0% E. histolytica. Conclusions: Our new multiplex real-time PCR for protozoa presents a sensitive method applicable to dried samples. As proof of concept, it worked well on stools collected from Guinea-Bissauan children with diarrhoea. It provides an epidemiological tool for analysing dried specimens from regions poor in resources.
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