| 1. |
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| 2. |
- Angelopoulus, M., et al.
(författare)
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Physical properties of sea ice cores from site MCS_FYI measured on legs 1 to 3 of the MOSAiC expedition.
- 2022
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Ingår i: PANGAEA.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We present sea ice temperature and salinity data from first-year ice (FYI) and second-year ice (SYI) relevant to the temporal development of sea ice permeability and brine drainage efficiency from the early growth phase in October 2019 to the onset of spring warming in May 2020. Our dataset was collected in the central Arctic Ocean during the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) Expedition in 2019 to 2020. MOSAiC was an international transpolar drift expedition in which the German icebreaker RV Polarstern anchored into an ice floe to gain new insights into Arctic climate over a full annual cycle. In October 2019, RV Polarstern moored to an ice floe in the Siberian sector of the Arctic at 85 degrees north and 137 degrees east to begin the drift towards the North Pole and the Fram Strait via the Transpolar Drift Stream. The data presented here were collected during the first three legs of the expedition, so all the coring activities took place on the same floe. The end dates of legs 1, 2, and 3 were 13 December, 24 February, and 4 June, respectively. The dataset contributed to a baseline study entitled, Deciphering the properties of different Arctic ice types during the growth phase of the MOSAiC floes: Implications for future studies. The study highlights downward directed gas pathways in FYI and SYI by inferring sea ice permeability and potential brine release from several time series of temperature and salinity measurements. The physical properties presented in this paper lay the foundation for subsequent analyses on actual gas contents measured in the ice cores, as well as air-ice and ice-ocean gas fluxes. Sea ice cores were collected with a Kovacs Mark II 9 cm diameter corer. To measure ice temperatures, about 4.5 cm deep holes were drilled into the core (intervals varied by site and leg) . The temperatures were measured by a digital thermometer within minutes after the cores were retrieved. The ice cores were placed into pre-labelled plastic sleeves sealed at the bottom end. The ice cores were transported to RV Polarstern and stored in a -20 degrees Celsius freezer. Each of the cores was sub-sampled, melted at room temperature, and processed for salinity within one or two days. The practical salinity was estimated by measuring the electrical conductivity and temperature of the melted samples using a WTW Cond 3151 salinometer equipped with a Tetra-Con 325 four-electrode conductivity cell. The practical salinity represents the the salinity estimated from the electrical conductivity of the solution. The dataset also contains derived variables, including sea ice density, brine volume fraction, and the Rayleigh number.
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| 3. |
- Angelopoulus, M., et al.
(författare)
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Physical properties of sea ice cores from site MCS-SYI measured on legs 1 to 3 of the MOSAiC expedition
- 2022
-
Ingår i: PANGAEA.
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We present sea ice temperature and salinity data from first-year ice (FYI) and second-year ice (SYI) relevant to the temporal development of sea ice permeability and brine drainage efficiency from the early growth phase in October 2019 to the onset of spring warming in May 2020. Our dataset was collected in the central Arctic Ocean during the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) Expedition in 2019 to 2020. MOSAiC was an international transpolar drift expedition in which the German icebreaker RV Polarstern anchored into an ice floe to gain new insights into Arctic climate over a full annual cycle. In October 2019, RV Polarstern moored to an ice floe in the Siberian sector of the Arctic at 85 degrees north and 137 degrees east to begin the drift towards the North Pole and the Fram Strait via the Transpolar Drift Stream. The data presented here were collected during the first three legs of the expedition, so all the coring activities took place on the same floe. The end dates of legs 1, 2, and 3 were 13 December, 24 February, and 4 June, respectively. The dataset contributed to a baseline study entitled, Deciphering the properties of different Arctic ice types during the growth phase of the MOSAiC floes: Implications for future studies. The study highlights downward directed gas pathways in FYI and SYI by inferring sea ice permeability and potential brine release from several time series of temperature and salinity measurements. The physical properties presented in this paper lay the foundation for subsequent analyses on actual gas contents measured in the ice cores, as well as air-ice and ice-ocean gas fluxes. Sea ice cores were collected with a Kovacs Mark II 9 cm diameter corer. To measure ice temperatures, about 4.5 cm deep holes were drilled into the core (intervals varied by site and leg) . The temperatures were measured by a digital thermometer within minutes after the cores were retrieved. The ice cores were placed into pre-labelled plastic sleeves sealed at the bottom end. The ice cores were transported to RV Polarstern and stored in a -20 degrees Celsius freezer. Each of the cores was sub-sampled, melted at room temperature, and processed for salinity within one or two days. The practical salinity was estimated by measuring the electrical conductivity and temperature of the melted samples using a WTW Cond 3151 salinometer equipped with a Tetra-Con 325 four-electrode conductivity cell. The practical salinity represents the the salinity estimated from the electrical conductivity of the solution. The dataset also contains derived variables, including sea ice density, brine volume fraction, and the Rayleigh number.
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| 4. |
- Noort, S., et al.
(författare)
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Analysis of rare driving events in pediatric acute myeloid leukemia
- 2023
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 108:1, s. 48-60
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Tidskriftsartikel (refereegranskat)abstract
- Elucidating genetic aberrations in pediatric acute myeloid leukemia (AML) provides insight in biology and may impact on risk-group stratification and clinical outcome. This study aimed to detect such aberrations in a selected series of samples without known (cyto)genetic aberration using molecular profiling. A cohort of 161 patients was selected from various study groups: DCOG, BFM, SJCRH, NOPHO and AEIOP. Samples were analyzed using RNA sequencing (n=152), whole exome (n=135) and/or whole genome sequencing (n=100). In 70 of 156 patients (45%), of whom RNA sequencing or whole genome sequencing was available, rearrangements were detected, 22 of which were novel; five involving ERG rearrangements and four NPM1 rearrangements. ERG rearrangements showed self-renewal capacity in vitro, and a distinct gene expression pattern. Gene set enrichment analysis of this cluster showed upregulation of gene sets derived from Ewing sarcoma, which was confirmed comparing gene expression profiles of AML and Ewing sarcoma. Furthermore, NPM1-rearranged cases showed cytoplasmic NPM1 localization and revealed HOXA/B gene overexpression, as described for NPM1 mutated cases. Single-gene mutations as identified in adult AML were rare. Patients had a median of 24 coding mutations (range, 7-159). Novel recurrent mutations were detected in UBTF (n=10), a regulator of RNA transcription. In 75% of patients an aberration with a prognostic impact could be detected. Therefore, we suggest these techniques need to become standard of care in diagnostics.
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| 5. |
- Dellenmark-Blom, Michaela, 1983, et al.
(författare)
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Establishment of a condition-specific quality-of-life questionnaire for children born with esophageal atresia aged 2-7 across 14 countries
- 2023
-
Ingår i: Frontiers in Pediatrics. - 2296-2360. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundEsophageal atresia (EA) is a rare congenital anomaly characterized by a discontinuity of the esophagus. Following surgical repair, survival rates have improved dramatically the past decenniums and today exceed 90%, but the children commonly present with esophageal and respiratory morbidity. In 2018, a condition-specific quality-of-life questionnaire for children with esophageal atresia (EA) aged 2-7 in Sweden-Germany was finalized (The EA-QOL questionnaire). The study aim was to describe the evaluation of the new translations across 12 new countries in Europe, Asia, Africa, Central-and North America.MethodsFollowing forward-backward translation into the new languages, the 17-item EA-QOL questionnaire was tested in cognitive debriefing interviews with parents of children with EA aged 2-7. Parents rated if each item was easy to understand (clarity) and sensitive to answer (interference with personal integrity). They could skip responding to a non-applicable/problematic item and give open comments. Predefined psychometric criteria were used; item clarity >= 80%/item sensitive to answer <= 20%/item feasibility <= 5% missing item responses. The decision to modify the translation was based on native expert, patient stakeholder, and instrument developer review, and the need for harmonization between translations.ResultsSimilar to findings in the Swedish-German cognitive debriefing, the cross-cultural analysis of input from 116 parents from 12 new countries (4-14 parents, median 9 parents/country) showed that all items in the EA-QOL questionnaire fulfilled the criteria for item clarity >= 80% and sensitive to answer (ranging from 1%-4.5%), although results varied between countries. Four items had missing responses between 5.2% and 13.4%, three within the same domain and were in line with parents' explanations. Poor translations and feasibility were improved.ConclusionsBased on parent input, the collaboration between native experts, patient stakeholders, and instrument developers, a linguistic version of the EA-QOL questionnaire for children aged 2-7 for use in and across 14 countries has been established. These efforts have set the conditions for a cross-cultural field test of the EA-QOL questionnaire and will open the doors for a new chapter in outcome research, registries, and clinical practice concerning children with EA. In the long-term, this will help increase knowledge of the disease's burden, promote patient-centeredness, exchange of information between nations, and strengthen evidence-based treatments for children born with EA.
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| 6. |
- Modvig, S, et al.
(författare)
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Value of flow cytometry for MRD-based relapse prediction in B-cell precursor ALL in a multicenter setting.
- 2021
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 35, s. 1894-1906
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Tidskriftsartikel (refereegranskat)abstract
- PCR of TCR/Ig gene rearrangements is considered the method of choice for minimal residual disease (MRD) quantification in BCP-ALL, but flow cytometry analysis of leukemia-associated immunophenotypes (FCM-MRD) is faster and biologically more informative. FCM-MRD performed in 18 laboratories across seven countries was used for risk stratification of 1487 patients with BCP-ALL enrolled in the NOPHO ALL2008 protocol. When no informative FCM-marker was available, risk stratification was based on real-time quantitative PCR. An informative FCM-marker was found in 96.2% and only two patients (0.14%) had non-informative FCM and non-informative PCR-markers. The overall 5-year event-free survival was 86.1% with a cumulative incidence of relapse (CIR5y) of 9.5%. FCM-MRD levels on days 15 (HzR 4.0, p<0.0001), 29 (HzR 2.7, p<0.0001), and 79 (HzR 3.5, p<0.0001) associated with hazard of relapse adjusted for age, cytogenetics, and WBC. The early (day 15) response associated with CIR5y adjusted for day 29 FCM-MRD, with higher levels in adults (median 2.4×10-2 versus 5.2×10-3, p<0.0001). Undetectable FCM- and/or PCR-MRD on day 29 identified patients with a very good outcome (CIR5y=3.2%). For patients who did not undergo transplantation, day 79 FCM-MRD>10-4 associated with a CIR5y=22.1%. In conclusion, FCM-MRD performed in a multicenter setting is a clinically useful method for MRD-based treatment stratification in BCP-ALL.
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| 7. |
- Stratmann, Svea, 1989-, et al.
(författare)
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Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children
- 2023
-
Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 37:3, s. 550-559
-
Tidskriftsartikel (refereegranskat)abstract
- Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients.
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| 8. |
- Angelopoulos, M., et al.
(författare)
-
Physical properties of sea ice cores from site BGC2 measured on legs 1 to 3 of the MOSAiC expedition
- 2022
-
Ingår i: PANGAEA.
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We present sea ice temperature and salinity data from first-year ice (FYI) and second-year ice (SYI) relevant to the temporal development of sea ice permeability and brine drainage efficiency from the early growth phase in October 2019 to the onset of spring warming in May 2020. Our dataset was collected in the central Arctic Ocean during the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) Expedition in 2019 to 2020. MOSAiC was an international transpolar drift expedition in which the German icebreaker RV Polarstern anchored into an ice floe to gain new insights into Arctic climate over a full annual cycle. In October 2019, RV Polarstern moored to an ice floe in the Siberian sector of the Arctic at 85 degrees north and 137 degrees east to begin the drift towards the North Pole and the Fram Strait via the Transpolar Drift Stream. The data presented here were collected during the first three legs of the expedition, so all the coring activities took place on the same floe. The end dates of legs 1, 2, and 3 were 13 December, 24 February, and 4 June, respectively. The dataset contributed to a baseline study entitled, Deciphering the properties of different Arctic ice types during the growth phase of the MOSAiC floes: Implications for future studies. The study highlights downward directed gas pathways in FYI and SYI by inferring sea ice permeability and potential brine release from several time series of temperature and salinity measurements. The physical properties presented in this paper lay the foundation for subsequent analyses on actual gas contents measured in the ice cores, as well as air-ice and ice-ocean gas fluxes. Sea ice cores were collected with a Kovacs Mark II 9 cm diameter corer. To measure ice temperatures, about 4.5 cm deep holes were drilled into the core (intervals varied by site and leg) . The temperatures were measured by a digital thermometer within minutes after the cores were retrieved. The ice cores were placed into pre-labelled plastic sleeves sealed at the bottom end. The ice cores were transported to RV Polarstern and stored in a -20 degrees Celsius freezer. Each of the cores was sub-sampled, melted at room temperature, and processed for salinity within one or two days. The practical salinity was estimated by measuring the electrical conductivity and temperature of the melted samples using a WTW Cond 3151 salinometer equipped with a Tetra-Con 325 four-electrode conductivity cell. The practical salinity represents the the salinity estimated from the electrical conductivity of the solution. The dataset also contains derived variables, including sea ice density, brine volume fraction, and the Rayleigh number.
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| 9. |
- Benetton, M., et al.
(författare)
-
Molecular Measurable Residual Disease Assessment before Hematopoietic Stem Cell Transplantation in Pediatric Acute Myeloid Leukemia Patients: A Retrospective Study by the I-BFM Study Group
- 2022
-
Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:7
-
Tidskriftsartikel (refereegranskat)abstract
- Hematopoietic stem cell transplantation (HSCT) is a curative post-remission treatment in patients with acute myeloid leukemia (AML), but relapse after transplant is still a challenging event. In recent year, several studies have investigated the molecular minimal residual disease (qPCR-MRD) as a predictor of relapse, but the lack of standardized protocols, cut-offs, and timepoints, especially in the pediatric setting, has prevented its use in several settings, including before HSCT. Here, we propose the first collaborative retrospective I-BFM-AML study assessing qPCR-MRD values in pretransplant bone marrow samples of 112 patients with a diagnosis of AML harboring t(8;21)(q22; q22)RUNX1::RUNX1T1, or inv(16)(p13q22)CBFB::MYH11, or t(9;11)(p21;q23)KMT2A::MLLT3, or FLT3-ITD genetic markers. We calculated an ROC cut-off of 2.1 x 10(-4) that revealed significantly increased OS (83.7% versus 57.1%) and EFS (80.2% versus 52.9%) for those patients with lower qPCR-MRD values. Then, we partitioned patients into three qPCR-MRD groups by combining two different thresholds, 2.1 x 10(-4) and one lower cut-off of 1 x 10(-2), and stratified patients into low-, intermediate-, and high-risk groups. We found that the 5-year OS (83.7%, 68.6%, and 39.2%, respectively) and relapse-free survival (89.2%, 73.9%, and 67.9%, respectively) were significantly different independent of the genetic lesion, conditioning regimen, donor, and stem cell source. These data support the PCR-based approach playing a clinical relevance in AML transplant management.
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| 10. |
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| 11. |
- Torinsson Naluai, Åsa, 1968, et al.
(författare)
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Transcriptomics unravels molecular changes associated with cilia and COVID-19 in chronic rhinosinusitis with nasal polyps
- 2023
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper respiratory tract complication where the pathogenesis is largely unknown. Herein, we investigated the transcriptome profile in nasal mucosa biopsies of CRSwNP patients and healthy individuals. We further integrated the transcriptomics data with genes located in chromosomal regions containing genome-wide significant gene variants for COVID-19. Among the most significantly upregulated genes in polyp mucosa were CCL18, CLEC4G, CCL13 and SLC9A3. Pathways involving "Ciliated epithelial cells" were the most differentially expressed molecular pathways when polyp mucosa and non-polyp mucosa from the same patient was compared. Natural killer T-cell (NKT) and viral pathways were the most statistically significant pathways in the mucosa of CRSwNP patients compared with those of healthy control individuals. Upregulated genes in polyp mucosa, located within the genome-wide associated regions of COVID-19, included LZTFL1, CCR9, SLC6A20, IFNAR1, IFNAR2 and IL10RB. Interestingly, the second most over-expressed gene in our study, CLEC4G, has been shown to bind directly to SARS-CoV-2 spike's N-terminal domain and mediate its entry and infection. Our results on altered expression of genes related to cilia and viruses point to the de-regulation of viral defenses in CRSwNP patients, and may give clues to future intervention strategies.
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| 12. |
- Willermark, Sara, 1988-, et al.
(författare)
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Where do we go from here? : Didactic and organizational questions after the pandemic
- 2022
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Ingår i: ICERI2022 Proceedings. - : iated Digital Library. - 9788409454761 ; , s. 1144-1151
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Konferensbidrag (refereegranskat)abstract
- COVID-19 changed the educational landscape as we know it. Due to the radical transformation of schooling, there is an imminent question of what lessons have been made and which transformations ‘will stick’ and become the ‘new normal’ after the obvious threats of the pandemic subsided [1]. There is a stream of research that addresses experiences from the pandemic [2-4]. In this study, we focus on the experiences of upper secondary schools in Sweden. The purpose of this paper is to synthesize teachers' and school leaders' experiences from the pandemic and, based on that, address implications for practice for future schooling. We conduct a meta-analysis of four studies within a research project in Sweden [5-8] where the data consists of surveys and workshops with teachers and school leaders and explores their experiences of the pandemic. The results show that Sweden has worked well in an international context, at the same time there are distinct differences regarding teachers' and school leaders' perceptions of what work effort was required, the result of the teaching, and its consequences. Contribution includes synthesizing experiences from the pandemic and pointing out its implications for future education.
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| 13. |
- Abrahamsson, B., et al.
(författare)
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Six years of progress in the oral biopharmaceutics area - A summary from the IMI OrBiTo project
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : ELSEVIER. - 0939-6411 .- 1873-3441. ; 152, s. 236-247
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Tidskriftsartikel (refereegranskat)abstract
- OrBiTo was a precompetitive collaboration focused on the development of the next generation of Oral Biopharmaceutics Tools. The consortium included world leading scientists from nine universities, one regulatory agency, one non-profit research organisation, three small/medium sized specialist technology companies together with thirteen pharmaceutical companies. The goal of the OrBiTo project was to deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This goal was achieved through novel prospective investigations to define new methodologies or refinement of existing tools. Extensive validation has been performed of novel and existing biopharmaceutics tools using historical datasets supplied by industry partners as well as laboratory ring studies. A combination of high quality in vitro and in vivo characterizations of active drugs and formulations have been integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of gastrointestinal drug absorption and some of the best practices has been highlighted. This approach has given an unparalleled opportunity to deliver transformational change in European industrial research and development towards model based pharmaceutical product development in accordance with the vision of model-informed drug development.
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| 14. |
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| 15. |
- Ahmad, Amais, et al.
(författare)
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IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 4 : Prediction accuracy and software comparisons with improved data and modelling strategies
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 156, s. 50-63
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Tidskriftsartikel (refereegranskat)abstract
- Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlusTM (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project.Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters.On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.
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| 16. |
- Andresen Bergström, Moa, 1978, et al.
(författare)
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Rethinking Drug Analysis in Health Care: High-Throughput Analysis of 71 Drugs of Abuse in Oral Fluid Using Ion Mobility-High-Resolution Mass Spectrometry
- 2022
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Ingår i: Journal of Analytical Toxicology. - : Oxford University Press (OUP). - 0146-4760 .- 1945-2403. ; 46:7, s. 765-775
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Tidskriftsartikel (refereegranskat)abstract
- We have identified a clinical need for a sensitive, specific, flexible, comprehensive and affordable analytical technology to efficiently detect polydrug use. In addition, the current standard practice of surveilled urine sampling is uncomfortable for the patient; hence, more patient-friendly sample collection methods are requested. To fill these needs, we have developed and validated a high-throughput liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method for the analysis of drugs of abuse (DoA) in oral fluid (OF). The method covers a panel of 71 substances including traditional DoA, prescription narcotics and new psychoactive substances (NPS), with a guaranteed limit of identification of <3 mu g/L for 87% of the analytes. Method validation showed high accuracy (>99.7%), sensitivity (>99.7%) and specificity (100%). Most analytes had a high process efficiency during the salting-out liquid-liquid extraction sample preparation and no or only a minor matrix effect during the analysis. We have implemented this method in clinical routine and present data from 18,579 OF samples collected during routine patient treatment in mainly psychiatric and addiction clinics in West Sweden between September 2020 and June 2021. Seventy-one percent of the samples were positive and a total of 41,472 DoA findings were detected. Amphetamine (27%), buprenorphine (25%), nordiazepam (18%) and alprazolam (16%) were most prevalent. New psychoactive substances were detected in 189 samples (1.0%). The occurrence of polydrug use was common; 34% of the positive samples contained three analytes or more and 12% six or more. To the best of our knowledge, this is the first method for comprehensive analysis of DoA in OF using LC-HRMS and the largest dataset published on the detection of DoA in OF. With the current complex and variable drug use pattern, this broad, cost-effective and reliable method has largely replaced immunoassay screening in urine in our laboratory.
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| 17. |
- Benavent, N., et al.
(författare)
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Substantial contribution of iodine to Arctic ozone destruction
- 2022
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Ingår i: Nature Geoscience. - : Springer Science and Business Media LLC. - 1752-0894 .- 1752-0908. ; 15, s. 770-773
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Tidskriftsartikel (refereegranskat)abstract
- Unlike bromine, the effect of iodine chemistry on the Arctic surface ozone budget is poorly constrained. We present ship-based measurements of halogen oxides in the high Arctic boundary layer from the sunlit period of March to October 2020 and show that iodine enhances springtime tropospheric ozone depletion. We find that chemical reactions between iodine and ozone are the second highest contributor to ozone loss over the study period, after ozone photolysis-initiated loss and ahead of bromine.
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| 18. |
- Dellenmark-Blom, Maria, 1983, et al.
(författare)
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Factors of family impact in a Swedish-German cohort of children born with esophageal atresia
- 2022
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background After repair of esophageal atresia (EA), childhood survivors commonly present with digestive and respiratory morbidity, and around 55% have associated anomalies. Although it is known that these problems can reduce health-related quality of life in children with EA, less is understood about the impact on the family. We aimed to identify factors related to family impact in children with EA. Methods One parent each of a child with EA (2-18 years) in 180 families from Sweden and Germany answered the PedsQL (TM) Family Impact Module as the dependent variable. The independent variables were the child's parent-reported health-related quality of life as measured by PedsQL (TM) 4.0, current symptoms, school situation, and parent/family characteristics together with child clinical data from the medical records. Results Stepwise multivariable regression analysis showed a multifactorial model of the total family impact scores (R-2 = 0.60), with independent factors being the child's overall generic health-related quality of life, school-absence >= 1/month, severe tracheomalacia, a family receiving carer's allowance, and a parent with no university/college education, p < 0.05. Logistic regression analysis showed that an increased number of symptoms in the child the preceding 4 weeks lowered the family impact scores; however, the child's feeding (R-2 = 0.35) and digestive symptoms (R-2 = 0.25) explained more in the variation of scores than the child's respiratory symptoms (R-2 = 0.09), p < 0.0001. Conclusions Family functioning may be a contributing factor to the maintenance of child health. The study findings suggest multifactorial explanations to family impact in children with EA, which are essential when optimizing the support to these families in clinical and psychosocial practice. Future research should explore experiences of family impact from all family members' perspectives and multicenter studies are warranted to understand better the effectiveness of psychosocial-educational interventions to families of children with EA.
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| 19. |
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| 20. |
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| 21. |
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| 22. |
- Lundqvist, M. H., et al.
(författare)
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Augmented cortisol-axis and symptom response to hypoglycaemia in individuals with overweight and insulin resistance
- 2020
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 63:SUPPL 1, s. S236-S236
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: An important role of the CNS in the pathogenesis of type 2 diabetes (T2D) has been suggested and is supported by animal studies. The brain senses fluctuations in systemic glucose levels and modulates glucoregulatory hormones and autonomic nerve activity to balance glucose levels. We hypothesize that the brain’s setpoint for glucose is gradually shifted upwards in the development of T2D. The aim of this study was to investigate if the neuroendocrine response to varying glucose levels differ in overweight and insulin-resistant compared to control subjects.Materials and methods: 30 subjects with no diagnosis of diabetes were recruited and allocated into two groups based on the median BMI: LO [BMI 23.4 kg/m2 (Range 18.9-26.9)] and HI [BMI 32.0 (27.0-48.7) kg/ m2 ]. Age and gender distribution were similar. On two separate occasions and in a randomized order, stepwise hypoglycemic (nadir 2.7 mM) and hyperglycemic (max +9 mM) clamps were performed with repeated measurements of hormones (glucagon, cortisol, ACTH, growth hormone), assessment of symptoms according to the Edinburgh Hypoglycemia Symptom Scale (ESS) and monitoring of heart rate variability (HRV). Mann-Whitney U-tests were used for group-wise comparisons.Results: In HI vs LO the response to hypoglycemia was augmented for both cortisol [ΔAUC 12382 nM*min (IQR 7058;15705) vs 4792(- 1200;11498, p=0.045] and ACTH [ΔAUC 448.3 pM*min (373.5;702.0) vs 162.0 (125.3;397.5), p=0.015]. Subjects in HI reported higher peak ESS Scores [21 (19;23) vs 18 (14;21), p=0.045] during hypoglycemia. By contrast, subjects in HI had loss of suppression of PHF (an HRV marker of parasympathetic nerve activity) during hypoglycemia [0.035 ms2 log (- 0.353;0.188) vs -0.219 ms2 log (-0.476;-0.132), p= 0.024]. The above perturbations were independently associated with insulin resistance but not with obesity per se according to multilinear regressions (Table). During hyperglycemia there was a trend toward higher glucagon levels in HI vs LO [AUC 539.5 pM*min (336.9;617.2) vs 390.5 pM*min (244.5;476.2), p=0.085). Subjects in HI had lower mean PLF/ PHF ratio, a marker of balance between sympathetic and parasympathetic nerve activity [0.383 (0.260;0.568) vs 0.154 (0.081;0.299), p=0.005].Conclusion: Overweight, insulin-resistant subjects had more symptoms during hypoglycemia and this was combined with central cortisol axis overactivity via pituitary ACTH release, altogether suggesting altered CNS responses. They also had less dynamic autonomic nerve activity. These neuroendocrine alterations were associated with insulin resistance independent of obesity, supporting a role of the brain in raising the glycemic setpoint in the development of T2D.
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| 23. |
- Martin, W. P., et al.
(författare)
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Medications Activating Tubular Fatty Acid Oxidation Enhance the Protective Effects of Roux-en-Y Gastric Bypass Surgery in a Rat Model of Early Diabetic Kidney Disease
- 2022
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Roux-en-Y gastric bypass surgery (RYGB) improves biochemical and histological parameters of diabetic kidney disease (DKD). Targeted adjunct medical therapy may enhance renoprotection following RYGB. Methods: The effects of RYGB and RYGB plus fenofibrate, metformin, ramipril, and rosuvastatin (RYGB-FMRR) on metabolic control and histological and ultrastructural indices of glomerular and proximal tubular injury were compared in the Zucker Diabetic Sprague Dawley (ZDSD) rat model of DKD. Renal cortical transcriptomic (RNA-sequencing) and urinary metabolomic (1H-NMR spectroscopy) responses were profiled and integrated. Transcripts were assigned to kidney cell types through in silico deconvolution in kidney single-nucleus RNA-sequencing and microdissected tubular epithelial cell proteomics datasets. Medication-specific transcriptomic responses following RYGB-FMRR were explored using a network pharmacology approach. Omic correlates of improvements in structural and ultrastructural indices of renal injury were defined using a molecular morphometric approach. Results: RYGB-FMRR was superior to RYGB alone with respect to metabolic control, albuminuria, and histological and ultrastructural indices of glomerular injury. RYGB-FMRR reversed DKD-associated changes in mitochondrial morphology in the proximal tubule to a greater extent than RYGB. Attenuation of transcriptomic pathway level activation of pro-fibrotic responses was greater after RYGB-FMRR than RYGB. Fenofibrate was found to be the principal medication effector of gene expression changes following RYGB-FMRR, which led to the transcriptional induction of PPARα-regulated genes that are predominantly expressed in the proximal tubule and which regulate peroxisomal and mitochondrial fatty acid oxidation (FAO). After omics integration, expression of these FAO transcripts positively correlated with urinary levels of PPARα-regulated nicotinamide metabolites and negatively correlated with urinary tricarboxylic acid (TCA) cycle intermediates. Changes in FAO transcripts and nicotinamide and TCA cycle metabolites following RYGB-FMRR correlated strongly with improvements in glomerular and proximal tubular injury. Conclusions: Integrative multi-omic analyses point to PPARα-stimulated FAO in the proximal tubule as a dominant effector of treatment response to combined surgical and medical therapy in experimental DKD. Synergism between RYGB and pharmacological stimulation of FAO represents a promising combinatorial approach to the treatment of DKD in the setting of obesity. Copyright © 2022 Martin, Chuah, Abdelaal, Pedersen, Malmodin, Abrahamsson, Hutter, Godson, Brennan, Fändriks, le Roux and Docherty.
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| 24. |
- Quist-Paulsen, P., et al.
(författare)
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T-cell acute lymphoblastic leukemia in patients 1-45 years treated with the pediatric NOPHO ALL2008 protocol
- 2020
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 34:2, s. 347-357
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Tidskriftsartikel (refereegranskat)abstract
- The NOPHO ALL2008 is a population-based study using an unmodified pediatric protocol in patients 1-45 years of age with acute lymphoblastic leukemia. Patients with T-ALL were given a traditional pediatric scheme if fast responding (minimal residual disease (MRD) < 0.1% day 29), or intensive block-based chemotherapy if slow responding (MRD > 0.1% day 29). Both treatment arms included pediatric doses of high-dose methotrexate and asparaginase. If MRD >= 5% on day 29 or >= 0.1% after consolidation, patients were assigned to allogeneic hematopoietic stem cell transplantation. The 5-year overall survival of the 278 T-ALL patients was 0.75 (95% CI 0.69-0.81), being 0.82 (0.74-0.88) for patients 1.0-9.9 years, 0.76 (0.66-0.86) for those 10.0-17.9 years, and 0.65 (0.55-0.75) for the older patients. The risk of death in first remission was significantly higher in adults (12%) compared with the 1-9 years group (4%). The MRD responses in the three age groups were similar, and only a nonsignificant increase in relapse risk was found in adults. In conclusion, an unmodified pediatric protocol in patients 1-45 years is effective in all age groups. The traditional pediatric treatment schedule was safe for all patients, but the intensive block therapy led to a high toxic death rate in adults.
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| 25. |
- Rank, Cecilie U., et al.
(författare)
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Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia : Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age
- 2020
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Ingår i: Journal of Clinical Oncology. - Alexandria : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 38:2, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored.PATIENTS AND METHODS: We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0-45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol.RESULTS: Compared with patients aged 1.0-9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0-17.9 years) and adults (18.0-45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0-9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0-45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0-9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse.CONCLUSION: Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse.
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| 26. |
- Ranta, S., et al.
(författare)
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High need for intensive care in paediatric acute myeloid leukaemia: A population-based study
- 2022
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 111:11, s. 2235-2241
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Tidskriftsartikel (refereegranskat)abstract
- Aim Risk of treatment-related life-threatening toxicity is high in childhood acute myeloid leukaemia (AML), and access to intensive care units (ICU) is crucial. We explored the ICU admission rate and outcome after intensive care in childhood AML in Sweden. Methods Patients diagnosed between 2008 and 2016 were identified from the Swedish Childhood Cancer Registry (SCCR), a national quality registry. Data from SCCR was cross-referenced with clinical questionnaire data from paediatric oncology centers and the Swedish Intensive Care Registry (SIR), another national quality registry. Results According to combined data, 46% of the children (58/126) were admitted to ICU, 17% (21/126) within 1 month from diagnosis. Overall, ICU mortality per admission was 12% and 6% during first-line treatment. There was a discrepancy between admission rate from the clinical questionnaires and SCCR (29%; 36/126 children) and SIR (44%; 55/126) All deaths during first-line treatment occurred at or after ICU care. Conclusion Although admission rate under AML treatment was high, the treatment-related mortality under first-line treatment was low. No child died under first-line treatment without admission to ICU, suggesting good availability. The discrepancy between the two registries, SCCR and SIR, highlights the need for future validation of registry data.
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| 27. |
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| 28. |
- Stratmann, Svea, 1989-, et al.
(författare)
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Genomic characterization of relapsed acute myeloid leukemia reveals novel putative therapeutic targets
- 2021
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 5:3, s. 900-912
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Tidskriftsartikel (refereegranskat)abstract
- Relapse is the leading cause of death of adult and pediatric patients with acute myeloid leukemia (AML). Numerous studies have helped to elucidate the complex mutational landscape at diagnosis of AML, leading to improved risk stratification and new therapeutic options. However, multi-whole-genome studies of adult and pediatric AML at relapse are necessary for further advances. To this end, we performed whole-genome and whole-exome sequencing analyses of longitudinal diagnosis, relapse, and/or primary resistant specimens from 48 adult and 25 pediatric patients with AML. We identified mutations recurrently gained at relapse in ARID1A and CSF1R, both of which represent potentially actionable therapeutic alternatives. Further, we report specific differences in the mutational spectrum between adult vs pediatric relapsed AML, with MGA and H3F3A p.Lys28Met mutations recurrently found at relapse in adults, whereas internal tandem duplications in UBTF were identified solely in children. Finally, our study revealed recurrent mutations in IKZF1, KANSL1, and NIPBL at relapse. All of the mentioned genes have either never been reported at diagnosis in de novo AML or have been reported at low frequency, suggesting important roles for these alterations predominantly in disease progression and/or resistance to therapy. Our findings shed further light on the complexity of relapsed AML and identified previously unappreciated alterations that may lead to improved outcomes through personalized medicine.
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| 29. |
- Stratmann, Svea, 1989-, et al.
(författare)
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Transcriptomic analysis reveals proinflammatory signatures associated with acute myeloid leukemia progression
- 2022
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 6:1, s. 152-164
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Tidskriftsartikel (refereegranskat)abstract
- Numerous studies have been performed over the last decade to exploit the complexity of genomic and transcriptomic lesions driving the initiation of acute myeloid leukemia (AML). These studies have helped improve risk classification and treatment options. Detailed molecular characterization of longitudinal AML samples is sparse, however; meanwhile, relapse and therapy resistance represent the main challenges in AML care. To this end, we performed transcriptome-wide RNA sequencing of longitudinal diagnosis, relapse, and/or primary resistant samples from 47 adult and 23 pediatric AML patients with known mutational background. Gene expression analysis revealed the association of short event-free survival with overexpression of GLI2 and IL1R1, as well as downregulation of ST18. Moreover, CR1 downregulation and DPEP1 upregulation were associated with AML relapse both in adults and children. Finally, machine learning–based and network-based analysis identified overexpressed CD6 and downregulated INSR as highly copredictive genes depicting important relapse-associated characteristics among adult patients with AML. Our findings highlight the importance of a tumor-promoting inflammatory environment in leukemia progression, as indicated by several of the herein identified differentially expressed genes. Together, this knowledge provides the foundation for novel personalized drug targets and has the potential to maximize the benefit of current treatments to improve cure rates in AML. ß 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
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| 30. |
- Tulstrup, M., et al.
(författare)
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Effects of germ line DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia
- 2020
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 136:10, s. 1161-1168
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Tidskriftsartikel (refereegranskat)abstract
- Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 x 10(-8)) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 x 10(-9)) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.
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| 31. |
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| 32. |
- Versluys, A. B., et al.
(författare)
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Hematopoietic cell transplant in pediatric acute myeloid leukemia after similar upfront therapy; a comparison of conditioning regimens
- 2021
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Ingår i: Bone Marrow Transplantation. - : Springer Science and Business Media LLC. - 0268-3369 .- 1476-5365. ; 56:6, s. 1426-1432
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Tidskriftsartikel (refereegranskat)abstract
- The impact of conditioning regimen prior to hematopoietic cell transplant (HCT) in pediatric AML-patients is not well studied. We retrospectively analyzed the impact of Busulfan-Cyclophosphamide (BuCy), Busulfan-Cyclophosphamide-Melphalan (BuCyMel) and Clofarabine-Fludarabine-Busulfan (CloFluBu) in pediatric AML-patients, with similar upfront leukemia treatment (NOPHO-DBHconsortium), receiving an HCT between 2010 and 2015. Outcomes of interest were LFS, relapse, TRM and GvHD. 103 patients were included; 30 received BuCy, 37 BuCyMel, and 36 CloFluBu. The 5-years LFS was 43.3% (SE +/- 9.0) in the BuCy group, 59.2 % (SE +/- 8.1) after BuCyMel, and 66.7 % (SE +/- 7.9) after CloFluBu. Multivariable Cox regression analysis showed a trend to lower LFS after BuCy compared to CloFluBu (p = 0.07). BuCy was associated with a higher relapse incidence compared to the other regimens (p = 0.06). Younger age was a predictor for relapse (p = 0.02). A strong correlation between Busulfan Therapeutic Drug Monitoring (TDM) and lower incidence of aGvHD (p < 0.001) was found. In conclusion, LFS after BuCyMel and CloFluBu was comparable, lower LFS was found after BuCy, due to higher relapse incidence. CloFluBu was associated with lower incidence of aGvHD, suggesting lower toxicity with this type of conditioning. This finding is also explained by the impact of Busulfan monitoring.
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| 33. |
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| 34. |
- Ziegler, P., et al.
(författare)
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A primary nasopharyngeal three-dimensional air-liquid interface cell culture model of the pseudostratified epithelium reveals differential donor- and cell type-specific susceptibility to Epstein-Barr virus infection
- 2021
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Ingår i: Plos Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 17:4
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Tidskriftsartikel (refereegranskat)abstract
- Epstein-Barr virus (EBV) is a ubiquitous gamma-herpesvirus with latent and lytic cycles. EBV replicates in the stratified epithelium but the nasopharynx is also composed of pseudostratified epithelium with distinct cell types. Latent infection is associated with nasopharyngeal carcinoma (NPC). Here, we show with nasopharyngeal conditionally reprogrammed cells cultured at the air-liquid interface that pseudostratified epithelial cells are susceptible to EBV infection. Donors varied in susceptibility to de novo EBV infection, but susceptible cultures also displayed differences with respect to pathogenesis. The cultures from one donor yielded lytic infection but cells from two other donors were positive for EBV-encoded EBERs and negative for other lytic infection markers. All cultures stained positive for the pseudostratified markers CK7, MUC5AC, alpha-tubulin in cilia, and the EBV epithelial cell receptor Ephrin receptor A2. To define EBV transcriptional programs by cell type and to elucidate latent/lytic infection-differential changes, we performed single cell RNA-sequencing on one EBV-infected culture that resulted in alignment with many EBV transcripts. EBV transcripts represented a small portion of the total transcriptome (similar to 0.17%). All cell types in the pseudostratified epithelium had detectable EBV transcripts with suprabasal cells showing the highest number of reads aligning to many EBV genes. Several restriction factors (IRF1, MX1, STAT1, C18orf25) known to limit lytic infection were expressed at lower levels in the lytic subcluster. A third of the differentially-expressed genes in NPC tumors compared to an uninfected pseudostratified ALI culture overlapped with the differentially-expressed genes in the latent subcluster. A third of these commonly perturbed genes were specific to EBV infection and changed in the same direction. Collectively, these findings suggest that the pseudostratified epithelium could harbor EBV infection and that the pseudostratified infection model mirrors many of the transcriptional changes imposed by EBV infection in NPC. Author summary It has been known for over 50 years that EBV latent infection is associated with NPC. Despite many advances from studies in 2-dimensional cell culture, many aspects of EBV molecular pathogenesis in the nasopharynx remain undefined because the cell types and the biology of the nasopharyngeal epithelium can only be faithfully captured in 3-dimensional cell culture. In the stratified epithelium, cellular differentiation triggers lytic infection but it is not clear to what degree the pseudostratified epithelium is involved. The pseudostratified epithelium is abundant in the lateral wall where the lymphoid-rich fossa of Rosenmuller is located and is a site where NPC tumors most often arises. While the oral epithelium is a site of EBV replication, whether the nasopharyngeal epithelium is a major source of EBV shedding in the nasopharynx is not well defined. Here, we present a 3-dimensional organoid model of the nasopharyngeal pseudostratified epithelium showing that such cells can be infected with EBV in some donor cultures, with examples of both latent and lytic infection. We propose that the cell types of the pseudostratified epithelium should be considered a component of EBV pathogenesis in the nasopharynx and that the difference in donor susceptibility and latent/lytic infection could influence EBV's fitness in the nasopharynx.
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| 35. |
- Abrahamsson, Dimitri, et al.
(författare)
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In Silico Structure Predictions for Non-targeted Analysis : From Physicochemical Properties to Molecular Structures
- 2022
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Ingår i: Journal of the American Society for Mass Spectrometry. - : American Chemical Society (ACS). - 1044-0305 .- 1879-1123. ; 33:7, s. 1134-1147
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Tidskriftsartikel (refereegranskat)abstract
- While important advances have been made in high-resolution mass spectrometry (HRMS) and its applications in non-targeted analysis (NTA), the number of identified compounds in biological and environmental samples often does not exceed 5% of the detected chemical features. Our aim was to develop a computational pipeline that leverages data from HRMS but also incorporates physicochemical properties (equilibrium partition ratios between organic solvents and water; Ksolvent–water) and can propose molecular structures for detected chemical features. As these physicochemical properties are often sufficiently different across isomers, when put together, they can form a unique profile for each isomer, which we describe as the “physicochemical fingerprint”. In our study, we used a comprehensive database of compounds that have been previously reported in human blood and collected their Ksolvent–water values for 129 partitioning systems. We used RDKit to calculate the number of RDKit fragments and the number of RDKit bits per molecule. We then developed and trained an artificial neural network, which used as an input the physicochemical fingerprint of a chemical feature and predicted the number and types of RDKit fragments and RDKit bits present in that structure. These were then used to search the database and propose chemical structures. The average success rate of predicting the right chemical structure ranged from 60 to 86% for the training set and from 48 to 81% for the testing set. These observations suggest that physicochemical fingerprints can assist in the identification of compounds with NTA and substantially improve the number of identified compounds.
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| 36. |
- Andersson, Marie, 1977, et al.
(författare)
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Urological results and patient satisfaction in adolescents after surgery for proximal hypospadias in childhood
- 2020
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Ingår i: Journal of Pediatric Urology. - : Elsevier BV. - 1477-5131 .- 1873-4898. ; 16:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Proximal hypospadias repair is associated with a considerable complication risk. Long-term follow-up is required to present realistic expectations in pre-operative counseling. Objective: To investigate adolescents after childhood surgery for proximal hypospadias in a prospective cohort study describing the urological outcome, complication rates and patient satisfaction with penile appearance. Study design: 39 adolescents ≥14 years with penoscrotal to perineal hypospadias and primary urethroplasty (tubularized incised plate (TIP), preputial flap as Onlay or tubularized (Duckett)) from 1996 to 2005 at a single center were evaluated. The clinical assessment, at Md 16.5 years (14–25), included voiding history, genital examination including the Hypospadias Objective Scoring Evaluation (HOSE), uroflowmetry plus chart data from previous urinary flows and evaluation of patient satisfaction using the Penile Perception Score (PPS). Results: Twenty-nine patients with penoscrotal and 10 with scrotal/perineal hypospadias underwent surgery with TIP (N = 14), Onlay (N = 14) and Duckett (N = 11). Uroflows improved significantly compared with prepubertal maximal flows. Impaired flow rate (<10 mL/s) was found in 14% (5/36). Fifty-one percent (20/39) required reoperations, 29% (4/14) of TIP, 50% (7/14) of Onlay and 82% (9/11) of Duckett (p = 0.0062). Median penile length in adolescence was 8.7 cm (4.0–11.0). Forty-four percent (12/27) of patients were dissatisfied with penile length. Patients were ‘satisfied’ or ‘very satisfied’ with meatal position and shape despite HOSE for meatal position being 11% (4/38) distal, 76% (29/38) proximal glanular and 13% (5/38) coronal. TIP patients had more curvature at puberty than Duckett (p = 0.0062). Patients that had a decurvature procedure had shorter penile length (p = 0.019). Discussion: A high complication rate is previously described, predominantly within the first years. Our study shows 50% of reoperations were performed after >3 years, illustrating the need for long-term follow-up. Patient satisfaction with a deviant meatal position is rarely reported [1,2]. Our results support a conservative approach to an asymptomatic retracted meatus. Limitations of this descriptive study are the non-comparable groups and the retrospective data for correlation, impeding evaluation of prognostic outcome-factors. The shorter penile length found in patients after plication, and increased curvature after TIP, is therefore merely descriptive. However, the findings are in line with earlier publications suggesting limited use of TIP, and plication (recommending ventral lengthening instead) to avoid penile shortening and curvature in these cases [3–5]. Conclusions: The urological long-term outcome after proximal hypospadias repair is good, although late reoperations are common. In adolescence, patients were dissatisfied with the short penile length but satisfied with meatal position, indicating that in proximal hypospadias, preserving penile length and correcting curvature are prioritized over a distal meatus. [Table presented] © 2020 The Author(s)
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| 37. |
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| 38. |
- Berg, Staffan, et al.
(författare)
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Impact of Intestinal Concentration and Colloidal Structure on the Permeation-Enhancing Efficiency of Sodium Caprate in the Rat
- 2022
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 19:1, s. 200-212
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Tidskriftsartikel (refereegranskat)abstract
- In this work, we set out to better understand how the permeation enhancer sodium caprate (C10) influences the intestinal absorption of macromolecules. FITC-dextran 4000 (FD4) was selected as a model compound and formulated with 50-300 mM C10. Absorption was studied after bolus instillation of liquid formulation to the duodenum of anesthetized rats and intravenously as a reference, whereafter plasma samples were taken and analyzed for FD4 content. It was found that the AUC and C-max of FD4 increased with increasing C10 concentration. Higher C10 concentrations were associated with an increased and extended absorption but also increased epithelial damage. Depending on the C10 concentration, the intestinal epithelium showed significant recovery already at 60-120 min after administration. At the highest studied C10 concentrations (100 and 300 mM), the absorption of FD4 was not affected by the colloidal structures of C10, with similar absorption obtained when C10 was administered as micelles (pH 8.5) and as vesicles (pH 6.5). In contrast, the FD4 absorption was lower when C10 was administered at 50 mM formulated as micelles as compared to vesicles. Intestinal dilution of C10 and FD4 revealed a trend of decreasing FD4 absorption with increasing intestinal dilution. However, the effect was smaller than that of altering the total administered C10 dose. Absorption was similar when the formulations were prepared in simulated intestinal fluids containing mixed micelles of bile salts and phospholipids and in simple buffer solution. The findings in this study suggest that in order to optimally enhance the absorption of macromolecules, high (>= 100 mM) initial intestinal C10 concentrations are likely needed and that both the concentration and total dose of C10 are important parameters.
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| 39. |
- Berg, Staffan, et al.
(författare)
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In Vitro and In Vivo Evaluation of 3D Printed Capsules with Pressure Triggered Release Mechanism for Oral Peptide Delivery
- 2021
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 110:1, s. 228-238
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Tidskriftsartikel (refereegranskat)abstract
- In this study a 3D printed capsule designed to break from the physiological pressures in the antropyloric region was evaluated for its ability to deliver the synthetic octapeptide octreotide in beagle dogs when co-formulated with the permeation enhancer sodium caprate. The pressure sensitive capsules were compared to traditional enteric coated hard gelatin capsules and enteric coated tablets. Paracetamol, which is completely absorbed in dogs, was included in the formulations and used as an absorption marker to give information about the in vivo performance of the dosage forms. The pressure sensitive capsules released drug in 50% of the dogs. In the cases where drug was released, there was no difference in octreotide bioavailability or C-max compared to the enteric coated dosage forms. When comparing all dosage forms, a correlation was seen between paracetamol C-max and octreotide bioavailability, suggesting that a high drug release rate may be beneficial for peptide absorption when delivered together with sodium caprate. (C) 2020 Published by Elsevier Inc.
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| 40. |
- Farooqi, Aijaz, et al.
(författare)
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One-year survival and outcomes of infants born at 22 and 23 weeks of gestation in Sweden 2004-2007, 2014-2016 and 2017-2019
- 2024
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Ingår i: Archives of Disease in Childhood-Fetal and Neonatal Edition. - : BMJ Publishing Group Ltd. - 1359-2998 .- 1468-2052. ; 109:1, s. 10-17
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo explore associations between perinatal activity and survival in infants born at 22 and 23 weeks of gestation in Sweden. Design/SettingData on all births at 22 and 23 weeks' gestational age (GA) were prospectively collected in 2004-2007 (T1) or obtained from national registers in 2014-2016 (T2) and 2017-2019 (T3). Infants were assigned perinatal activity scores based on 3 key obstetric and 4 neonatal interventions. Main outcomeOne-year survival and survival without major neonatal morbidities (MNM): intraventricular haemorrhage grade 3-4, cystic periventricular leucomalacia, surgical necrotising enterocolitis, retinopathy of prematurity stage 3-5 or severe bronchopulmonary dysplasia. The association of GA-specific perinatal activity score and 1-year survival was also determined. Results977 infants (567 live births and 410 stillbirths) were included: 323 born in T1, 347 in T2 and 307 in T3. Among live-born infants, survival at 22 weeks was 5/49 (10%) in T1 and rose significantly to 29/74 (39%) in T2 and 31/80 (39%) in T3. Survival was not significantly different between epochs at 23 weeks (53%, 61% and 67%). Among survivors, the proportions without MNM in T1, T2 and T3 were 20%, 17% and 19% for 22 weeks and 17%, 25% and 25% for 23 weeks' infants (p>0.05 for all comparisons). Each 5-point increment in GA-specific perinatal activity score increased the odds for survival in first 12 hours of life (adjusted OR (aOR) 1.4; 95% CI 1.3 to 1.6) in addition to 1-year survival (aOR 1.2; 95% CI 1.1 to 1.3), and among live-born infants it was associated with increased survival without MNM (aOR 1.3; 95% CI 1.1 to 1.4). ConclusionIncreased perinatal activity was associated with reduced mortality and increased chances of survival without MNM in infants born at 22 and 23 weeks of GA.
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| 41. |
- Gulje, F. L., et al.
(författare)
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Comparison of 6-mm and 11-mm dental implants in the posterior region supporting fixed dental prostheses: 5-year results of an open multicenter randomized controlled trial
- 2021
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Ingår i: Clinical Oral Implants Research. - : Wiley. - 0905-7161 .- 1600-0501. ; 32:1, s. 15-22
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Tidskriftsartikel (refereegranskat)abstract
- Objective The aim of this multicenter, randomized controlled trial was to compare the clinical and radiographic outcomes of 6-mm or 11-mm implants, placed in the posterior maxilla and mandible, during a 5-year follow-up period. Materials and methods Ninety-five patients with adequate bone height for 11-mm implants, were randomly allocated to a 6-mm group (test group with short implants) or an 11-mm group (control group with standard-length implants). Two or three implants of the same length were placed in each patient and after 6 weeks loaded with a splinted provisional restoration. This was followed by definitive splinted restoration 6 months after implant placement. Clinical and radiographic parameters, including the occurrence of complications were recorded. Results A total of 49 patients were enrolled to receive 6-mm implants (n = 108) and 46 patients to receive 11-mm implants (n = 101). Three implants (two of 6 mm and one of 11 mm in length) were lost before loading and one 6-mm implant after 15 months of function, and one 11-mm implant was lost during the first year of function. The 5-year survival rates were 96.0% and 98.9% in the 6-mm and 11-mm group, respectively. The mean marginal bone level changes 5 years post-loading were 0.01 +/- 0.45 mm (bone gain) in the 6-mm group and -0.12 +/- 0.93 mm (bone loss) in the 11-mm group (p = .7670). Clinical parameters, including plaque, bleeding on probing and pocket probing depth were not significantly different between the groups, and also technical complications were low. Conclusion The clinical and radiographic outcomes of 6-mm short and 11-mm standard-length implants were not different during a 5-year evaluation period.
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| 43. |
- Kanabar, Hrutvik, et al.
(författare)
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PureCake: A Verified Compiler for a Lazy Functional Language
- 2023
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Ingår i: Proceedings of the ACM on Programming Languages. - 2475-1421. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- We present PureCake, a mechanically-verified compiler for PureLang, a lazy, purely functional programming language with monadic effects. PureLang syntax is Haskell-like and indentation-sensitive, and its constraint-based Hindley-Milner type system guarantees safe execution. We derive sound equational reasoning principles over its operational semantics, dramatically simplifying some proofs. We prove end-To-end correctness for the compilation of PureLang down to machine code-The first such result for any lazy language-by targeting CakeML and composing with its verified compiler. Multiple optimisation passes are necessary to handle realistic lazy idioms effectively. We develop PureCake entirely within the HOL4 interactive theorem prover.
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| 44. |
- Li, Bo, et al.
(författare)
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Human Milk Oligosaccharides Protect against Necrotizing Enterocolitis by Activating Intestinal Cell Differentiation
- 2020
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Ingår i: Molecular Nutrition & Food Research. - : WILEY. - 1613-4125 .- 1613-4133. ; 64:21
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Tidskriftsartikel (refereegranskat)abstract
- Scope Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency and currently the leading cause of mortality in preterm infants. Recent studies show that human milk oligosaccharides (HMOs) reduce the frequency and incidence of NEC; however, the molecular mechanisms for their protection are largely unexplored. Methods and results To address this gap, a genome-wide profiling of the intestinal epithelial transcriptome in response to HMOs using RNA-sequencing is performed. It is found that HMOs alter the host transcriptome in 225 unique target genes pertaining to cell proliferation and differentiation, including upregulation of stem cell differentiation marker HMGCS2. To validate these results, differentiation in Caco-2Bbe1 (Caco-2) intestinal cells is verified by Alcian Blue staining and transepithelial electrical resistance (TER) recordings. Furthermore, an in vivo model of NEC is also employed whereby neonatal pups are gavage fed HMOs. Interestingly, HMOs-fed pups show enhanced cell MUC2 differentiation and HMGCS2 expression. Conclusions These findings demonstrate HMOs protect against NEC in part by altering the differentiation of the crypt-villus axis. In addition, this study suggests that pooled HMOs directly induce a series of biological processes, which provide mechanistic insights to how HMOs protect the host intestine.
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| 45. |
- Liedberg, F., et al.
(författare)
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Robot-assisted nephroureterectomy for upper tract urothelial carcinoma—feasibility and complications : a single center experience
- 2022
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 56:4, s. 301-307
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Tidskriftsartikel (refereegranskat)abstract
- Background: Robot-assisted nephroureterectomy (RANU) is the primary treatment for upper tract urothelial carcinoma (UTUC) at our hospital for patients with clinical stage less than T2, and for patients with invasive tumours, but unfit for major surgery. Objective: To assess peri-operative conditions and outcomes of RANU at our unit, and to evaluate the safety of the procedure. Methods: The medical records of all 166 patients undergoing RANU for suspected UTUC and followed for more than three months in a large university hospital in Sweden were reviewed retrospectively. After the exclusion of twenty patients because of previous cystectomy, simultaneous surgical procedure, or other tumour types than UTUC in the pathological report, 146 patients remained for the analyses. The primary endpoint was complication rate according to Clavien-Dindo at 90 days. Secondary endpoints were perioperative bleeding, violation of oncological surgical principles, hospital stay, and re-admission within 90 days. Results: The median age was 75 [(Inter Quartile Range) IQR 70–80] years and 57% of the patients had an ASA score above 2. According to Clavien-Dindo, one patient had a grade 3 complication, and no patient had a grade 4–5 complication. The median blood loss was 50 (IQR 20–100) ml and the median hospital stay was 6 (IQR 5–7) days. Twelve patients were re-admitted to the hospital within 90 days (eight with urinary tract infection/haematuria, one with hematoma, and three with other diseases). Conclusion: Robot-assisted nephroureterectomy is a safe procedure for patients with upper tract urothelial carcinoma, with a low risk of major surgical complications.
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| 46. |
- Olausson, Josefin, 1983, et al.
(författare)
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Optimization of cerebrospinal fluid microbial DNA metagenomic sequencing diagnostics
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Infection in the central nervous system is a severe condition associated with high morbidity and mortality. Despite ample testing, the majority of encephalitis and meningitis cases remain undiagnosed. Metagenomic sequencing of cerebrospinal fluid has emerged as an unbiased approach to identify rare microbes and novel pathogens. However, several major hurdles remain, including establishment of individual limits of detection, removal of false positives and implementation of universal controls. Twenty-one cerebrospinal fluid samples, in which a known pathogen had been positively identified by available clinical techniques, were subjected to metagenomic DNA sequencing. Fourteen samples contained minute levels of Epstein-Barr virus. The detection threshold for each sample was calculated by using the total leukocyte content in the sample and environmental contaminants found in the bioinformatic classifiers. Virus sequences were detected in all ten samples, in which more than one read was expected according to the calculations. Conversely, no viral reads were detected in seven out of eight samples, in which less than one read was expected according to the calculations. False positive pathogens of computational or environmental origin were readily identified, by using a commonly available cell control. For bacteria, additional filters including a comparison between classifiers removed the remaining false positives and alleviated pathogen identification. Here we show a generalizable method for identification of pathogen species using DNA metagenomic sequencing. The choice of bioinformatic method mainly affected the efficiency of pathogen identification, but not the sensitivity of detection. Identification of pathogens requires multiple filtering steps including read distribution, sequence diversity and complementary verification of pathogen reads.
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| 47. |
- Ottosson, Filip, et al.
(författare)
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Unraveling the metabolomic architecture of autism in a large Danish population-based cohort
- 2024
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Ingår i: BMC Medicine. - 1741-7015. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children, and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental, and prenatal factors, the molecular etiology of autism is largely unknown. Here, we use untargeted metabolomics to characterize the neonatal metabolome from dried blood spots collected shortly after birth. Methods: We analyze the metabolomic profiles of a subset of a large Danish population-based cohort (iPSYCH2015) consisting of over 1400 newborns, who later are diagnosed with autism and matching controls and in two Swedish population-based cohorts comprising over 7000 adult participants. Mass spectrometry analysis was performed by a timsTOF Pro operated in QTOF mode, using data-dependent acquisition. By applying an untargeted metabolomics approach, we could reproducibly measure over 800 metabolite features. Results: We detected underlying molecular perturbations across several metabolite classes that precede autism. In particular, the cyclic dipeptide cyclo-leucine-proline (FDR-adjusted p = 0.003) and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) (FDR-adjusted p = 0.03), were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy (FDR-adjusted p < 0.05) and with variants near SLC22A4 and SLC22A5 (p < 5.0e − 8), coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels. Conclusions: Cyclo-leucine-proline and 5-AVAB are associated with future diagnosis of autism in Danish neonates, both representing novel early biomarkers for autism. 5-AVAB is potentially modifiable and may influence carnitine homeostasis.
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