| 1. |
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| 2. |
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| 3. |
- Campinoti, Sara, et al.
(författare)
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Rat liver extracellular matrix and perfusion bioreactor culture promote human amnion epithelial cell differentiation towards hepatocyte-like cells
- 2023
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Ingår i: Journal of Tissue Engineering. - : SAGE Publications. - 2041-7314. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Congenital and chronic liver diseases have a substantial health burden worldwide. The most effective treatment available for these patients is whole organ transplantation; however, due to the severely limited supply of donor livers and the side effects associated with the immunosuppressive regimen required to accept allograft, the mortality rate in patients with end-stage liver disease is annually rising. Stem cell-based therapy aims to provide alternative treatments by either cell transplantation or bioengineered construct transplantation. Human amnion epithelial cells (AEC) are a widely available, ethically neutral source of cells with the plasticity and potential of multipotent stem cells and immunomodulatory properties of perinatal cells. AEC have been proven to be able to achieve functional improvement towards hepatocyte-like cells, capable of rescuing animals with metabolic disorders; however, they showed limited metabolic activities in vitro. Decellularised extracellular matrix (ECM) scaffolds have gained recognition as adjunct biological support. Decellularised scaffolds maintain native ECM components and the 3D architecture instrumental of the organ, necessary to support cells’ maturation and function. We combined ECM-scaffold technology with primary human AEC, which we demonstrated being equipped with essential ECM-adhesion proteins, and evaluated the effects on AEC differentiation into functional hepatocyte-like cells (HLC). This novel approach included the use of a custom 4D bioreactor to provide constant oxygenation and media perfusion to cells in 3D cultures over time. We successfully generated HLC positive for hepatic markers such as ALB, CYP3A4 and CK18. AEC-derived HLC displayed early signs of hepatocyte phenotype, secreted albumin and urea, and expressed Phase-1 and -2 enzymes. The combination of liver-specific ECM and bioreactor provides a system able to aid differentiation into HLC, indicating that the innovative perfusion ECM-scaffold technology may support the functional improvement of multipotent and pluripotent stem cells, with important repercussions in the bioengineering of constructs for transplantation.
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| 4. |
- Eklundh, A., et al.
(författare)
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Etiology of Clinical Community-Acquired Pneumonia in Swedish Children Aged 1-59 Months with High Pneumococcal Vaccine Coverage-The TREND Study
- 2021
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Ingår i: Vaccines. - : MDPI AG. - 2076-393X. ; 9:4
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Tidskriftsartikel (refereegranskat)abstract
- (1) Immunization with pneumococcal conjugate vaccines has decreased the burden of community-acquired pneumonia (CAP) in children and likely led to a shift in CAP etiology. (2) The Trial of Respiratory infections in children for ENhanced Diagnostics (TREND) enrolled children 1-59 months with clinical CAP according to the World Health Organization (WHO) criteria at Sachs' Children and Youth Hospital, Stockholm, Sweden. Children with rhonchi and indrawing underwent "bronchodilator challenge". C-reactive protein and nasopharyngeal PCR detecting 20 respiratory pathogens, were collected from all children. Etiology was defined according to an a priori defined algorithm based on microbiological, biochemical, and radiological findings. (3) Of 327 enrolled children, 107 (32%) required hospitalization; 91 (28%) received antibiotic treatment; 77 (24%) had a chest X-ray performed; and 60 (18%) responded to bronchodilator challenge. 243 (74%) episodes were classified as viral, 11 (3%) as mixed viral-bacterial, five (2%) as bacterial, two (0.6%) as atypical bacterial and 66 (20%) as undetermined etiology. After exclusion of children responding to bronchodilator challenge, the proportion of bacterial and mixed viral-bacterial etiology was 1% and 4%, respectively. (4) The novel TREND etiology algorithm classified the majority of clinical CAP episodes as of viral etiology, whereas bacterial etiology was uncommon. Defining CAP in children <5 years is challenging, and the WHO definition of clinical CAP is not suitable for use in children immunized with pneumococcal conjugate vaccines.
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| 5. |
- Gaudenzi, Giulia, et al.
(författare)
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Point-of-Care Approaches for Meningitis Diagnosis in a Low-Resource Setting (Southwestern Uganda) : Observational Cohort Study Protocol of the "PI-POC" Trial
- 2020
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Ingår i: Journal of Medical Internet Research. - : JMIR Publications Inc.. - 1438-8871. ; 22:11
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Tidskriftsartikel (refereegranskat)abstract
- Background: A timely differential diagnostic is essential to identify the etiology of central nervous system (CNS) infections in children, in order to facilitate targeted treatment, manage patients, and improve clinical outcome. Objective: The Pediatric Infection-Point-of-Care (PI-POC) trial is investigating novel methods to improve and strengthen the differential diagnostics of suspected childhood CNS infections in low-income health systems such as those in Southwestern Uganda. This will be achieved by evaluating (1) a novel DNA-based diagnostic assay for CNS infections, (2) a commercially available multiplex PCR-based meningitis/encephalitis (ME) panel for clinical use in a facility-limited laboratory setting, (3) proteomics profiling of blood from children with severe CNS infection as compared to outpatient controls with fever yet not severely ill, and (4) Myxovirus resistance protein A (MxA) as a biomarker in blood for viral CNS infection. Further changes in the etiology of childhood CNS infections after the introduction of the pneumococcal conjugate vaccine against Streptococcus pneumoniae will be investigated. In addition, the carriage and invasive rate of Neisseria meningitidis will be recorded and serotyped, and the expression of its major virulence factor (polysaccharide capsule) will be investigated. Methods: The PI-POC trial is a prospective observational study of children including newborns up to 12 years of age with clinical features of CNS infection, and age-/sex-matched outpatient controls with fever yet not severely ill. Participants are recruited at 2 Pediatric clinics in Mbarara, Uganda. Cerebrospinal fluid (for cases only), blood, and nasopharyngeal (NP) swabs (for both cases and controls) sampled at both clinics are analyzed at the Epicentre Research Laboratory through gold-standard methods for CNS infection diagnosis (microscopy, biochemistry, and culture) and a commercially available ME panel for multiplex PCR analyses of the cerebrospinal fluid. An additional blood sample from cases is collected on day 3 after admission. After initial clinical analyses in Mbarara, samples will be transported to Stockholm, Sweden for (1) validation analyses of a novel nucleic acid-based POC test, (2) biomarker research, and (3) serotyping and molecular characterization of S. pneumoniae and N. meningitidis. Results: A pilot study was performed from January to April 2019. The PI-POC trial enrollment of patients begun in April 2019 and will continue until September 2020, to include up to 300 cases and controls. Preliminary results from the PI-POC study are expected by the end of 2020. Conclusions: The findings from the PI-POC study can potentially facilitate rapid etiological diagnosis of CNS infections in low-resource settings and allow for novel methods for determination of the severity of CNS infection in such environment.
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| 6. |
- Gaudenzi, Giulia
(författare)
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Transcriptional regulation of neural development and degeneration
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The architecture and functional interactions of the cerebral cortex are fascinating in their complexity of billions of neurons and glial cells connected in intricate circuitries and spatial regions. During development, transcription factors and chromatin modifiers work together to coordinate gene expression programs that drive the formation of the cerebral cortex. Notably, neurological aberrations can arise when perturbation occurs in these tightly regulated programs. Although our understanding of corticogenesis has advanced with the identification of master regulators of neural development, we only have rudimentary knowledge of the molecular mechanisms these factors use to execute the developmental programs. The aim of this thesis is to investigate the transcriptional mechanisms of gene regulation by key transcription factors involved in telencephalic development and disease, using primarily human neural progenitors as an in vitro model of development. Study I reports a novel mechanism through an interaction between the co-repressor NCOR and the transcription factor FOXP2. Genome-wide mapping of common binding sites of NCOR/FOXP2 in human iPS-derived neural progenitors included two putative regulatory elements in the proximity of the SLITRK gene cluster. Chromosome conformation capture (3C) confirmed the interaction between the SLITRK cluster gene promoters and the regulatory elements where FOXP2/NCOR binds, which proposes a possible role for this regulatory mechanism in accurate development and possibly evolution of vocal and motor skills. Study II demonstrates that the transcription factor PAX6 can function as a repressor and recruit the histone demethylase KDM5C to repress a subset of genes involved in Notch signaling, which is critical for several neuronal functions, proposing that neurodevelopmental aberrations by PAX6 and/or KDM5C mutations maybe be associated with defects in Notch signaling. Study III explores the gene regulation effects on pluripotency mediated by different handling techniques of human embryonic stem cells and human induced pluripotent stem cells, and shows that reversible gene expression changes indeed occur during prolonged culture in enzymatic conditions. Study IV reveals that a single nucleotide polymorphism (SNP) in the promoter of the HTT gene, responsible for Huntington’s disease, disrupts the NF-κB binding and transcriptional regulation of the HTT gene, indicating that silencing of the HTT gene is a promising therapeutic strategy in Huntington’s disease. Taken together, the work of this thesis strengthens the hypothesis that the interplay between transcription factors and chromatin structure is critical for maintaining neurological fitness.
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| 7. |
- Khati, Vamakshi, et al.
(författare)
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3D Bioprinting of Multi-Material Decellularized Liver Matrix Hydrogel at Physiological Temperatures
- 2022
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Ingår i: Biosensors. - : MDPI AG. - 2079-6374. ; 12:7
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Tidskriftsartikel (refereegranskat)abstract
- Bioprinting is an acclaimed technique that allows the scaling of 3D architectures in an organized pattern but suffers from a scarcity of appropriate bioinks. Decellularized extracellular matrix (dECM) from xenogeneic species has garnered support as a biomaterial to promote tissue-specific regeneration and repair. The prospect of developing dECM-based 3D artificial tissue is impeded by its inherent low mechanical properties. In recent years, 3D bioprinting of dECM-based bioinks modified with additional scaffolds has advanced the development of load-bearing constructs. However, previous attempts using dECM were limited to low-temperature bioprinting, which is not favorable for a longer print duration with cells. Here, we report the development of a multi-material decellularized liver matrix (dLM) bioink reinforced with gelatin and polyethylene glycol to improve rheology, extrudability, and mechanical stability. This shear-thinning bioink facilitated extrusion-based bioprinting at 37 degrees C with HepG2 cells into a 3D grid structure with a further enhancement for long-term applications by enzymatic crosslinking with mushroom tyrosinase. The heavily crosslinked structure showed a 16-fold increase in viscosity (2.73 Pa s(-1)) and a 32-fold increase in storage modulus from the non-crosslinked dLM while retaining high cell viability (85-93%) and liver-specific functions. Our results show that the cytocompatible crosslinking of dLM bioink at physiological temperatures has promising applications for extended 3D-printing procedures.
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| 8. |
- Khati, Vamakshi, et al.
(författare)
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A tunable decellularized liver-based hybrid bioink
- 2021
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Ingår i: MicroTAS 2021 - 25th International Conference on Miniaturized Systems for Chemistry and Life Sciences. - : Chemical and Biological Microsystems Society. ; , s. 281-282
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Konferensbidrag (refereegranskat)abstract
- Decellularized extracellular matrix is a tissue-specific biomaterial that recapitulates the complexity of the inherent tissue environment to elicit cellular response. Here, a multi-material decellularized liver (dLM)-based bioink with gelatin is developed and polyethylene glycol crosslinking is used to enhance the viscoelasticity of the dLM. We evaluated the necessity of a post-printing secondary cross-linker mushroom tyrosinase to improve robustness and long term stability. We further demonstrate it's biocompatibility using liver specific gene analysis of HepG2 cells.
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| 9. |
- Khati, Vamakshi, 1991-
(författare)
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Decellularized liver extracellular matrix as a 3D scaffold for bioengineering applications
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The increasing global burden of end-stage liver disease has increased the need for liver transplantation, the definitive cure. However, there is a huge discrepancy between the number of available organ donors and the number of patients waiting for transplantation, resulting in the deaths of a significant number of patients on the waiting list as only 10% of the global need for transplantation is met. Liver tissue engineering is a promising alternative solution to this problem, which utilizes bioengineering techniques to create an ex vivo microenvironment niche for liver cells embedded in a liver-specific extracellular matrix (ECM) for cell growth and function. Despite many advances in this field, the scarcity of appropriate ECM-mimicking biomaterials with good mechanical properties for biofabrication technique remains limited. To address this, different biofabrication techniques, such as bioprinting and biomaterial scaffolds, are studied to simulate liver microarchitecture for different applications. This thesis presents the development and application of a decellularized liver extracellular matrix hydrogel combined with the liver cell line HepG2 (papers 1-3). It also focuses on the decellularized whole liver scaffold to differentiate amniotic epithelial cells (paper 4). The decellularized liver extracellular matrix (dLM) is a cell-free scaffold that retains liver-specific components to direct cell growth and functions. The dLM can be digested to form hydrogel for 3D bioprinting applications, or it can be used as a biomaterial scaffold to seed the cells directly. In paper I, porcine dLM hydrogel was modified with gelatin and a PEG-based crosslinker to induce a cytocompatible gelation mechanism to generate a robust bioink with a 16-fold increment in viscosity and a 32-fold increment in storage modulus as compared to unmodified dLM hydrogel. This work established the application of dLM with other biofabrication methods, such as Indirect bioprinting, where a sacrificial biopolymer is 3D printed, and the scaffold material is subsequently added. In paper II, a 3D-printed polyvinyl alcohol framework resembling the liver lobules was used as a sacrificial scaffold to impart its structure to the dLM hydrogel modified with PEG-based crosslinker and mushroom tyrosinase. The crosslinked dLM hydrogel with co-culture of HepG2 and NIH 3T3 fibroblasts cell line retained the structure of PVA to create a scaled-up liver-like microarchitecture with lobules. The PVA dissolved with cell culture media leaving behind a robust 3D construct of dLM hydrogel. In paper III, cellulose nanofibril-coated HepG2 spheroids incorporating dLM hydrogel were studied for tumor modeling. The dLM incorporation affected the spheroid formation and growth depending on the time of addition. In paper IV, the functional differentiation of amniotic epithelial cells into hepatocyte-like cells was performed in a decellularized rat liver scaffold in a perfusion bioreactor with dynamic oxygenation and media exchange. This dLM perfusion technology supported the maturation and proliferation of amniotic epithelial cells into hepatocyte-like cells. This is a preliminary step into developing a liver-like organ model in a laboratory setting. To conclude, this thesis presents different bioengineering approaches, such as 3D bioprinting and perfusion decellularization, to study the 3D dLM scaffolds for HepG2 and amniotic epithelial cell culture. 3D bioprinting technique utilized a robust dLM hydrogel to create a scaled-up microarchitecture, whereas perfusion decellularization retained the natural 3D architecture of the whole liver ECM and the native vascular system for recellularizing the scaffold with stem cells. We successfully modified and characterized the dLM hydrogel to enhance its printability to develop complex structures such as liver lobules and microchannels. We utilized different cell systems, including monoculture, co-culture, and spheroids, to analyze the biocompatibility, cell proliferation, and liver-specific functions of the dLM scaffold. Ultimately, the advancement of dLM as a biomaterial presented in this thesis could improve the application and modification of various decellularized tissues to generate larger-scale models for in vitro testing and organ transplantation.
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| 10. |
- Khati, Vamakshi, et al.
(författare)
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Development of robust sacrificial support construct with decellularized liver extracellular matrix
- 2022
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Ingår i: MicroTAS 2022. - : Chemical and Biological Microsystems Society. ; , s. 432-433
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Konferensbidrag (refereegranskat)abstract
- 3D bioprinting is an acclaimed technology to develop architecturally significant tissue models, however most bioinks require a secondary support structure to create a clinically relevant sized model. In this work, we develop a 3D sacrificial support structure of polyvinyl alcohol (PVA) with decellularized liver extracellular matrix (dECM) bioink with HepG2 cells. The PVA backbone imparts its 3D structure to dECM and dissolves in cell culture media. We evaluated the PVA dissolution using refractometry and microscopic observation. We further tested the crosslinking of dECM with a PEG-based crosslinker using scanning electron microscopy (SEM). Alamar blue assay and gene expression analysis results demonstrated an increase in cell proliferation within the 3D structure.
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| 11. |
- Khati, Vamakshi, et al.
(författare)
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Indirect 3D Bioprinting of a Robust Trilobular Hepatic Construct with Decellularized Liver Matrix Hydrogel
- 2022
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Ingår i: Bioengineering. - : MDPI AG. - 2306-5354. ; 9:11, s. 603-603
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Tidskriftsartikel (refereegranskat)abstract
- The liver exhibits complex geometrical morphologies of hepatic cells arranged in a hexagonal lobule with an extracellular matrix (ECM) organized in a specific pattern on a multi-scale level. Previous studies have utilized 3D bioprinting and microfluidic perfusion systems with various biomaterials to develop lobule-like constructs. However, they all lack anatomical relevance with weak control over the size and shape of the fabricated structures. Moreover, most biomaterials lack liver-specific ECM components partially or entirely, which might limit their biomimetic mechanical properties and biological functions. Here, we report 3D bioprinting of a sacrificial PVA framework to impart its trilobular hepatic structure to the decellularized liver extracellular matrix (dLM) hydrogel with polyethylene glycol-based crosslinker and tyrosinase to fabricate a robust multi-scale 3D liver construct. The 3D trilobular construct exhibits higher crosslinking, viscosity (182.7 ± 1.6 Pa·s), and storage modulus (2554 ± 82.1 Pa) than non-crosslinked dLM. The co-culture of HepG2 liver cells and NIH 3T3 fibroblast cells exhibited the influence of fibroblasts on liver-specific activity over time (7 days) to show higher viability (90–91.5%), albumin secretion, and increasing activity of four liver-specific genes as compared to the HepG2 monoculture. This technique offers high lumen patency for the perfusion of media to fabricate a densely populated scaled-up liver model, which can also be extended to other tissue types with different biomaterials and multiple cells to support the creation of a large functional complex tissue.
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| 12. |
- Rasti, Reza, et al.
(författare)
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Point-of-care testing in a high-income country paediatric emergency department : a qualitative study in Sweden
- 2021
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 11:11
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Tidskriftsartikel (refereegranskat)abstract
- Objectives In many resource-limited health systems, point-of-care tests (POCTs) are the only means for clinical patient sample analyses. However, the speed and simplicity of POCTs also makes their use appealing to clinicians in high-income countries (HICs), despite greater laboratory accessibility. Although also part of the clinical routine in HICs, clinician perceptions of the utility of POCTs are relatively unknown in such settings as compared with others. In a Swedish paediatric emergency department (PED) where POCT use is routine, we aimed to characterise healthcare providers' perspectives on the clinical utility of POCTs and explore their implementation in the local setting; to discuss and compare such perspectives, to those reported in other settings; and finally, to gather requests for ideal novel POCTs. Design Qualitative focus group discussions study. A data-driven content analysis approach was used for analysis. Setting The PED of a secondary paediatric hospital in Stockholm, Sweden. Participants Twenty-four healthcare providers clinically active at the PED were enrolled in six focus groups. Results A range of POCTs was routinely used. The emerging theme Utility of our POCT use is double-edged illustrated the perceived utility of POCTs. While POCT services were considered to have clinical and social value, the local routine for their use was named to distract clinicians from the care for patients. Requests were made for ideal POCTs and their implementation. Conclusion Despite their clinical integration, deficient implementation routines limit the benefits of POCT services to this well-resourced paediatric clinic. As such deficiencies are shared with other settings, it is suggested that some characteristics of POCTs and of their utility are less related to resource level and more to policy deficiency. To address this, we propose the appointment of skilled laboratory personnel as ambassadors to hospital clinics offering POCT services, to ensure higher utility of such services.
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| 13. |
- Rhedin, Samuel, et al.
(författare)
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Myxovirus resistance protein A for discriminating between viral and bacterial lower respiratory tract infections in children- The TREND study
- 2022
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Ingår i: Clinical Microbiology and Infection. - : Elsevier BV. - 1198-743X .- 1469-0691. ; 28:9, s. 1251-1257
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Discriminating between viral and bacterial lower respiratory tract infection (LRTI) in children is challenging, leading to an excessive use of antibiotics. Myxovirus resistance protein A (MxA) is a promising biomarker for viral infections. The primary aim of the study was to assess differences in blood MxA levels between children with viral and bacterial LRTI. Secondary aims were to assess differences in blood MxA levels between children with viral LRTI and asymptomatic controls and to assess MxA levels in relation to different respiratory viruses. Methods: Children with LRTI were enrolled as cases at Sachs' Children and Youth Hospital, Stockholm, Sweden. Nasopharyngeal aspirates and blood samples for analysis of viral PCR, MxA, and C-reactive protein were systematically collected from all study subjects in addition to standard laboratory/radiology assessment. Aetiology was defined according to an algorithm based on laboratory and radiological findings. Asymptomatic children with minor surgical disease were enrolled as controls. Results: MxA levels were higher in children with viral LRTI (n = 242) as compared to both bacterial (n = 5) LRTI (p < 0.01, area under the curve (AUC) 0.90, 95% CI: 0.81 to 0.99), and controls (AUC 0.92, 95% CI: 0.88 to 0.95). In the subgroup of children with pneumonia diagnosis, a cutoff of MxA 430 mg/l discriminated between viral (n = 29) and bacterial (n = 4) aetiology with 93% (95% CI: 78-99%) sensi-tivity and 100% (95% CI: 51-100%) specificity (AUC 0.98, 95% CI: 0.94 to 1.00). The highest MxA levels were seen in cases PCR positive for influenza (median MxA 1699 mg/l, interquartile range: 732 to 2996) and respiratory syncytial virus (median MxA 1115 mg/l, interquartile range: 679 to 2489). Discussion: MxA accurately discriminated between viral and bacterial aetiology in children with LRTI, particularly in the group of children with pneumonia diagnosis, but the number of children with bacterial LRTI was low.
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| 14. |
- Urrutia Iturritza, Miren, et al.
(författare)
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An automated microfluidic diagnostics pipeline for infectious disease detection in low resource settings
- 2020
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Ingår i: MicroTAS 2020 - 24th International Conference on Miniaturized Systems for Chemistry and Life Sciences. - : Chemical and Biological Microsystems Society. ; , s. 1197-1198
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Konferensbidrag (refereegranskat)abstract
- While diagnostics are critical for accurate and timely diagnosis, gold-standard diagnostic tests are commonly high- performance laboratory-based tests that require multi-step protocols for complex sample processing and highly trained personnel, both scarce in low-resource settings. Here, we address the need for an easy-to-use, rapid and reliable diagnostic testing pipeline by presenting a solution combining open-source modular automation and automation compatible microfluidics, easily adaptable to a pipeline for infectious diseases diagnosis. We demonstrate an automation compatible microfluidics pipeline for Neisseria meningitidis diagnosis by on-chip nucleic acids isolation and isothermal amplification, as well as pathogen detection on a paper-based microarray.
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| 15. |
- Urrutia Iturritza, Miren, et al.
(författare)
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An Automated Versatile Diagnostic Workflow for Infectious Disease Detection in Low-Resource Settings
- 2024
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Ingår i: Micromachines. - : MDPI AG. - 2072-666X. ; 15:6
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Tidskriftsartikel (refereegranskat)abstract
- Laboratory automation effectively increases the throughput in sample analysis, reduces human errors in sample processing, as well as simplifies and accelerates the overall logistics. Automating diagnostic testing workflows in peripheral laboratories and also in near-patient settings -like hospitals, clinics and epidemic control checkpoints- is advantageous for the simultaneous processing of multiple samples to provide rapid results to patients, minimize the possibility of contamination or error during sample handling or transport, and increase efficiency. However, most automation platforms are expensive and are not easily adaptable to new protocols. Here, we address the need for a versatile, easy-to-use, rapid and reliable diagnostic testing workflow by combining open-source modular automation (Opentrons) and automation-compatible molecular biology protocols, easily adaptable to a workflow for infectious diseases diagnosis by detection on paper-based diagnostics. We demonstrated the feasibility of automation of the method with a low-cost Neisseria meningitidis diagnostic test that utilizes magnetic beads for pathogen DNA isolation, isothermal amplification, and detection on a paper-based microarray. In summary, we integrated open-source modular automation with adaptable molecular biology protocols, which was also faster and cheaper to perform in an automated than in a manual way. This enables a versatile diagnostic workflow for infectious diseases and we demonstrated this through a low-cost N. meningitidis test on paper-based microarrays.
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| 16. |
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| 17. |
- Zanni, G., et al.
(författare)
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Lithium treatment reverses irradiation-induced changes in rodent neural progenitors and rescues cognition
- 2019
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:1, s. 322-340
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Tidskriftsartikel (refereegranskat)abstract
- Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context. Lithium, a well-known mood stabilizer, has both neuroprotective, pro-neurogenic as well as antitumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation. Female mice received a single 4 Gy whole-brain radiation dose on postnatal day (PND) 21 and were randomized to 0.24% Li2CO3 chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed on PND 77, 91, and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors, but neuronal integration occurred only after it was discontinued. Also, the treatment ameliorated deficits in spatial learning and memory retention observed in irradiated mice. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with microtubule stabilization, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced loss of hippocampal neurogenesis and cognitive impairment even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.
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