| 1. |
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| 2. |
- Ivanchenko, M, et al.
(author)
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Natural killer cells and type II interferon in Ro/SSA and La/SSB autoantibody-exposed newborns at risk of congenital heart block
- 2021
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In: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 80:2, s. 194-202
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Journal article (peer-reviewed)abstract
- Congenital heart block (CHB) with immune cell infiltration develops in the fetus after exposure to maternal Ro/La autoantibodies. CHB-related serology has been extensively studied, but reports on immune-cell profiles of anti-Ro/La-exposed neonates are lacking. In the current study, we characterised circulating immune-cell populations in anti-Ro/La+mothers and newborns, and explored potential downstream effects of skewed neonatal cell populations.MethodsIn total, blood from mothers (n=43) and neonates (n=66) was sampled at birth from anti-Ro/La+ (n=36) and control (n=30) pregnancies with or without rheumatic disease and CHB. Flow cytometry, microarrays and ELISA were used for characterising cells and plasma.ResultsSimilar to non-pregnant systemic lupus erythematosus and Sjögren-patients, anti-Ro/La+mothers had altered B-cell subset frequencies, relative T-cell lymphopenia and lower natural killer (NK)-cell frequencies. Surprisingly, their anti-Ro/La exposed neonates presented higher frequencies of CD56dimCD16hiNK cells (p<0.01), but no other cell frequency differences compared with controls. Type I and II interferon (IFN) gene-signatures were revealed in neonates of anti-Ro/La+ pregnancy, and exposure of fetal cardiomyocytes to type I IFN induced upregulation of several NK-cell chemoattractants and activating ligands. Intracellular flow cytometry revealed IFNγ production by NK cells, CD8+and CD4+T cells in anti-Ro/La exposed neonates. IFNγ was also detectable in their plasma.ConclusionOur study demonstrates an increased frequency of NK cells in anti-Ro/La exposed neonates, footprints of type I and II IFN and an upregulation of ligands activating NK cells in fetal cardiac cells after type I IFN exposure. These novel observations demonstrate innate immune activation in neonates of anti-Ro/La+pregnancy, which could contribute to the risk of CHB.
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| 3. |
- Murray, Alison E., et al.
(author)
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Roadmap for naming uncultivated Archaea and Bacteria
- 2020
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In: Nature Microbiology. - : NATURE PUBLISHING GROUP. - 2058-5276. ; 5:8, s. 987-994
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Journal article (peer-reviewed)abstract
- The assembly of single-amplified genomes (SAGs) and metagenome-assembled genomes (MAGs) has led to a surge in genome-based discoveries of members affiliated with Archaea and Bacteria, bringing with it a need to develop guidelines for nomenclature of uncultivated microorganisms. The International Code of Nomenclature of Prokaryotes (ICNP) only recognizes cultures as 'type material', thereby preventing the naming of uncultivated organisms. In this Consensus Statement, we propose two potential paths to solve this nomenclatural conundrum. One option is the adoption of previously proposed modifications to the ICNP to recognize DNA sequences as acceptable type material; the other option creates a nomenclatural code for uncultivated Archaea and Bacteria that could eventually be merged with the ICNP in the future. Regardless of the path taken, we believe that action is needed now within the scientific community to develop consistent rules for nomenclature of uncultivated taxa in order to provide clarity and stability, and to effectively communicate microbial diversity. In this Consensus Statement, the authors discuss the issue of naming uncultivated prokaryotic microorganisms, which currently do not have a formal nomenclature system due to a lack of type material or cultured representatives, and propose two recommendations including the recognition of DNA sequences as type material.
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| 4. |
- Badholm, M, et al.
(author)
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Cerebrospinal fluid cell count variability is a major confounding factor in external ventricular drain-associated infection surveillance diagnostics: a prospective observational study
- 2021
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In: Critical care (London, England). - : Springer Science and Business Media LLC. - 1466-609X .- 1364-8535. ; 25:1, s. 291-
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Journal article (peer-reviewed)abstract
- BackgroundExternal ventricular drain (EVD)-related infections (EVDIs) are feared complications that are difficult to rapidly and correctly diagnose, which can lead to unnecessary treatment with broad-spectrum antibiotics. No readily available diagnostic parameters have been identified to reliably predict or identify EVDIs. Moreover, intraventricular hemorrhage is common and affect cerebrospinal fluid (CSF) cellularity. The relationship between leukocytes and erythrocytes is often used to identify suspected infection and triggers the use of antibiotics pending results of cultures, which may take days. Cell count based surveillance diagnostics assumes a homogeneous distribution of cells in the CSF. Given the intraventricular sedimentation of erythrocytes on computed tomography scans this assumption may be erroneous and could affect diagnostics.AimsTo evaluate the consistency of cell counts in serially sampled CSF from EVDs, with and without patient repositioning, to assess the effect on infection diagnostics.MethodsWe performed a prospective single-center study where routine CSF sampling was followed by a second sample after 10 min, allocated around a standard patient repositioning, or not. Changes in absolute and pairwise cell counts and ratios were analyzed, including mixed regression models.ResultsData from 51 patients and 162 paired samples were analyzed. We observed substantial changes in CSF cellularity as the result of both resampling and repositioning, with repositioning found to be an independent predictor of bidirectional cellular change. Glucose and lactate levels were affected, however clinically non-significant. No positive CSF cultures were seen during the study. Thirty percent (30%) of patients changed suspected EVDI status, as defined by the cell component of local and national guidelines, when resampling after repositioning.ConclusionsCSF cell counts are not consistent and are affected by patient movement suggesting a heterogeneity in the intraventricular space. The relationship between leukocytes and erythrocytes was less affected than absolute changes. Importantly, cell changes are found to increase with increased cellularity, often leading to changes in suspected EVDI status. Faster and more precise diagnostics are needed, and methods such as emerging next generation sequencing techniques my provide tools to more timely and accurately guide antibiotic treatment.Trial RegistrationNCT04736407, Clinicaltrials.gov, retrospectively registered 2nd February 2021.
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| 5. |
- Birgegard, Andreas, et al.
(author)
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Proposal for increasing diagnostic clarity in research and clinical practice by renaming and reframing atypical anorexia nervosa as "Restrictive Eating Disorder" (RED)
- 2023
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In: Eating Behaviors. - : ELSEVIER. - 1471-0153 .- 1873-7358. ; 50
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Journal article (peer-reviewed)abstract
- Atypical anorexia nervosa (AAN) in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM5), is characterized by meeting all criteria for anorexia nervosa (AN) except for weight being within or above the "normal" range despite significant weight loss. The current definition is plagued by several problems, resulting in widely heterogeneous operationalizations in research and clinical practice. As such, the poorly defined diagnosis of AAN negatively impacts affected individuals and frustrates research attempts to better understand the syndrome. We consider conceptual flaws in the AAN description and contend that the undefined weight range and nature of weight loss renders these two factors functionally inapplicable in research and practice. They also represent a departure from the originally intended use of the AAN category, i.e., arresting a negative weight trajectory likely to result in AN, making the target population, and the application of the label, unclear. We propose revised criteria and a new name, restrictive eating disorder (RED), intended to reduce stigma and encompass a wide but better-defined range of presentations. The RED criteria focus on clinically significant restrictive behavior that disrupts normal living (i.e., impairment), and cognitive symptoms of overevaluation, disturbed experience, and lack of recognition of illness seriousness. We believe that RED may enable more appropriate clinical application, but also inspire coordinated research toward a more valid psychiatric nosology in the eating disorders field.
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| 6. |
- Castiglione, Fabio, et al.
(author)
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Long-term consequences of bilateral cavernous crush injury in normal and diabetic rats : a functional study
- 2022
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In: International Journal of Impotence Research. - : Springer Science and Business Media LLC. - 0955-9930 .- 1476-5489. ; 34:8, s. 781-785
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Journal article (peer-reviewed)abstract
- A recent statement from the European-Society-for-Sexual-Medicine has highlighted the limitations of using the rat model for nerve-sparing prostatectomy. The use of young rats with no comorbidities and the early evaluation of the erectile function (EF) are deemed a source of bias. Our aim was to evaluate the long-term consequences in EF of bilateral nerve cavernous crush- injury (BNCI) in type 1 diabetic (DM) rats 30-male/12-week-old rats were divided into four groups: Sham, BNCI, DM, and BNCI + DM. Sham group underwent an intraperitoneal injection (IP) of saline solution and after 1 month underwent a sham laparotomy. BNCI underwent an IP of saline solution and after 1 month to BNCI. DM underwent an IP of 60 mg/kg-1-streptozotocin (STZ) and after 1 month to a sham laparotomy. BNCI + DM underwent an IP of 60 mg/kg-1-STZ and after 1 month to BNCI. After 5 months from the induction of diabetes, all rats underwent measurement of intracorporeal pressure (ICP) and mean arterial pressure (MAP) during CN-electrostimulation. Multiple groups were compared using Kruskal–Wallis one-way analysis of variance followed by Mann–Whitney U test for post hoc comparisons. Blood glucose-level was higher (p < 0.05) in the groups with DM and BNCI + DM. After 5-months, DM and BNCI + DM also showed a lower weight compared to other groups (p < 0.05). No differences were noted in ICP/MAP between the sham and BNCI. BNCI + DM showed lower ICP/MAP compared to all the groups (p < 0.05). DM Showed lower ICP/MAP compared to Sham and BNCI (p < 0.05). BNCI in rats without comorbidities did not induce long-term erectile dysfunction (ED) suggesting a spontaneous EF recovery. BNCI in DM induced long-term ED. The results of previous short-term studies can only provide evidence on the time to recovery of spontaneous EF as to the actual EF recovery rate.
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| 7. |
- Jutzi, D, et al.
(author)
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Aberrant interaction of FUS with the U1 snRNA provides a molecular mechanism of FUS induced amyotrophic lateral sclerosis
- 2020
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 6341-
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Journal article (peer-reviewed)abstract
- Mutations in the RNA-binding protein Fused in Sarcoma (FUS) cause early-onset amyotrophic lateral sclerosis (ALS). However, a detailed understanding of central RNA targets of FUS and their implications for disease remain elusive. Here, we use a unique blend of crosslinking and immunoprecipitation (CLIP) and NMR spectroscopy to identify and characterise physiological and pathological RNA targets of FUS. We find that U1 snRNA is the primary RNA target of FUS via its interaction with stem-loop 3 and provide atomic details of this RNA-mediated mode of interaction with the U1 snRNP. Furthermore, we show that ALS-associated FUS aberrantly contacts U1 snRNA at the Sm site with its zinc finger and traps snRNP biogenesis intermediates in human and murine motor neurons. Altogether, we present molecular insights into a FUS toxic gain-of-function involving direct and aberrant RNA-binding and strengthen the link between two motor neuron diseases, ALS and spinal muscular atrophy (SMA).
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| 8. |
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| 9. |
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| 10. |
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| 11. |
- Meisgen, S, et al.
(author)
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Auxilin is a novel susceptibility gene for congenital heart block which directly impacts fetal heart function
- 2022
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In: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 81:8, s. 1151-1161
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Journal article (peer-reviewed)abstract
- Neonatal lupus erythematosus (NLE) may develop after transplacental transfer of maternal autoantibodies with cardiac manifestations (congenital heart block, CHB) including atrioventricular block, atrial and ventricular arrhythmias, and cardiomyopathies. The association with anti-Ro/SSA antibodies is well established, but a recurrence rate of only 12%–16% despite persisting maternal autoantibodies suggests that additional factors are required for CHB development. Here, we identify fetal genetic variants conferring risk of CHB and elucidate their effects on cardiac function.MethodsA genome-wide association study was performed in families with at least one case of CHB. Gene expression was analysed by microarrays, RNA sequencing and PCR and protein expression by western blot, immunohistochemistry, immunofluorescence and flow cytometry. Calcium regulation and connectivity were analysed in primary cardiomyocytes and cells induced from pleuripotent stem cells. Fetal heart performance was analysed by Doppler/echocardiography.ResultsWe identified DNAJC6 as a novel fetal susceptibility gene, with decreased cardiac expression of DNAJC6 associated with the disease risk genotype. We further demonstrate that fetal cardiomyocytes deficient in auxilin, the protein encoded by DNAJC6, have abnormal connectivity and Ca2+ homoeostasis in culture, as well as decreased cell surface expression of the Cav1.3 calcium channel. Doppler echocardiography of auxilin-deficient fetal mice revealed cardiac NLE abnormalities in utero, including abnormal heart rhythm with atrial and ventricular ectopias, as well as a prolonged atrioventricular time intervals.ConclusionsOur study identifies auxilin as the first genetic susceptibility factor in NLE modulating cardiac function, opening new avenues for the development of screening and therapeutic strategies in CHB.
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| 12. |
- Nizzardo, M, et al.
(author)
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Synaptotagmin 13 is neuroprotective across motor neuron diseases
- 2020
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In: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 139:5, s. 837-853
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Journal article (peer-reviewed)abstract
- In amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), spinal and lower brainstem motor neurons degenerate, but some motor neuron subtypes are spared, including oculomotor neurons (OMNs). The mechanisms responsible for this selective degeneration are largely unknown, but the molecular signatures of resistant and vulnerable motor neurons are distinct and offer clues to neuronal resilience and susceptibility. Here, we demonstrate that healthy OMNs preferentially express Synaptotagmin 13 (SYT13) compared to spinal motor neurons. In end-stage ALS patients, SYT13 is enriched in both OMNs and the remaining relatively resilient spinal motor neurons compared to controls. Overexpression of SYT13 in ALS and SMA patient motor neurons in vitro improves their survival and increases axon lengths. Gene therapy with Syt13 prolongs the lifespan of ALS mice by 14% and SMA mice by 50% by preserving motor neurons and delaying muscle denervation. SYT13 decreases endoplasmic reticulum stress and apoptosis of motor neurons, both in vitro and in vivo. Thus, SYT13 is a resilience factor that can protect motor neurons and a candidate therapeutic target across motor neuron diseases.
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| 13. |
- Osman, Ahmed M., et al.
(author)
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Radiation Triggers a Dynamic Sequence of Transient Microglial Alterations in Juvenile Brain
- 2020
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In: Cell Reports. - : CELL PRESS. - 2211-1247. ; 31:9
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Journal article (peer-reviewed)abstract
- Cranial irradiation (IR), an effective tool to treat malignant brain tumors, triggers a chronic pro-inflammatory microglial response, at least in the adult brain. Using single-cell and bulk RNA sequencing, combined with histology, we show that the microglial response in the juvenile mouse hippocampus is rapid but returns toward normal within 1 week. The response is characterized by a series of temporally distinct homeostasis-, sensome-, and inflammation-related molecular signatures. We find that a single microglial cell simultaneously upregulates transcripts associated with pro- and anti-inflammatory microglial phenotypes. Finally, we show that juvenile and adult irradiated microglia are already transcriptionally distinct in the early phase after IR. Our results indicate that microglia are involved in the initial stages but may not be responsible for driving long-term inflammation in the juvenile brain.
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Temmesfeld, M. J., et al.
(author)
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Surgical helmets can be converted into efficient disinfectable powered air-purifying respirators
- 2022
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In: American Journal of Infection Control. - : Elsevier BV. - 0196-6553. ; 50:6, s. 624-630
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Journal article (peer-reviewed)abstract
- Background: Filtering facepiece respirators often fail to provide sufficient protection due to a poor fit. Powered air-purifying respirators (PAPRs) are not designed for healthcare personnel, and are challenging to disinfect. Surgical helmets (SH) are available in many United States hospitals but do not provide respiratory protection. Several modifications to SH have been suggested, but none are sufficiently compliant with safety and efficiency standards. The purpose of this investigation was the development of a filter adaptor, which converts SHs into efficient, safe, and disinfectable PAPRs. Methods: Four critical features were investigated close to regulatory requirements: total inward leakage of particles, CO2 concentrations, intra-helmet differential pressure, and automated disinfection. Results: The average total inward leakage in the 2 independent tests were 0.005% and 0.01%. CO2 concentrations were lower than in the original SH. The modification generates a positive differential pressure. The filter's performance was not compromised after 50 cycles in a sterilization machine. Discussion: The modified SH provides several hundred times better protection than FFP-3 masks. Conclusions: Surgical helmets can be modified into safe, efficient, and disinfectable PAPRs, suitable for HCP and the operating room in particular. They can play a role in the preparedness for upcoming events requiring efficient respiratory protection.
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| 18. |
- Wasserman, D, et al.
(author)
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Compulsory admissions of patients with mental disorders: State of the art on ethical and legislative aspects in 40 European countries
- 2020
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In: European psychiatry : the journal of the Association of European Psychiatrists. - : Royal College of Psychiatrists. - 1778-3585. ; 63:1, s. e82-
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Journal article (peer-reviewed)abstract
- Background.Compulsory admission procedures of patients with mental disorders vary between countries in Europe. The Ethics Committee of the European Psychiatric Association (EPA) launched a survey on involuntary admission procedures of patients with mental disorders in 40 countries to gather information from all National Psychiatric Associations that are members of the EPA to develop recommendations for improving involuntary admission processes and promote voluntary care.Methods.The survey focused on legislation of involuntary admissions and key actors involved in the admission procedure as well as most common reasons for involuntary admissions.Results.We analyzed the survey categorical data in themes, which highlight that both medical and legal actors are involved in involuntary admission procedures.Conclusions.We conclude that legal reasons for compulsory admission should be reworded in order to remove stigmatization of the patient, that raising awareness about involuntary admission procedures and patient rights with both patients and family advocacy groups is paramount, that communication about procedures should be widely available in lay-language for the general population, and that training sessions and guidance should be available for legal and medical practitioners. Finally, people working in the field need to be constantly aware about the ethical challenges surrounding compulsory admissions.
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| 19. |
- Barsoe, S, et al.
(author)
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RT-qPCR assay for detection of mink astrovirus in outbreaks of diarrhea on Danish mink farms
- 2021
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In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 16:5, s. e0252022-
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Journal article (peer-reviewed)abstract
- Diarrhea in mink kits is a major cause of disease and mortality in the mink production. The etiology remains unknown in most outbreaks due to a lack of diagnostic assays. In the current study we present an RT-qPCR method to detect mink astrovirus in fecal samples from mink kits with diarrhea. All sampled animals were classified based on age and patoanatomical evaluation as having pre-weaning diarrhea, diarrhea in the growth period or as having no macroscopic signs of diarrhea. Fecal samples were analyzed for MiAstV with RT-qPCR, next generation sequencing and electron microscopy in parallel. Mink astrovirus was detected with RT-qPCR in 92 out of 203 samples. This detection was confirmed by next generation sequencing in a high proportion of samples (22/27), and by visualization of astrovirus particles with EM in some of the samples. Mink astrovirus was highly prevalent (68%) among kits in the outbreaks of pre-weaning diarrhea, in particular outbreaks from May, while less prevalent in outbreaks in June. Mink astrovirus was detected in outbreaks of diarrhea in the growth period, though in a much lesser extent than in the pre-weaning period. The role of mink astrovirus in the diarrhea disease complex of mink remain to be investigated, and for that purpose this sensitive and robust RT-qPCR can be a valuable tool in the future.
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| 20. |
- Berggrund, Malin, et al.
(author)
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Temporal changes in the vaginal microbiota in self-samples and its association with persistent HPV16 infection and CIN2
- 2020
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In: Virology Journal. - : Springer Science and Business Media LLC. - 1743-422X. ; 17
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Journal article (peer-reviewed)abstract
- BackgroundThe vaginal microbiota has been reported to be associated with HPV infection and cervical cancer. This study was performed to compare the vaginal microbiota at two timepoints in women performing self-sampling and had a persistent or transient HPV16 infection. The women were tested for 12 high-risk HPV (hrHPV) types but only women with single type (HPV16) were included to reduce confounding variables.MethodsIn total 96 women were included in this study. Of these, 26 were single positive for HPV16 in the baseline test and HPV negative in the follow-up test and 38 were single positive for HPV16 in both tests and diagnosed with CIN2+ in histology. In addition, 32 women that were negative for all 12 HPV tested were included. The samples of vaginal fluid were analyzed with the Ion 16S™ Metagenomics Kit and Ion 16S™ metagenomics module within the Ion Reporter™ software.ResultsK-means clustering resulted in two Lactobacillus-dominated groups, one with Lactobacillus sp. and the other specifically with Lactobacillus iners. The two remaining clusters were dominated by a mixed non-Lactobacillus microbiota. HPV negative women had lower prevalence (28%) of the non-Lactobacill dominant cluster in the baseline test, as compared to women with HPV16 infection (42%) (p value = 0.0173). Transition between clusters were more frequent in women with persistent HPV16 infection (34%) as compared in women who cleared the HPV16 infection (19%) (p value = 0.036).ConclusionsThe vaginal microbiota showed a higher rate of transitioning between bacterial profiles in women with persistent HPV16 infection as compared to women with transient infection. This indicate an instability in the microenvironment in women with persistent HPV infection and development of CIN2+.
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| 21. |
- Birgegard, Andreas, et al.
(author)
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Validity of eating disorder diagnoses in the Swedish national patient register
- 2022
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In: Journal of Psychiatric Research. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0022-3956 .- 1879-1379. ; 150, s. 227-230
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Journal article (peer-reviewed)abstract
- The Swedish National Patient Register (NPR) includes population-level longitudinal data, and determining the validity of NPR diagnoses is critical to undergirding the research and policy recommendations they inform. Sweden also has the integrated "Riksa & BULL;t " and "Stepwise " National Quality Registers (QR), with data from specialized eating disorder (ED) treatment based on structured, valid assessment methods. To validate NPR ED diagnoses, we compared ICD-10-based anorexia nervosa (AN), bulimia nervosa (BN), and unspecified ED in NPR to DSM-IV-based AN, BN, and ED not otherwise specified category (EDNOS) in QR. Patients' first diagnoses registered in QR between February 2008 and August 2013 were compared with NPR diagnoses entered within & PLUSMN;1 month (N = 2074). QR registration includes the semi-structured DSM-IV-based Structured ED Interview. Each ED diagnosis was analyzed separately for degree of match using several indices: overall agreement, sensitivity, positive predictive value, specificity, negative predictive value, area under the curve, and Cohen's kappa. Results showed moderate to excellent agreement depending on estimate (e.g. positive predictive values AN: 0.747; BN:.836; EDNOS: 0.761), except for a somewhat low sensitivity for BN, and EDNOS agreement was overall the lowest. Case prevalence in the NPR and QR was highly similar for AN, and within five percentage points for BN and EDNOS. Generalizability is hampered by limited age range and diagnostic resolution as well as few males. Available data precluded study of presence/absence of ED, and complementary approaches are considered for future research. We conclude that NPR ED diagnoses have acceptable validity and are appropriate for use in research.
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| 22. |
- Costantini, E. A.C., et al.
(author)
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Local adaptation strategies to increase or maintain soil organic carbon content under arable farming in Europe : Inspirational ideas for setting operational groups within the European innovation partnership
- 2020
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In: Journal of Rural Studies. - : Elsevier BV. - 0743-0167. ; 79, s. 102-115
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Journal article (peer-reviewed)abstract
- In the European Union, the setting of Operational Groups (OG) is supported by the European Innovation Partnership to tackle specific problems and favor innovation in agriculture. They constitute an important aspect of the current Common Agricultural Policy. Increasing or maintaining soil organic carbon (SOC) content under arable farming has been acknowledged as a primary target of European agriculture. SOC-preserving agriculture needs its techniques to be tailored to local conditions, namely, the combination of factors related to the environment (climate and soil characteristics), to the farming system (land use type, farm specialization, crop management), but also to the social and cultural context (market and availability of production means, subsidies, farmers’ education, propensity for innovation and change). In this paper we present inspirational ideas and show success examples of local adaptations strategies to increase or maintain SOC content in soils under arable farming in Europe. They include: · Adoption of soil management strategies to improve SOC storage in irrigated systems. · Precision farming and other high-tech solutions able to generate local diagnosis and adaptive strategies for increasing SOC and reducing greenhouse gasses emissions. · Innovative strategies for extending soil cover periods and introducing cover crops in rotations in areas with limited water availability or prone to harsh weather conditions. · Management of rainfed and low input crops to maintain and increase SOC in dry climates and erosive prone soils. These case studies could facilitate the setting up of OGs and the application of innovative practices in different European countries.
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| 23. |
- Garbe, Edeltraut, et al.
(author)
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Long-Term Safety of Roflumilast in Patients with Chronic Obstructive Pulmonary Disease , a Multinational Observational Database Cohort
- 2024
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In: INTERNATIONAL JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. - 1178-2005. ; 19, s. 1879-1892
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Journal article (peer-reviewed)abstract
- Purpose: This study evaluated the long-term safety of roflumilast in patients with chronic obstructive pulmonary disease or chronic bronchitis using electronic healthcare databases from Germany, Norway, Sweden, and the United States (US). Patients and Methods: The study population consisted of patients aged >= 40 years who had been exposed to roflumilast and a matched cohort unexposed to roflumilast. The matching was based on sex, age, calendar year of cohort entry date (2010-2011, 2012, or 2013), and a propensity score that included variables such as demographics, markers of chronic obstructive pulmonary disease (COPD) severity and morbidity, and comorbidities. In comparison to the unexposed matched cohort (never use), three exposure definitions were used for the exposed matched cohort: ever use, use status (current, recent, past use), and cumulative duration of use. The main outcome was 5-year allcause mortality. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CI). Results: 112,541 unexposed and 23,239 exposed patients across countries were included. Some variables remained unbalanced after matching, indicating higher COPD disease severity among the exposed patients. Adjusted HRs of 5-year all-cause mortality for "ever use" of roflumilast, compared to "never use", were 1.12 (95% CI, 1.08-1.17) in Germany, 1.00 (95% CI, 0.92-1.08) in Norway, 0.98 (95% CI, 0.92-1.04) in Sweden, and 1.16 (95% CI, 1.12-1.20) in the US. Compared to never users, there was a decrease in 5-year Conclusion: There was no observed increase in 5-year mortality risk with the use of roflumilast in Sweden or Norway. A small confounding by indication.
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| 24. |
- Hedlund, Emma, et al.
(author)
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Month of birth and the risk of developing type 1 diabetes among children in the Swedish national Better Diabetes Diagnosis Study
- 2022
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In: Acta Paediatrica. - Chichester, United Kingdom : Wiley. - 0803-5253 .- 1651-2227. ; 111:12, s. 2378-2383
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Journal article (peer-reviewed)abstract
- Aim Previous studies have reported an association between month of birth and incidence of type 1 diabetes. Using population-based data, including almost all newly diagnosed children with type 1 diabetes in Sweden, we tested whether month of birth influences the risk of type 1 diabetes. Methods For 8761 children diagnosed with type 1 diabetes between May 2005 and December 2016 in the Better Diabetes Diagnosis study, month of birth, sex and age were compared. Human leucocyte antigen (HLA) genotype and autoantibodies at diagnosis were analysed for a subset of the cohort (n = 3647). Comparisons with the general population used data from Statistics Sweden. Results We found no association between month of birth or season and the incidence of type 1 diabetes in the cohort as a whole. However, boys diagnosed before 5 years were more often born in May (p = 0.004). We found no correlation between month of birth and HLA or antibodies. Conclusion In this large nationwide study, the impact of month of birth on type 1 diabetes diagnosis was weak, except for boys diagnosed before 5 years of age, who were more likely born in May. This may suggest different triggers for different subgroups of patients with type 1 diabetes.
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| 25. |
- Hedlund, Hampus, et al.
(author)
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Single-cell quantification and dose-response of cytosolic siRNA delivery
- 2023
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- Endosomal escape and subsequent cytosolic delivery of small interfering RNA (siRNA) therapeutics is believed to be highly inefficient. Since it has not been possible to quantify cytosolic amounts of delivered siRNA at therapeutic doses, determining delivery bottlenecks and total efficiency has been difficult. Here, we present a confocal microscopy-based method to quantify cytosolic delivery of fluorescently labeled siRNA during lipid-mediated delivery. This method enables detection and quantification of sub-nanomolar cytosolic siRNA release amounts from individual release events with measures of quantitation confidence for each event. Single-cell kinetics of siRNA-mediated knockdown in cells expressing destabilized eGFP unveiled a dose-response relationship with respect to knockdown induction, depth and duration in the range from several hundred to thousands of cytosolic siRNA molecules. Accurate quantification of cytosolic siRNA, and the establishment of the intracellular dose-response relationships, will aid the development and characterization of novel delivery strategies for nucleic acid therapeutics.
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| 26. |
- Hedlund Lindberg, Julia, et al.
(author)
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Toward ovarian cancer screening with protein biomarkers using dried, self-sampled cervico-vaginal fluid
- 2024
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In: iScience. - : Cell Press. - 2589-0042. ; 27:2
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Journal article (peer-reviewed)abstract
- Early detection is key for increased survival in ovarian cancer, but no general screening program exists today due to lack of biomarkers and overall cost versus benefit over traditional clinical methods. Here, we used dried cervico-vaginal fluid (CVF) as sampling matrix coupled with mass spectrometry for detection of protein biomarkers. We find that self-collected CVF on paper cards yields robust results and is suitable for high-throughput proteomics. Artificial intelligence–based methods were used to identify an 11-protein panel that separates cases from controls. In validation data, the panel achieved a sensitivity of 0.97 (95% CI 0.91–1.00) at a specificity of 0.67 (0.40–0.87). Analyses of samples collected prior to development of symptoms indicate that the panel is informative also of future risk of disease. Dried CVF is used in cervical cancer screening, and our results opens the possibility for a screening program also for ovarian cancer, based on self-collected CVF samples.
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| 27. |
- Hedlund, Martin, et al.
(author)
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BlocklyVR : Exploring Block-based Programming in Virtual Reality
- 2023
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In: MUM'23: Proceedings of the 22nd International Conference on Mobile and Ubiquitous Multimedia. - : Association for Computing Machinery. - 9798400709210 ; , s. 251-263
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Conference paper (peer-reviewed)abstract
- As programming is typically a static activity in front of a screen, we perform an initial exploration around the capabilities of block-based programming in the immersive space using Virtual Reality (VR) to make an early charting on how programming could involve moving the programmer's body. We created a block-based programming interface in a VR space called BlocklyVR based on the existing Blockly programming environment. To investigate programmer performance and experience in BlocklyVR, we conducted a controlled lab experiment (N = 20) with eight programming tasks that covered mathematical operations, if-statements, and function creation. Our initial exploration contributes by classifying movement types made by BlocklyVR programmers and reflecting on how these movements are related to the programming tasks. Additionally, our data suggests that participant performance in BlocklyVR was not affected compared to the 2D Blockly, even if participants were physically moving in VR space. We also found that the virtual reality sickness was marginal. Lastly, we identified four types of interaction that can potentially be employed by VR designers and developers aiming to convert a static task, like programming at a desk, into a "mobile"immersive experience. © 2023 Owner/Author.
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| 28. |
- Hedlund, Martin, et al.
(author)
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Creating a Post-sedentary Work Context for Software Engineering
- 2022
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In: IFIP Conference on Human-Computer Interaction INTERACT 2021. - Cham : Springer Nature. ; , s. 123-138
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Conference paper (peer-reviewed)abstract
- Software engineers are sedentary and need technological help for a more healthy life. Current software engineering tasks are mostly confined to the standard sedentary desktop user interface. We believe that software engineering should be restructured so that it offers a non-sedentary alternative. In this paper, we describe a new research approach, called Post-sedentary Software Engineering. Our ambition with this approach is to provide an alternative, healthier work context without decreasing productivity. We take a spatial approach to post-sedentary tool design, starting from the assumption an interactive 3D environment with appropriate metaphors is necessary for full body movement. We discuss available technologies for achieving this goal and outline four studies that incorporate the software engineering phases of code comprehension, code creation and debugging in a non-sedentary context.
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| 29. |
- Hedlund, Martin, et al.
(author)
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Jogging-in-Place : Exploring Body-Steering Methods for Jogging in Virtual Environments
- 2023
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In: Proceedings of MUM 2023 - The 22nd International Conference on Mobile and Ubiquitous Multimedia. - : Association for Computing Machinery (ACM). ; , s. 371-379, s. 377-385
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Conference paper (peer-reviewed)abstract
- Walk-in-Place is an established locomotion technique for walking in virtual environments, as it incorporates body motion similar to regular walking. Although there is extensive research on the performance and experience of walking in virtual reality spaces, it typically requires minimal-to-moderate physical movement, e.g., stepping forward and turning around, to explore virtual spaces. Therefore, the question we ask ourselves in this work is how user experience and performance are affected when the user is actively moving in place. In this paper, we explored three body-steering methods for jogging-in-place in virtual environments: (1) head-, (2) hand-, and (3) torso-based. To investigate the performance of the proposed body-steering methods for jogging in virtual reality, we conducted a controlled lab experiment (N = 12) to assess task completion time, number of steps, and VR sickness. We discovered that hand- and torso-based methods require fewer steps than the head-based method, and the torso-based is slower than the other two. Moreover, the number of collisions and virtual reality sickness were comparable among the methods.
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| 30. |
- Hedlund, Martin, et al.
(author)
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Rowing Beyond: A Demonstration of Steering Methods for Rowing-based Locomotion in Virtual Environments
- 2024
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In: CHI 2024 - Extended Abstracts of the 2024 CHI Conference on Human Factors in Computing Sytems. - : Association for Computing Machinery (ACM).
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Conference paper (peer-reviewed)abstract
- Rowing has great potential in Virtual Reality (VR) exergames as it requires physical effort and uses physical motion to map the locomotion in a virtual space. However, rowing in VR is currently restricted to locomotion along one axis, leaving 2D and 3D locomotion out of the scope. To facilitate rowing-based locomotion, we implemented three steering techniques based on head, hands, and feet movements for 2D and 3D VR environments.
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| 31. |
- Hedlund, Martin, et al.
(author)
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Rowing Beyond: Investigating Steering Methods for Rowing-based Locomotion in Virtual Environments
- 2024
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In: CHI 2024 - Proceedings of the 2024 CHI Conference on Human Factors in Computing Sytems. - : Association for Computing Machinery.
-
Conference paper (peer-reviewed)abstract
- Rowing has great potential in Virtual Reality (VR) exergames as it requires physical effort and uses physical motion to map the locomotion in a virtual space. However, rowing in VR is currently restricted to locomotion along one axis, leaving 2D and 3D locomotion out of the scope. To facilitate rowing-based locomotion, we implemented three steering techniques based on head, hands, and feet movements for 2D and 3D VR environments. To investigate these methods, we conducted a controlled experiment (N = 24) to assess the user performance, experience and VR sickness. We found that head steering leads to fast and precise steering in 2D and 3D, and hand steering is the most realistic. Feet steering had the largest performance difference between 2D and 3D but comparable precision to hands in 2D. Lastly, head steering is the least mentally demanding, and all methods had comparable VR sickness.
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| 32. |
- Hermansson, Ruth S., et al.
(author)
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Incidence of oncogenic HPV and HPV-related dysplasia five years after a negative HPV test by self-sampling in elderly women
- 2022
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In: Infectious Agents and Cancer. - : Springer Nature. - 1750-9378. ; 17:42
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Journal article (peer-reviewed)abstract
- Purpose: Cervical cancer prevention for older women can be challenging since there are no specific guidelines for this group. This study aimed to determine the incidence of oncogenic HPV and HPV-related dysplasia in elderly women 5 years after being HPV negative.Methods: Invited women participated five years earlier in a study where self-sampling for HPV testing was applied, at this time, they were all HPV negative. The women were now, five years later invited to perform self-sampling for HPV testing. Women with a positive result performed a repeat HPV test. Those with a positive repeat HPV test were examined by colposcopy, biopsy and cytology.Results: Of the 804 invited women, 634 (76.9%) agreed to participate in the study and a self-sampling kit was sent to them. Of these, 99.6% (632/634) sent a sample to the HPV laboratory. The participation rate in each age group was 93.3% at age 65, 74.0% at age 70, 80.7% at age 75 and 64.6% at age 80. Overall 18 women (2.8%, 95% CI 3.2 to 6.0) were HPV positive in the first test and 8 (1.3%, 95% CI 0.6 to 2.6) in the second test. Sampling for the second test was done on average 5.4 months after the first test. Fifty per cent (4/8) of the women with a positive repeat test had dysplasia in histology.Conclusions: The incidence of HPV in previously HPV-negative elderly women was low. Among women who were HPV positive in a repeat test, there was a high prevalence of low grade dysplasia.
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| 33. |
- Jaca, Carmen, et al.
(author)
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Integrating Sustainable Development Goals (SDGs) into Quality Subjects for Higher Education Students
- 2024
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In: International Conference on Quality Engineering and Management. - : Universidade do Minho. - 9789895491124 ; , s. 328-344
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Conference paper (peer-reviewed)abstract
- The purpose of this study is to explore how quality tools can be applied to develop sustainable education among higher education students, with a particular focus the analysis and understanding the challenges associated with the Sustainable Development Goals (SDGs). Design/Methodology/Approach: In a master's course in an Engineering School, focusing on quality tools, the SDGs were introduced as a subject of study for students to apply the aforementioned tools. Later, students’ assignments were analyzed employing a mixed-methods approach to understand the impact of integrating SDGs into the curriculum. Findings: The assessment of the conducted exercise was well-received by students, demonstrating proficient use of the assigned tool. It has been proven that the introduction of basic quality tools to analyze problems related to the SDGs is effective, demonstrating that their use extends beyond the analysis of quality-related issues. The gender analysis reveals differing perspectives on sustainable development among male and female students, providing valuable insights for inclusive educational interventions. Moreover, preliminary results show variations in students' preferences for specific SDGs, indicating potential areas for targeted educational campaigns and interventions. Research Limitations/Implications: The study's scope may be limited by sample size or specific institutional contexts. However, these findings contribute to sustainable development education by demonstrating the efficacy of quality tools in the integration of the SDGs, identifying gender-based differences in engagement, and highlighting variations in SDG popularity among higher education students. These insights are crucial for educators, curriculum developers and policy makers seeking to develop informed and committed individuals for the SDGs.
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| 34. |
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| 35. |
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| 36. |
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| 37. |
- Nichterwitz, S, et al.
(author)
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LCM-seq reveals unique transcriptional adaptation mechanisms of resistant neurons and identifies protective pathways in spinal muscular atrophy
- 2020
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In: Genome research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 30:8, s. 1083-1096
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Journal article (peer-reviewed)abstract
- Somatic motor neurons are selectively vulnerable in spinal muscular atrophy (SMA), which is caused by a deficiency of the ubiquitously expressed survival of motor neuron protein. However, some motor neuron groups, including oculomotor and trochlear (ocular), which innervate eye muscles, are for unknown reasons spared. To reveal mechanisms of vulnerability and resistance in SMA, we investigate the transcriptional dynamics in discrete neuronal populations using laser capture microdissection coupled with RNA sequencing (LCM-seq). Using gene correlation network analysis, we reveal a TRP53-mediated stress response that is intrinsic to all somatic motor neurons independent of their vulnerability, but absent in relatively resistant red nucleus and visceral motor neurons. However, the temporal and spatial expression analysis across neuron types shows that the majority of SMA-induced modulations are cell type–specific. Using Gene Ontology and protein network analyses, we show that ocular motor neurons present unique disease-adaptation mechanisms that could explain their resilience. Specifically, ocular motor neurons up-regulate (1) Syt1, Syt5, and Cplx2, which modulate neurotransmitter release; (2) the neuronal survival factors Gdf15, Chl1, and Lif; (3) Aldh4, that protects cells from oxidative stress; and (4) the caspase inhibitor Pak4. Finally, we show that GDF15 can rescue vulnerable human spinal motor neurons from degeneration. This confirms that adaptation mechanisms identified in resilient neurons can be used to reduce susceptibility of vulnerable neurons. In conclusion, this in-depth longitudinal transcriptomics analysis in SMA reveals novel cell type–specific changes that, alone and combined, present compelling targets, including Gdf15, for future gene therapy studies aimed toward preserving vulnerable motor neurons.
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| 38. |
- Oxblom, A., et al.
(author)
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Careful patient selection together with optimal implant positioning may reduce but does not eliminate the risk of elevated serum cobalt and chrome levels following metal-on-metal hip resurfacing
- 2023
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In: Hip International. - : SAGE Publications. - 1120-7000 .- 1724-6067. ; 33:5, s. 872-879
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Journal article (peer-reviewed)abstract
- Background: Elevated serum chrome (sCr) and cobalt (sCo) concentrations are associated with local tissue adverse reactions to metal debris following metal-on-metal hip resurfacing (MoM-HR). Serum metal ions 5 mu g/l. Patients and methods: This is a retrospective, single-institution cohort study of 410 consecutive patients operated on with a Birmingham Hip Resurfacing (BHR) implant between 2001 and 2014. 288 of these had a unilateral MoM-HR, pelvic and true lateral radiographs, and a related sCo and sCr sample, and were included in the final analysis. They were allocated to either a presumed "optimal group" consisting of only men aged <60 years old, with femoral head component >48 mm diameter, and with a cup positioned within Lewinnek's safe zones, or a "suboptimal group" consisting of the remaining patients. Fisher ' s exact test and multiple logistic regression analyses were performed. Results: In the optimal group 48% (47/97) had serum metal ions >2 mu g/l and 8% (8/97) >5 mu g/l compared to 61% (116/191) and 18% (34/191) in the suboptimal group, p = 0.059 and p = 0.034 respectively. Acetabular cups with an anteversion <5 degrees had the highest odds ratio, 6.5 (95% CI, 3.0-14.3), of having sCo and sCr concentrations exceeding 5 mu g/l. Conclusions: A well oriented BHR acetabular component in a presumably "optimal" patient reduces the risk of having elevated serum metal ions but does not eliminate it. Insufficient cup anteversion seems to be the strongest associated factor of elevated serum metals.
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| 39. |
- Veerkamp, Clara J., et al.
(author)
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A review of studies assessing ecosystem services provided by urban green and blue infrastructure
- 2021
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In: Ecosystem Services. - : Elsevier BV. - 2212-0416. ; 52
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Research review (peer-reviewed)abstract
- Urban green and blue infrastructure (GBI) and associated ecosystem services (ES) are increasingly recognized for their potential to address urban sustainability challenges. This has resulted in an increase in studies quantifying ES in cities. In this review, we analysed 850 peer-reviewed publications to characterize urban ES assessment in terms of geographical location, urban GBI type and methodological aspects (e.g. ES indicators). The analyses covered six ES: local temperature regulation, stormwater regulation, waste treatment, air quality regulation, pollination, and recreation and aesthetic appreciation. The majority of ES assessments focused on local temperature regulation (36%) and recreation and aesthetic appreciation (23%) and assessments were often conducted within unspecified green space (30%) and parks (26%). A common method to assess GBI performance was the comparison of ES delivery along a gradient of vegetation cover (24%). Moreover, assessments used a wide variety of ES indicators. Most assessments quantified ecosystem properties (59%), while a minority assessed actual benefits to people, recognized values or societal demands. To advance insights in the effectiveness of GBI, we recommend increased research attention towards i) increasing the coverage of less studied ES, GBI types and geographical regions, ii) quantifying actual benefits of GBI by comparing ES supply and societal demand, and iii) comparing effectiveness across different GBI types and in relation to grey infrastructure.
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| 40. |
- Woschitz, Victoria, et al.
(author)
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Mouse models of SMA show divergent patterns of neuronal vulnerability and resilience
- 2022
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In: Skeletal Muscle. - : Springer Science and Business Media LLC. - 2044-5040. ; 12:1
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Journal article (peer-reviewed)abstract
- Background: Spinal muscular atrophy (SMA) is a form of motor neuron disease affecting primarily children characterised by the loss of lower motor neurons (MNs). Breakdown of the neuromuscular junctions (NMJs) is an early pathological event in SMA. However, not all motor neurons are equally vulnerable, with some populations being lost early in the disease while others remain intact at the disease end-stage. A thorough understanding of the basis of this selective vulnerability will give critical insight into the factors which prohibit pathology in certain motor neuron populations and consequently help identify novel neuroprotective strategies.Methods: To retrieve a comprehensive understanding of motor neuron susceptibility in SMA, we mapped NMJ pathology in 20 muscles from the Smn2B/- SMA mouse model and cross-compared these data with published data from three other commonly used mouse models. To gain insight into the molecular mechanisms regulating selective resilience and vulnerability, we analysed published RNA sequencing data acquired from differentially vulnerable motor neurons from two different SMA mouse models.Results: In the Smn2B/- mouse model of SMA, we identified substantial NMJ loss in the muscles from the core, neck, proximal hind limbs and proximal forelimbs, with a marked reduction in denervation in the distal limbs and head. Motor neuron cell body loss was greater at T5 and T11 compared with L5. We subsequently show that although widespread denervation is observed in each SMA mouse model (with the notable exception of the Taiwanese model), all models have a distinct pattern of selective vulnerability. A comparison of previously published data sets reveals novel transcripts upregulated with a disease in selectively resistant motor neurons, including genes involved in axonal transport, RNA processing and mitochondrial bioenergetics.Conclusions: Our work demonstrates that the Smn2B/- mouse model shows a pattern of selective vulnerability which bears resemblance to the regional pathology observed in SMA patients. We found drastic differences in patterns of selective vulnerability across the four SMA mouse models, which is critical to consider during experimental design. We also identified transcript groups that potentially contribute to the protection of certain motor neurons in SMA mouse models.
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| 41. |
- Wronski, Marie-Louis, et al.
(author)
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Co-existing mental and somatic conditions in Swedish children with the avoidant restrictive food intake disorder phenotype
- 2024
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In: medRxiv : the preprint server for health sciences.
-
Other publication (other academic/artistic)abstract
- BACKGROUND: Avoidant restrictive food intake disorder (ARFID) is a feeding and eating disorder, characterized by limited variety and/or quantity of food intake impacting physical health and psychosocial functioning. Children with ARFID often present with a range of psychiatric and somatic symptoms, and therefore consult various pediatric subspecialties; large-scale studies mapping comorbidities are however lacking. To characterize health care needs of people with ARFID, we systematically investigated ARFID-related mental and somatic conditions in 616 children with ARFID and >30,000 children without ARFID.METHODS: In a Swedish twin cohort, we identified the ARFID phenotype in 6-12-year-old children based on parent-reports and register data. From >1,000 diagnostic ICD-codes, we specified mental and somatic conditions within/across ICD-chapters, number of distinct per-person diagnoses, and inpatient treatment days between birth and 18th birthday (90 outcomes). Hazard ratios (HR) and incidence rate ratios (IRR) were calculated.FINDINGS: Relative risks of neurodevelopmental, gastrointestinal, endocrine/metabolic, respiratory, neurological, and allergic disorders were substantially increased in ARFID (e.g., autism HR[CI95%]=9.7[7.5-12.5], intellectual disability 10.3[7.6-13.9], gastroesophageal reflux disease 6.7[4.6-9.9], pituitary conditions 5.6[2.7-11.3], chronic lower respiratory diseases 4.9[2.4-10.1], epilepsy 5.8[4.1-8.2]). ARFID was not associated with elevated risks of autoimmune illnesses and obsessive-compulsive disorder. Children with ARFID had a significantly higher number of distinct mental diagnoses (IRR[CI95%]=4.7[4.0-5.4]) and longer duration of hospitalizations (IRR[CI95%]=5.5[1.7-17.6]) compared with children without ARFID. Children with ARFID were diagnosed earlier with a mental condition than children without ARFID. No sex-specific differences emerged.INTERPRETATION: This study yields the broadest and most detailed evidence of co-existing mental and somatic conditions in the largest sample of children with ARFID to date. Findings suggest a complex pattern of health needs in youth with ARFID, underscoring the critical importance of attention to the illness across all pediatric specialties.FUNDING: Fredrik and Ingrid Thurings Foundation, Mental Health Foundation.
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