| 1. |
- Beal, Jacob, et al.
(author)
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Robust estimation of bacterial cell count from optical density
- 2020
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In: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Journal article (peer-reviewed)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 2. |
- Brenner, David, et al.
(author)
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Hot-spot KIF5A mutations cause familial ALS
- 2018
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In: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 141, s. 688-697
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Journal article (peer-reviewed)abstract
- Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 x 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p. Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 x 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.
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| 3. |
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| 4. |
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| 5. |
- Kattge, Jens, et al.
(author)
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TRY plant trait database - enhanced coverage and open access
- 2020
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In: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Journal article (peer-reviewed)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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| 6. |
- Lill, Christina M., et al.
(author)
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The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease
- 2015
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In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:12, s. 1407-1416
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Journal article (peer-reviewed)abstract
- A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Ab42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 x 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR 5 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR 5 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Ab42 suggesting that TREM2's role in AD may involve tau dysfunction. (C) 2015 The Alzheimer's Association.
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| 7. |
- Mattsson, Niklas, 1979, et al.
(author)
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The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.
- 2011
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In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 7:4
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Journal article (peer-reviewed)abstract
- The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.
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| 8. |
- Spitzer, Philipp, et al.
(author)
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cNEUPRO: Novel Biomarkers for Neurodegenerative Diseases.
- 2010
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In: International journal of Alzheimer's disease. - : Hindawi Limited. - 2090-0252. ; 2010
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Research review (peer-reviewed)abstract
- "clinical NEUroPROteomics of neurodegenerative diseases" (cNEUPRO) is a Specific Targeted Research Project (STREP) within the sixth framework program of the European Commission dedicated to the search for novel biomarker candidates for Alzheimer's disease and other neurodegenerative diseases. The ultimate goal of cNEUPRO is to identify one or more valid biomarker(s) in blood and CSF applicable to support the early and differential diagnosis of dementia disorders. The consortium covers all steps required for the discovery of novel biomarker candidates such as acquisition of high quality CSF and blood samples from relevant patient groups and controls, analysis of body fluids by various methods, and finally assay development and assay validation. Here we report the standardized procedures for diagnosis and preanalytical sample-handling within the project, as well as the status of the ongoing research activities and some first results.
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| 9. |
- van Rheenen, Wouter, et al.
(author)
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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
- 2016
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
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Journal article (peer-reviewed)abstract
- To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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| 10. |
- Abdelhak, Ahmed, et al.
(author)
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Prognostic performance of blood neurofilament light chain protein in hospitalized COVID-19 patients without major central nervous system manifestations: an individual participant data meta-analysis.
- 2023
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In: Journal of neurology. - : Springer. - 1432-1459 .- 0340-5354. ; 270:7, s. 3315-3328
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Journal article (peer-reviewed)abstract
- To investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19).We conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU)admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL.We identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2±15.0years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13-3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with ahigher likelihood of ICU admission, need ofMV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need ofMV and ICU admission, respectively.Blood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19.
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| 11. |
- Abu-Rumeileh, Samir, et al.
(author)
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The multifaceted role of neurofilament light chain protein in non-primary neurological diseases.
- 2023
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 146:2, s. 421-437
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Journal article (peer-reviewed)abstract
- The advancing validation and exploitation of cerebrospinal fluid and blood neurofilament light chain protein as a biomarker of neuroaxonal damage has deeply changed the current diagnostic and prognostic approach to neurological diseases. Further, recent studies have provided evidence of potential new applications of this biomarker also in non-primary neurological diseases. In the present review we summarise the current evidence, future perspectives, but also limitations, of neurofilament light chain protein as a cerebrospinal fluid and blood biomarker in several medical fields, including intensive care, surgery, internal medicine and psychiatry. In particular, neurofilament light chain protein is associated with the degree of neurologic impairment and outcome in patients admitted to intensive care units or in the perioperative phase and it seems to be highly interconnected with cardiovascular risk factors. Beyond that, interesting diagnostic and prognostic insights have been provided by the investigation of neurofilament light chain protein in psychiatric disorders as well as in the current coronavirus disease 19 (COVID-19) pandemic and in normal aging. Altogether, current data outline a multifaceted applicability of cerebrospinal fluid and blood neurofilament light chain protein ranging from the critical clinical setting to the development of precision medicine models suggesting a strict interplay between the nervous system pathophysiology and the health-illness continuum.
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| 12. |
- Alix, James J. P., et al.
(author)
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Assessment of the reliability of the motor unit size index (MUSIX) in single subject "round-robin" and multi-centre settings
- 2019
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In: Clinical Neurophysiology. - : ELSEVIER IRELAND LTD. - 1388-2457 .- 1872-8952. ; 130:5, s. 666-674
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Journal article (peer-reviewed)abstract
- Objective: The motor unit size index (MUSIX) is incorporated into the motor unit number index (MUNIX). Our objective was to assess the intra-/inter-rater reliability of MUSIX in healthy volunteers across single subject "round robin" and multi-centre settings.Methods: Data were obtained from (i) a round-robin assessment in which 12 raters (6 with prior experience and 6 without) assessed six muscles (abductor pollicis brevis, abductor digiti minimi, biceps brachii, tibialis anterior, extensor digitorum brevis and abductor hallucis) and (ii) a multi-centre study with 6 centres studying the same muscles in 66 healthy volunteers. Intrafinter-rater data were provided by 5 centres, 1 centre provided only intra-rater data. Intrafinter-rater variability was assessed using the coefficient of variation (COV), Bland-Altman plots, bias and 95% limits of agreement.Results: In the round-robin assessment intra-rater COVs for MUSIX ranged from 7.8% to 28.4%. Inter-rater variability was between 7.8% and 16.2%. Prior experience did not impact on MUSIX values. In the multi-centre study MUSIX was more consistent than the MUNIX. Abductor hallucis was the least reliable muscle.Conclusions: The MUSIX is a reliable neurophysiological biomarker of reinnervation.Significance: MUSIX could provide insights into the pathophysiology of a range of neuromuscular disorders, providing a quantitative biomarker of reinnervation.
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| 13. |
- Allanach, Benjamin C., et al.
(author)
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Simple and statistically sound strategies for analysing physical theories
- 2022
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In: Reports on progress in physics (Print). - : Institute of Physics Publishing (IOPP). - 0034-4885 .- 1361-6633. ; 85:5
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Research review (peer-reviewed)abstract
- Physical theories that depend on many parameters or are tested against data from many different experiments pose unique challenges to statistical inference. Many models in particle physics, astrophysics and cosmology fall into one or both of these categories. These issues are often sidestepped with statistically unsound ad hoc methods, involving intersection of parameter intervals estimated by multiple experiments, and random or grid sampling of model parameters. Whilst these methods are easy to apply, they exhibit pathologies even in low-dimensional parameter spaces, and quickly become problematic to use and interpret in higher dimensions. In this article we give clear guidance for going beyond these procedures, suggesting where possible simple methods for performing statistically sound inference, and recommendations of readily-available software tools and standards that can assist in doing so. Our aim is to provide any physicists lacking comprehensive statistical training with recommendations for reaching correct scientific conclusions, with only a modest increase in analysis burden. Our examples can be reproduced with the code publicly available at Zenodo.
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| 14. |
- Andersen, Lars L, et al.
(author)
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Effect of physical exercise on workplace social capital: cluster randomized controlled trial
- 2015
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In: Scandinavian Journal of Public Health. - : SAGE Publications. - 1651-1905 .- 1403-4948. ; 43:8, s. 810-818
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Journal article (peer-reviewed)abstract
- While workplace health promotion with group-based physical exercise can improve workers' physical health, less is known about potential carry-over effects to psychosocial factors. This study investigates the effect of physical exercise on social capital at work.
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| 15. |
- Baker, Tim, et al.
(author)
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Single Deranged Physiologic Parameters Are Associated With Mortality in a Low-Income Country
- 2015
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In: Critical Care Medicine. - 0090-3493 .- 1530-0293. ; 43:10, s. 2171-2179
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Journal article (peer-reviewed)abstract
- Objective: To investigate whether deranged physiologic parameters at admission to an ICU in Tanzania are associated with in-hospital mortality and compare single deranged physiologic parameters to a more complex scoring system. Design: Prospective, observational cohort study of patient notes and admission records. Data were collected on vital signs at admission to the ICU, patient characteristics, and outcomes. Cutoffs for deranged physiologic parameters were defined a priori and their association with in-hospital mortality was analyzed using multivariable logistic regression. Setting: ICU at Muhimbili National Hospital, Dar es Salaam, Tanzania. Patients: All adults admitted to the ICU in a 15-month period. Measurements and Main Results: Two hundred sixty-nine patients were included: 54% female, median age 35 years. In-hospital mortality was 50%. At admission, 69% of patients had one or more deranged physiologic parameter. Sixty-four percent of the patients with a deranged physiologic parameter died in hospital compared with 18% without (p < 0.001). The presence of a deranged physiologic parameter was associated with mortality (adjusted odds ratio, 4.64; 95% CI, 1.95-11.09). Mortality increased with increasing number of deranged physiologic parameters (odds ratio per deranged physiologic parameter, 2.24 [1.53-3.26]). Every individual deranged physiologic parameter was associated with mortality with unadjusted odds ratios between 1.92 and 16.16. A National Early Warning Score of greater than or equal to 7 had an association with mortality (odds ratio, 2.51 [1.23-5.14]). Conclusion: Single deranged physiologic parameters at admission are associated with mortality in a critically ill population in a low-income country. As a measure of illness severity, single deranged physiologic parameters are as useful as a compound scoring system in this setting and could be termed danger signs. Danger signs may be suitable for the basis of routines to identify and treat critically ill patients.
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| 16. |
- Baker, Tim, et al.
(author)
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Vital Signs Directed Therapy : Improving Care in an Intensive Care Unit in a Low-Income Country
- 2015
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:12
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Journal article (peer-reviewed)abstract
- Background Global Critical Care is attracting increasing attention. At several million deaths per year, the worldwide burden of critical illness is greater than generally appreciated. Low income countries (LICs) have a disproportionally greater share of critical illness, and yet critical care facilities are scarce in such settings. Routines utilizing abnormal vital signs to identify critical illness and trigger medical interventions have become common in high-income countries but have not been investigated in LICs. The aim of the study was to assess whether the introduction of a vital signs directed therapy protocol improved acute care and reduced mortality in an Intensive Care Unit (ICU) in Tanzania. Methods and Findings Prospective, before-and-after interventional study in the ICU of a university hospital in Tanzania. A context-appropriate protocol that defined danger levels of severely abnormal vital signs and stipulated acute treatment responses was implemented in a four week period using sensitisation, training, job aids, supervision and feedback. Acute treatment of danger signs at admission and during care in the ICU and in-hospital mortality were compared pre and post-implementation using regression models. Danger signs from 447 patients were included: 269 pre-implementation and 178 post-implementation. Acute treatment of danger signs was higher post-implementation (at admission: 72.9% vs 23.1%, p<0.001; in ICU: 16.6% vs 2.9%, p<0.001). A danger sign was five times more likely to be treated post-implementation (Prevalence Ratio (PR) 4.9 (2.9-8.3)). Intravenous fluids were given in response to 35.0% of hypotensive episodes post-implementation, as compared to 4.1% pre-implementation (PR 6.4 (2.5-16.2)). In patients admitted with hypotension, mortality was lower post-implementation (69.2% vs 92.3% p = 0.02) giving a numbers-needed-to-treat of 4.3. Overall in-hospital mortality rates were unchanged (49.4% vs 49.8%, p = 0.94). Conclusion The introduction of a vital signs directed therapy protocol improved the acute treatment of abnormal vital signs in an ICU in a low-income country. Mortality rates were reduced for patients with hypotension at admission but not for all patients.
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| 17. |
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| 18. |
- Benatar, Michael, et al.
(author)
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Design of a randomized, placebo-controlled, phase 3 trial of tofersen initiated in clinically presymptomatic SOD1 variant carriers : the Atlas study
- 2022
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In: Neurotherapeutics. - : Springer. - 1933-7213 .- 1878-7479. ; 19, s. 1248-1258
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Journal article (peer-reviewed)abstract
- Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS.
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| 19. |
- Bergström, Sofia
(author)
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Multiplexed antibody-based protein profiling in the pursuit of CSF biomarkers for neurodegenerative diseases
- 2021
-
Doctoral thesis (other academic/artistic)abstract
- There is a desire for a transition from generic treatments designed for the average patient, towards more individual-based precision medicine. An increased knowledge about disease pathophysiology on a molecular level would be beneficial for this transition. The study of proteins can contribute with valuable insights into etiology and pathogenesis of different diseases and thereby aid the clinical assessment of patients and guide future treatments.Neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia, are characterized by a progressive loss of function, and eventually death of neurons. Neurons allow the brain to communicate with the rest of the body, and a deteriorated function of neurons can result in problems with mobility or mental functions. Neurodegenerative diseases progress slowly over many years, with a long silent asymptomatic phase before symptom onset. It is hard to rebuild what is already lost, but disease-modifying treatments might be able to slow down or halt the deterioration of the brain. Therefore, there is a major research focus on investigating the early stages of disease pathogenesis in order to elucidate this critical phase in disease progression.The four papers included in this thesis focus on identifying altered protein profiles in cerebrospinal fluid from patients with neurodegenerative diseases. For this purpose, multiplexed antibody-based suspension bead arrays have been used. This method allows for hundreds of proteins to be analyzed in hundreds of samples in the same assay. Paper I focuses on Alzheimer’s disease and investigates the profiles of 200 proteins when comparing patients with controls. Six proteins were identified at altered levels and were further investigated in relation to the progression from mild cognitive impairment to Alzheimer’s disease. Paper II explores 100 protein profiles in relation to the core Alzheimer’s disease biomarkers in asymptomatic 70-year-olds to elucidate patterns preceding potential disease onset. Paper III investigates the transition to cognitive impairment in patients with Parkinson’s disease and explores potential associations between protein profiles and cognitive assessment tests. Finally, Paper IV explores panels of proteins in the context of frontotemporal dementia. Panels of proteins, instead of single biomarkers, have an increased potential to capture the range of biological processes within these types of complex and multifactorial diseases.Neurodegenerative diseases are often heterogeneous which puts high demands on the study design including an appropriate selection of study population. However, significant similarities are also present which makes it advantageous to have a broad perspective and work with several neurodegenerative disorders. This thesis presents the results from multiplexed antibody-based protein profiling as a contribution to a better understanding of neurodegenerative diseases.
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| 20. |
- Boström, Gustaf, et al.
(author)
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Different Inflammatory Signatures in Alzheimer's Disease and Frontotemporal Dementia Cerebrospinal Fluid
- 2021
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 81:2, s. 629-640
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Journal article (peer-reviewed)abstract
- Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases.Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD.Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing.Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14-1.53, q = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20-1.94, q = 0.045; and FTD: FC = 1.42, 95% CI 1.10-1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05).Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.
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| 21. |
- Brockmann, Sarah J., et al.
(author)
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CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency
- 2018
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In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 27:4, s. 706-715
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Journal article (peer-reviewed)abstract
- Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p. R15L and p. G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p. P34S in vitro, in patient cells as well as in the vertebrate in vivo model zebrafish. We demonstrate a reduction of CHCHD10 protein levels in p. R15L and p. G66V mutant patient cells to approximately 50%. Quantitative real-time PCR revealed that expression of CHCHD10 p. R15L, but not of CHCHD10 p. G66V, is already abrogated at the mRNA level. Altered secondary structure and rapid protein degradation are observed with regard to the CHCHD10 p. G66V mutant. In contrast, no significant differences in expression, degradation rate or secondary structure of non-pathogenic CHCHD10 p. P34S are detected when compared with wild-type protein. Knockdown of CHCHD10 expression in zebrafish to about 50% causes motoneuron pathology, abnormal myofibrillar structure and motility deficits in vivo. Thus, our data show that the CHCHD10 mutations p. R15L and p. G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10.
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| 22. |
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| 23. |
- Bussy, Aurélie, et al.
(author)
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Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia
- 2023
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In: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 44:7, s. 2684-2700
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Journal article (peer-reviewed)abstract
- Recent studies have reported early cerebellar and subcortical impact in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the cerebello-subcortical circuitry in FTD has been understudied despite its essential role in cognition and behaviors related to FTD symptomatology. The present study aims to investigate the association between cerebellar and subcortical atrophy, and neuropsychiatric symptoms across genetic mutations. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative including mutation carriers and noncarrier first-degree relatives of known symptomatic carriers. Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed, and partial least squares analyses (PLS) were used to link morphometry and behavior. In presymptomatic C9orf72 expansion carriers, thalamic atrophy was found compared to noncarriers, suggesting the importance of this structure in FTD prodromes. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to neuropsychiatric symptoms, with significant overlap in brain/behavior patterns, but also specificity for each genetic mutation group. The largest differences were in the cerebellar atrophy (larger extent in C9orf72 expansion group) and more prominent amygdalar volume reduction in the MAPT group. Brain scores in the C9orf72 expansion carriers and MAPT carriers demonstrated covariation patterns concordant with atrophy patterns detectable up to 20 years before expected symptom onset. Overall, these results demonstrated the important role of the subcortical structures in genetic FTD symptom expression, particularly the cerebellum in C9orf72 and the amygdala in MAPT carriers.
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| 24. |
- Delaby, Constance, et al.
(author)
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Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview.
- 2022
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In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 18:10, s. 1868-1879
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Journal article (peer-reviewed)abstract
- The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests.We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients.The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis.This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD.
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| 25. |
- Devos, David, et al.
(author)
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Trial of Deferiprone in Parkinson’s Disease
- 2022
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In: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 387:22, s. 2045-2055
-
Journal article (peer-reviewed)abstract
- BACKGROUNDIron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear.METHODSWe conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome.RESULTSA total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants.CONCLUSIONSIn participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks.
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| 26. |
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| 27. |
- Escott-Price, Valentina, et al.
(author)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
-
Journal article (peer-reviewed)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 28. |
- Ezer, Shlomit, et al.
(author)
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Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity
- 2022
-
In: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 145:3, s. 872-878
-
Journal article (peer-reviewed)abstract
- Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity. We identified a homozygous 3-bp in-frame deletion in SOD1. cDNA analysis predicted the loss of a single valine residue from a tandem pair (p.Val119/Val120) in the wild-type protein, yet expression levels and splicing were preserved. Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls. Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration. Thus, we provide confirmatory evidence of a second biallelic variant in an infant with a severe neurological syndrome and suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1. We highlight the importance of the valine residues at positions V119-120, and suggest possible implications for future therapeutics research.
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| 29. |
- Fahmy, Nagia, et al.
(author)
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A novel homozygous p.Ser69Pro SOD1 mutation causes severe young-onset ALS with decreased enzyme activity
- 2023
-
In: Journal of Neurology. - : Springer. - 0340-5354 .- 1432-1459. ; 270, s. 1770-1773
-
Journal article (peer-reviewed)abstract
- Background: The dose–effect of various SOD1 mutations on SOD1 enzymatic activity offers valuable insights into ALS pathogenesis with possible therapeutic implications. Homozygous SOD1 mutations, yet scarce, are of special interest. We report a novel homozygous SOD1 mutation with decreased enzymatic activity and severe early onset ALS phenotype.Methods: Whole exome sequencing and targeted screening of commonly implicated genes were conducted. Repeat-primed PCR and fragment length analysis were used for C9orf72. Bi-directional Sanger sequencing was used for SOD1 and other genes. SOD1 activity was measured by direct spectrophotometry. Serum neurofilament light chain level was measured by the ELLA immunoassay system.Results: The homozygous patient for a novel SOD1 variant p.Ser69Pro showed poor SOD1 enzymatic activity (16% of controls) and an early onset ALS phenotype predominantly affecting lower motor neurons with rapid involvement of the trunk, upper limbs and bulbar muscles. The asymptomatic heterozygous relatives had at least 68% of normal enzyme activity. Level of serum neurofilament light chain was much higher (148 pg/ml) in the patient than the relatives who had normal levels (6–10 pg/ml).Conclusion: This novel mutation adds knowledge to the ALS genotype–phenotype spectrum and supports the strong dose–effect of SOD1 mutations associated with severely decreased enzymatic activity.
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| 30. |
- Fazey, Ioan, et al.
(author)
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Transforming knowledge systems for life on Earth : Visions of future systems and how to get there
- 2020
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In: Energy Research & Social Science. - : Elsevier. - 2214-6296 .- 2214-6326. ; 70
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Journal article (peer-reviewed)abstract
- Formalised knowledge systems, including universities and research institutes, are important for contemporary societies. They are, however, also arguably failing humanity when their impact is measured against the level of progress being made in stimulating the societal changes needed to address challenges like climate change. In this research we used a novel futures-oriented and participatory approach that asked what future envisioned knowledge systems might need to look like and how we might get there. Findings suggest that envisioned future systems will need to be much more collaborative, open, diverse, egalitarian, and able to work with values and systemic issues. They will also need to go beyond producing knowledge about our world to generating wisdom about how to act within it. To get to envisioned systems we will need to rapidly scale methodological innovations, connect innovators, and creatively accelerate learning about working with intractable challenges. We will also need to create new funding schemes, a global knowledge commons, and challenge deeply held assumptions. To genuinely be a creative force in supporting longevity of human and non-human life on our planet, the shift in knowledge systems will probably need to be at the scale of the enlightenment and speed of the scientific and technological revolution accompanying the second World War. This will require bold and strategic action from governments, scientists, civic society and sustained transformational intent.
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| 31. |
- Festari, Cristina, et al.
(author)
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European consensus for the diagnosis of MCI and mild dementia : Preparatory phase
- 2023
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In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:5, s. 1729-1741
-
Journal article (peer-reviewed)abstract
- Introduction: Etiological diagnosis of neurocognitive disorders of middle-old age relies on biomarkers, although evidence for their rational use is incomplete. A European task force is defining a diagnostic workflow where expert experience fills evidence gaps for biomarker validity and prioritization. We report methodology and preliminary results. Methods: Using a Delphi consensus method supported by a systematic literature review, 22 delegates from 11 relevant scientific societies defined workflow assumptions. Results: We extracted diagnostic accuracy figures from literature on the use of biomarkers in the diagnosis of main forms of neurocognitive disorders. Supported by this evidence, panelists defined clinical setting (specialist outpatient service), application stage (MCI-mild dementia), and detailed pre-assessment screening (clinical-neuropsychological evaluations, brain imaging, and blood tests). Discussion: The Delphi consensus on these assumptions set the stage for the development of the first pan-European workflow for biomarkers’ use in the etiological diagnosis of middle-old age neurocognitive disorders at MCI-mild dementia stages. Highlights: Rational use of biomarkers in neurocognitive disorders lacks consensus in Europe. A consensus of experts will define a workflow for the rational use of biomarkers. The diagnostic workflow will be patient-centered and based on clinical presentation. The workflow will be updated as new evidence accrues.
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| 32. |
- Freischmidt, Axel, et al.
(author)
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Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
- 2015
-
In: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 18:5, s. 631-
-
Journal article (peer-reviewed)abstract
- Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.
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| 33. |
- Freischmidt, Axel, et al.
(author)
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Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers
- 2014
-
In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 137:11, s. 2938-2950
-
Journal article (peer-reviewed)abstract
- Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.
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| 34. |
- Frisoni, Giovanni B., et al.
(author)
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European intersocietal recommendations for the biomarker-based diagnosis of neurocognitive disorders
- 2024
-
In: The Lancet Neurology. - 1474-4422 .- 1474-4465. ; 23:3, s. 302-312
-
Research review (peer-reviewed)abstract
- The recent commercialisation of the first disease-modifying drugs for Alzheimer's disease emphasises the need for consensus recommendations on the rational use of biomarkers to diagnose people with suspected neurocognitive disorders in memory clinics. Most available recommendations and guidelines are either disease-centred or biomarker-centred. A European multidisciplinary taskforce consisting of 22 experts from 11 European scientific societies set out to define the first patient-centred diagnostic workflow that aims to prioritise testing for available biomarkers in individuals attending memory clinics. After an extensive literature review, we used a Delphi consensus procedure to identify 11 clinical syndromes, based on clinical history and examination, neuropsychology, blood tests, structural imaging, and, in some cases, EEG. We recommend first-line and, if needed, second-line testing for biomarkers according to the patient's clinical profile and the results of previous biomarker findings. This diagnostic workflow will promote consistency in the diagnosis of neurocognitive disorders across European countries.
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| 35. |
- Helferich, Anika M., et al.
(author)
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Dysregulation of a novel miR-1825/TBCB/TUBA4A pathway in sporadic and familial ALS
- 2018
-
In: Cellular and Molecular Life Sciences (CMLS). - : Springer. - 1420-682X .- 1420-9071. ; 75:23, s. 4301-4319
-
Journal article (peer-reviewed)abstract
- Genetic and functional studies suggest diverse pathways being affected in the neurodegenerative disease amyotrophic lateral sclerosis (ALS), while knowledge about converging disease mechanisms is rare. We detected a downregulation of microRNA-1825 in CNS and extra-CNS system organs of both sporadic (sALS) and familial ALS (fALS) patients. Combined transcriptomic and proteomic analysis revealed that reduced levels of microRNA-1825 caused a translational upregulation of tubulin-folding cofactor b (TBCB). Moreover, we found that excess TBCB led to depolymerization and degradation of tubulin alpha-4A (TUBA4A), which is encoded by a known ALS gene. Importantly, the increase in TBCB and reduction of TUBA4A protein was confirmed in brain cortex tissue of fALS and sALS patients, and led to motor axon defects in an in vivo model. Our discovery of a microRNA-1825/TBCB/TUBA4A pathway reveals a putative pathogenic cascade in both fALS and sALS extending the relevance of TUBA4A to a large proportion of ALS cases.
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| 36. |
- Herukka, Sanna-Kaisa, et al.
(author)
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Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment.
- 2017
-
In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 13:3, s. 285-295
-
Journal article (peer-reviewed)abstract
- This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β1-42, tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost-effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add-on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre- and post-biomarker counseling.
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| 37. |
- Hvarfner, Anna, et al.
(author)
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Oxygen provision to severely ill COVID-19 patients at the peak of the 2020 pandemic in a Swedish district hospital.
- 2022
-
In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:1
-
Journal article (peer-reviewed)abstract
- Oxygen is a low-cost and life-saving therapy for patients with COVID-19. Yet, it is a limited resource in many hospitals in low income countries and in the 2020 pandemic even hospitals in richer countries reported oxygen shortages. An accurate understanding of oxygen requirements is needed for capacity planning. The World Health Organization estimates the average flow-rate of oxygen to severe COVID-19-patients to be 10 l/min. However, there is a lack of empirical data about the oxygen provision to patients. This study aimed to estimate the oxygen provision to COVID-19 patients with severe disease in a Swedish district hospital. A retrospective, medical records-based cohort study was conducted in March to May 2020 in a Swedish district hospital. All adult patients with severe COVID-19 -those who received oxygen in the ward and had no ICU-admission during their hospital stay-were included. Data were collected on the oxygen flow-rates provided to the patients throughout their hospital stay, and summary measures of oxygen provision calculated. One-hundred and twenty-six patients were included, median age was 70 years and 43% were female. On admission, 27% had a peripheral oxygen saturation of ≤91% and 54% had a respiratory rate of ≥25/min. The mean oxygen flow-rate to patients while receiving oxygen therapy was 3.0 l/min (SD 2.9) and the mean total volume of oxygen provided per patient admission was 16,000 l (SD 23,000). In conclusion, the provision of oxygen to severely ill COVID-19-patients was lower than previously estimated. Further research is required before global estimates are adjusted.
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| 38. |
- Hvarfner, Anna, et al.
(author)
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Vital Signs Directed Therapy for the Critically Ill : Improved Adherence to the Treatment Protocol Two Years after Implementation in an Intensive Care Unit in Tanzania
- 2020
-
In: Emergency Medicine International. - : HINDAWI LTD. - 2090-2840 .- 2090-2859. ; 2020
-
Journal article (peer-reviewed)abstract
- Treating deranged vital signs is a mainstay of critical care throughout the world. In an ICU in a university hospital in Tanzania, the implementation of the Vital Signs Directed Therapy Protocol in 2014 led to an increase in acute treatments for deranged vital signs. The mortality rate for hypotensive patients decreased from 92% to 69%. In this study, the aim was to investigate the sustainability of the implementation two years later. An observational, patient-record-based study was conducted in the ICU in August 2016. Data on deranged vital signs and acute treatments were extracted from the patients' charts. Adherence to the protocol, defined as an acute treatment in the same or subsequent hour following a deranged vital sign, was calculated and compared with before and immediately after implementation. Two-hundred and eighty-nine deranged vital signs were included. Adherence was 29.8% two years after implementation, compared with 16.6% (p<0.001) immediately after implementation and 2.9% (p<0.001) before implementation. Consequently, the implementation of the Vital Signs Directed Therapy Protocol appears to have led to a sustainable increase in the treatment of deranged vital signs. The protocol may have potential to improve patient safety in other settings where critically ill patients are managed.
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| 39. |
- Jones, Lesley, et al.
(author)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
-
In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
-
Journal article (peer-reviewed)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 40. |
- Kayambankadzanja, Raphael Kazidule, et al.
(author)
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The Prevalence and Outcomes of Sepsis in Adult Patients in Two Hospitals in Malawi
- 2020
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In: American Journal of Tropical Medicine and Hygiene. - : American Society of Tropical Medicine and Hygiene. - 0002-9637 .- 1476-1645. ; 102:4, s. 896-901
-
Journal article (peer-reviewed)abstract
- There are an estimated 19.4 million sepsis cases every year, many of them in low-income countries. The newly adopted definition of sepsis uses Sequential Organ Failure Assessment Score (SOFA), a score which is not feasible in many low-resource settings. A simpler quick-SOFA (qSOFA) based solely on vital signs score has been devised for identification of suspected sepsis. This study aimed to determine in-hospital prevalence and outcomes of sepsis, as defined as suspected infection and a qSOFA score of 2 or more, in two hospitals in Malawi. The secondary aim was to evaluate qSOFA as a predictor of mortality. A cross-sectional study of adult in-patients in two hospitals in Malawi was conducted using prospectively collected single-day point-prevalence data and in-hospital follow-up. Of 1,135 participants, 81 (7.1%) had sepsis. Septic patients had a higher hospital mortality rate (17.5%) than non-septic infected patients (9.0%, p = 0.027, odds ratio 2.1 [1.1-4.3]), although the difference was not statistically significant after adjustment for baseline characteristics. For in-hospital mortality among patients with suspected infection, qSOFA ≥ 2 had a sensitivity of 31.8%, specificity of 82.1%, a positive predictive value of 17.5%, and a negative predictive value of 91.0%. In conclusion, sepsis is common and is associated with a high risk of death in admitted patients in hospitals in Malawi. In low-resource settings, qSOFA score that uses commonly available vital signs data may be a tool that could be used for identifying patients at risk-both for those with and without a suspected infection.
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| 41. |
- Kayambankadzanja, Raphael Kazidule, et al.
(author)
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Unmet need of essential treatments for critical illness in Malawi
- 2021
-
In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 16:9
-
Journal article (peer-reviewed)abstract
- BackgroundCritical illness is common throughout the world and has been the focus of a dramatic increase in attention during the COVID-19 pandemic. Severely deranged vital signs such as hypoxia, hypotension and low conscious level can identify critical illness. These vital signs are simple to check and treatments that aim to correct derangements are established, basic and low-cost. The aim of the study was to estimate the unmet need of such essential treatments for severely deranged vital signs in all adults admitted to hospitals in Malawi.MethodsWe conducted a point prevalence cross-sectional study of adult hospitalized patients in Malawi. All in-patients aged >= 18 on single days Queen Elizabeth Central Hospital (QECH) and Chiradzulu District Hospital (CDH) were screened. Patients with hypoxia (oxygen saturation <90%), hypotension (systolic blood pressure <90mmHg) and reduced conscious level (Glasgow Coma Scale <9) were included in the study. The a-priori defined essential treatments were oxygen therapy for hypoxia, intravenous fluid for hypotension and an action to protect the airway for reduced consciousness (placing the patient in the lateral position, insertion of an oro-pharyngeal airway or endo-tracheal tube or manual airway protection).ResultsOf the 1135 hospital in-patients screened, 45 (4.0%) had hypoxia, 103 (9.1%) had hypotension, and 17 (1.5%) had a reduced conscious level. Of those with hypoxia, 40 were not receiving oxygen (88.9%). Of those with hypotension, 94 were not receiving intravenous fluids (91.3%). Of those with a reduced conscious level, nine were not receiving an action to protect the airway (53.0%).ConclusionThere was a large unmet need of essential treatments for critical illness in two hospitals in Malawi.
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| 42. |
- Khalil, Michael, et al.
(author)
-
Neurofilaments as biomarkers in neurological disorders - towards clinical application.
- 2024
-
In: Nature Reviews Neurology. - 1759-4758 .- 1759-4766. ; 20:5, s. 269-287
-
Journal article (peer-reviewed)abstract
- Neurofilament proteins have been validated as specific body fluid biomarkers of neuro-axonal injury. The advent of highly sensitive analytical platforms that enable reliable quantification of neurofilaments in blood samples and simplify longitudinal follow-up has paved the way for the development of neurofilaments as a biomarker in clinical practice. Potential applications include assessment of disease activity, monitoring of treatment responses, and determining prognosis in many acute and chronic neurological disorders as well as their use as an outcome measure in trials of novel therapies. Progress has now moved the measurement of neurofilaments to the doorstep of routine clinical practice for the evaluation of individuals. In this Review, we first outline current knowledge on the structure and function of neurofilaments. We then discuss analytical and statistical approaches and challenges in determining neurofilament levels in different clinical contexts and assess the implications of neurofilament light chain (NfL) levels in normal ageing and the confounding factors that need to be considered when interpreting NfL measures. In addition, we summarize the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of neurological disorders, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. We also consider the steps needed to complete the translation of neurofilaments from the laboratory to the management of neurological diseases in clinical practice.
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| 43. |
- Kuechenhof, Jan, et al.
(author)
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INCORPORATING FIELD EFFECTS INTO THE DESIGN OF MODULAR PRODUCT FAMILIES
- 2023
-
In: Proceedings of the Design Society. - 2732-527X. ; 3, s. 2275-2284
-
Conference paper (peer-reviewed)abstract
- With advancing digitalization, new technologies with more and more digital components make it necessary to integrate new components into current and future products. Sensors and actuators, such as motors, emit electromagnetic and thermal fields that can greatly affect product performance. Recent work has considered fields at the functional level using functional structures and at the system level using DSM. In this paper, the effects of fields on product architecture are investigated at the component level. Using an appropriate visualization, the impact of fields on the product structure is considered. Architectural guidelines are then used to develop suitable product structures. The methodological approach is then applied to a product family of vacuum cleaner robots. The overlaid field information helps to gain deeper insights into the product architecture. The approach is useful for representing alternative structures. The new mapping of functional and structural relationships by moving module boundaries against fields can help promote architectural innovation.
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| 44. |
- Leuzy, Antoine, et al.
(author)
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Pittsburgh compound B imaging and cerebrospinal fluid amyloid-β in a multicentre European memory clinic study.
- 2016
-
In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 139:Pt 9, s. 2540-53
-
Journal article (peer-reviewed)abstract
- The aim of this study was to assess the agreement between data on cerebral amyloidosis, derived using Pittsburgh compound B positron emission tomography and (i) multi-laboratory INNOTEST enzyme linked immunosorbent assay derived cerebrospinal fluid concentrations of amyloid-β42; (ii) centrally measured cerebrospinal fluid amyloid-β42 using a Meso Scale Discovery enzyme linked immunosorbent assay; and (iii) cerebrospinal fluid amyloid-β42 centrally measured using an antibody-independent mass spectrometry-based reference method. Moreover, we examined the hypothesis that discordance between amyloid biomarker measurements may be due to interindividual differences in total amyloid-β production, by using the ratio of amyloid-β42 to amyloid-β40 Our study population consisted of 243 subjects from seven centres belonging to the Biomarkers for Alzheimer's and Parkinson's Disease Initiative, and included subjects with normal cognition and patients with mild cognitive impairment, Alzheimer's disease dementia, frontotemporal dementia, and vascular dementia. All had Pittsburgh compound B positron emission tomography data, cerebrospinal fluid INNOTEST amyloid-β42 values, and cerebrospinal fluid samples available for reanalysis. Cerebrospinal fluid samples were reanalysed (amyloid-β42 and amyloid-β40) using Meso Scale Discovery electrochemiluminescence enzyme linked immunosorbent assay technology, and a novel, antibody-independent, mass spectrometry reference method. Pittsburgh compound B standardized uptake value ratio results were scaled using the Centiloid method. Concordance between Meso Scale Discovery/mass spectrometry reference measurement procedure findings and Pittsburgh compound B was high in subjects with mild cognitive impairment and Alzheimer's disease, while more variable results were observed for cognitively normal and non-Alzheimer's disease groups. Agreement between Pittsburgh compound B classification and Meso Scale Discovery/mass spectrometry reference measurement procedure findings was further improved when using amyloid-β42/40 Agreement between Pittsburgh compound B visual ratings and Centiloids was near complete. Despite improved agreement between Pittsburgh compound B and centrally analysed cerebrospinal fluid, a minority of subjects showed discordant findings. While future studies are needed, our results suggest that amyloid biomarker results may not be interchangeable in some individuals.
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| 45. |
- Lewczuk, Piotr, et al.
(author)
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Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry.
- 2018
-
In: The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry. - : Informa UK Limited. - 1814-1412. ; 19:4, s. 244-328
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Journal article (peer-reviewed)abstract
- In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimer's disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-β positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.
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| 46. |
- Linnemann, Christoph, et al.
(author)
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NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study
- 2024
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In: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY. - 0022-3050 .- 1468-330X.
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Journal article (peer-reviewed)abstract
- BackgroundBlood neurofilament light chain (NfL) is increasingly considered as a key trial biomarker in genetic frontotemporal dementia (gFTD). We aimed to facilitate the use of NfL in gFTD multicentre trials by testing its (1) reliability across labs; (2) reliability to stratify gFTD disease stages; (3) comparability between blood matrices and (4) stability across recruiting sites.MethodsComparative analysis of blood NfL levels in a large gFTD cohort (GENFI) for (1)-(4), with n=344 samples (n=148 presymptomatic, n=11 converter, n=46 symptomatic subjects, with mutations in C9orf72, GRN or MAPT; and n=139 within-family controls), each measured in three different international labs by Simoa HD-1 analyzer.ResultsNfL revealed an excellent consistency (intraclass correlation coefficient (ICC) 0.964) and high reliability across the three labs (maximal bias (pg/mL) in Bland-Altman analysis: 1.12 +/- 1.20). High concordance of NfL across laboratories was moreover reflected by high areas under the curve for discriminating conversion stage against the (non-converting) presymptomatic stage across all three labs. Serum and plasma NfL were largely comparable (ICC 0.967). The robustness of NfL across 13 recruiting sites was demonstrated by a linear mixed effect model.ConclusionsOur results underline the suitability of blood NfL in gFTD multicentre trials, including cross-lab reliable stratification of the highly trial-relevant conversion stage, matrix comparability and cross-site robustness.
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| 47. |
- Ljungqvist, Martin Georg, et al.
(author)
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Object Detector Differences when Using Synthetic and Real Training Data
- 2023
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In: SN Computer Science. - : Springer Science and Business Media LLC. - 2662-995X .- 2661-8907. ; 4:3
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Journal article (peer-reviewed)abstract
- To train well-performing generalizing neural networks, sufficiently large and diverse datasets are needed. Collecting data while adhering to privacy legislation becomes increasingly difficult and annotating these large datasets is both a resource-heavy and time-consuming task. An approach to overcome these difficulties is to use synthetic data since it is inherently scalable and can be automatically annotated. However, how training on synthetic data affects the layers of a neural network is still unclear. In this paper, we train the YOLOv3 object detector on real and synthetic images from city environments. We perform a similarity analysis using Centered Kernel Alignment (CKA) to explore the effects of training on synthetic data on a layer-wise basis. The analysis captures the architecture of the detector while showing both different and similar patterns between different models. With this similarity analysis, we want to give insights on how training synthetic data affects each layer and to give a better understanding of the inner workings of complex neural networks. The results show that the largest similarity between a detector trained on real data and a detector trained on synthetic data was in the early layers, and the largest difference was in the head part. The results also show that no major difference in performance or similarity could be seen between frozen and unfrozen backbone.
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| 48. |
- Marjonen, Heidi, et al.
(author)
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A Web Portal for Communicating Polygenic Risk Score Results for Health Care Use—The P5 Study
- 2021
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In: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 12
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Journal article (peer-reviewed)abstract
- We present a method for communicating personalized genetic risk information to citizens and their physicians using a secure web portal. We apply the method for 3,177 Finnish individuals in the P5 Study where estimates of genetic and absolute risk, based on genetic and clinical risk factors, of future disease are reported to study participants, allowing individuals to participate in managing their own health. Our method facilitates using polygenic risk score as a personalized tool to estimate a person’s future disease risk while offering a way for health care professionals to utilize the polygenic risk scores as a preventive tool in patient care.
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| 49. |
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| 50. |
- Mueller, Kathrin, et al.
(author)
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Comprehensive analysis of the mutation spectrum in 301 German ALS families
- 2018
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In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 89:8, s. 817-827
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Journal article (peer-reviewed)abstract
- Objectives Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.Methods Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.Results 49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.Conclusions We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.
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