| 1. |
- Anderson, Ryan T, et al.
(author)
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Association Between Seroclearance of Hepatitis B Surface Antigen and Long-term Clinical Outcomes of Patients With Chronic Hepatitis B Virus Infection : Systematic Review and Meta-analysis.
- 2021
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In: Clinical Gastroenterology and Hepatology. - : Elsevier. - 1542-3565 .- 1542-7714. ; 19:3, s. 463-472
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Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: Seroclearance of hepatitis B surface antigen (HBsAg) is the desired end point of treatment for chronic hepatitis B virus (HBV) infection, according to guidelines. We performed a systematic review and meta-analysis to evaluate the strength of the association between HBsAg seroclearance and long-term clinical outcomes.METHODS: We performed a systematic review of the PubMed, EMBASE, and Cochrane Library databases for articles that assessed HBsAg status and reported the incidence of hepatocellular carcinoma (HCC), liver decompensation, liver transplantation, and/or all-cause mortality during follow-up evaluation. We performed a meta-analysis of rate ratios (RR) using a random-effects model independently for each end point and for a composite end point.RESULTS: We analyzed data from 28 studies, comprising a total of 188,316 patients with chronic HBV infection (treated and untreated), and 1,486,081 person-years (PY) of follow-up evaluation; 26 reported data on HCC, 7 on liver decompensation, and 13 on liver transplantation and/or death. The composite event rates were 0.19/1000 PY for the HBsAg seroclearance group and 2.45/1000 PY for the HBsAg-persistent group. Pooled RRs for the HBsAg seroclearance group were 0.28 for liver decompensation (95% CI, 0.13-0.59; P = .001), 0.30 for HCC (95% CI, 0.20-0.44; P < .001), 0.22 for liver transplantation and/or death (95% CI, 0.13-0.39; P < .001), and 0.31 for the composite end point (95% CI, 0.23-0.43; P < .001). No differences in RR estimates were observed among subgroups of different study or patient characteristics.CONCLUSIONS: In a systematic review and meta-analysis, we found seroclearance of HBsAg to be associated significantly with improved patient outcomes. The results are consistent among different types of studies, in all patient subpopulations examined, and support the use of HBsAg seroclearance as a primary end point of trials of patients with chronic HBV infection.
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| 2. |
- Bergman, Erik, et al.
(author)
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A full-document analysis of the semantic relation between European Public Assessment Reports and EMA guidelines using a BERT language model
- 2023
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 18:12
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Journal article (peer-reviewed)abstract
- In the European Union, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) develop guidelines to guide drug development, supporting development of efficacious and safe medicines. A European Public Assessment Report (EPAR) is published for every medicine application that has been granted or refused marketing authorisation within the EU. In this work, we study the use of text embeddings and similarity metrics to investigate the semantic similarity between EPARs and EMA guidelines. All 1024 EPARs for initial marketing authorisations from 2008 to 2022 was compared to the 669 current EMA scientific guidelines. Documents were converted to plain text and split into overlapping chunks, generating 265,757 EPAR and 27,649 guideline text chunks. Using a Sentence BERT language model, the chunks were transformed into embeddings and fed into an in-house piecewise matching algorithm to estimate the full-document semantic distance. In an analysis of the document distance scores and product characteristics using a linear regression model, EPARs of anti-virals for systemic use (ATC code J05) and antihemorrhagic medicines (B02) present with statistically significant lower overall semantic distance to guidelines compared to other therapeutic areas, also when adjusting for product age and EPAR length. In conclusion, we believe our approach provides meaningful insight into the interplay between EMA scientific guidelines and the assessment made during regulatory review, and could potentially be used to answer more specific questions such as which therapeutic areas could benefit from additional regulatory guidance.
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| 3. |
- Bergman, Erik, et al.
(author)
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A natural language processing approach towards harmonisation of European medicinal product information
- 2022
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:10
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Journal article (peer-reviewed)abstract
- Product information (PI) is a vital part of any medicinal product approved for use within the European Union and consists of a summary of products characteristics (SmPC) for healthcare professionals and package leaflet (PL) for patients, together with the product packaging. In this study, based on the English corpus of the EMA product information documents for all centrally approved medicinal products within the EU, a BERT sentence embedding model was used together with clustering and dimensional reduction techniques to identify sentence similarity clusters that could be candidates for standardization. A total of 1258 medicinal products were included in the study. From these, a total of 783 K sentences were extracted from SmPC and PL documents which were aggregated into a total of 284 and 129 semantic similarity clusters, respectively. The spread distribution among clusters shows separation into different cluster types. Examples of clusters with low spread include those with identical word embeddings due to current standardization, such as section headings and standard phrases. Others show minor linguistic variations, while the group with the largest variability contains variable wording but with significant semantic overlap. The sentence clusters identified could serve as candidates for further standardization of the PI. Moving from free text human wording to auto-generated text elements based on multiple-choice input for appropriate parts of the package leaflet and summary of product characteristics, could reduce both time and complexity for applicants as well as regulators, and ultimately provide patients and prescribers with documents that are easier to understand and better adapted for search availabilities.
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| 4. |
- Bergman, Erik, et al.
(author)
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BERT based natural language processing for triage of adverse drug reaction reports shows close to human-level performance
- 2023
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In: PLOS Digital Health. - : Public Library of Science (PLoS). - 2767-3170. ; 2:12
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Journal article (peer-reviewed)abstract
- Post-marketing reports of suspected adverse drug reactions are important for establishing the safety profile of a medicinal product. However, a high influx of reports poses a challenge for regulatory authorities as a delay in identification of previously unknown adverse drug reactions can potentially be harmful to patients. In this study, we use natural language processing (NLP) to predict whether a report is of serious nature based solely on the free-text fields and adverse event terms in the report, potentially allowing reports mislabelled at time of reporting to be detected and prioritized for assessment. We consider four different NLP models at various levels of complexity, bootstrap their train-validation data split to eliminate random effects in the performance estimates and conduct prospective testing to avoid the risk of data leakage. Using a Swedish BERT based language model, continued language pre-training and final classification training, we achieve close to human-level performance in this task. Model architectures based on less complex technical foundation such as bag-of-words approaches and LSTM neural networks trained with random initiation of weights appear to perform less well, likely due to the lack of robustness that a base of general language training provides.
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| 5. |
- Cunningham, Janet, et al.
(author)
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Antibody Responses to Severe Acute Respiratory Syndrome Coronavirus 2 in the Serum and Cerebrospinal Fluid of Patients With Coronavirus Disease 2019 and Neurological Symptoms
- 2022
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In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 225:6, s. 965-970
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Journal article (peer-reviewed)abstract
- Antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in serum and cerebrospinal fluid (CSF) samples from 16 patients with coronavirus disease 2019 and neurological symptoms were assessed using 2 independent methods. Immunoglobulin G (IgG) specific for the virus spike protein was found in 81% of patients in serum and in 56% in CSF. SARS-CoV-2 IgG in CSF was observed in 2 patients with negative serological findings. Levels of IgG in both serum and CSF were associated with disease severity (P < .05). All patients with elevated markers of central nervous system damage in CSF also had CSF antibodies (P = .002), and CSF antibodies had the highest predictive value for neuronal damage markers of all tested clinical variables.
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| 6. |
- Cunningham, Janet L, et al.
(author)
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Anti-SARS-CoV2 antibody responses in serum and cerebrospinal fluid of COVID-19 patients with neurological symptoms.
- 2022
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In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 225:6, s. 965-970
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Journal article (peer-reviewed)abstract
- Antibody responses to SARS-CoV-2 in serum and CSF from 16 COVID-19 patients with neurological symptoms were assessed using two independent methods. IgG specific for the virus spike protein was found in 81% of cases in serum and in 56% in CSF. SARS-CoV-2 IgG in CSF was observed in two cases with negative serology. Levels of IgG in both serum and CSF were associated with disease severity (p<0.05). All patients with elevated markers of CNS damage in CSF also had CSF antibodies (p=0.002), and CSF antibodies had the highest predictive value for neuronal damage markers of all tested clinical variables.
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| 7. |
- Dong, Guojun, et al.
(author)
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Optimizing Signal Management in a Vaccine Adverse Event Reporting System : A Proof-of-Concept with COVID-19 Vaccines Using Signs, Symptoms, and Natural Language Processing
- 2024
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In: Drug Safety. - : Adis. - 0114-5916 .- 1179-1942. ; 47:2, s. 173-
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Journal article (peer-reviewed)abstract
- Introduction: The Vaccine Adverse Event Reporting System (VAERS) has already been challenged by an extreme increase in the number of individual case safety reports (ICSRs) after the market introduction of coronavirus disease 2019 (COVID-19) vaccines. Evidence from scientific literature suggests that when there is an extreme increase in the number of ICSRs recorded in spontaneous reporting databases (such as the VAERS), an accompanying increase in the number of disproportionality signals (sometimes referred to as ‘statistical alerts’) generated is expected. Objectives: The objective of this study was to develop a natural language processing (NLP)-based approach to optimize signal management by excluding disproportionality signals related to listed adverse events following immunization (AEFIs). COVID-19 vaccines were used as a proof-of-concept. Methods: The VAERS was used as a data source, and the Finding Associated Concepts with Text Analysis (FACTA+) was used to extract signs and symptoms of listed AEFIs from MEDLINE for COVID-19 vaccines. Disproportionality analyses were conducted according to guidelines and recommendations provided by the US Centers for Disease Control and Prevention. By using signs and symptoms of listed AEFIs, we computed the proportion of disproportionality signals dismissed for COVID-19 vaccines using this approach. Nine NLP techniques, including Generative Pre-Trained Transformer 3.5 (GPT-3.5), were used to automatically retrieve Medical Dictionary for Regulatory Activities Preferred Terms (MedDRA PTs) from signs and symptoms extracted from FACTA+. Results: Overall, 17% of disproportionality signals for COVID-19 vaccines were dismissed as they reported signs and symptoms of listed AEFIs. Eight of nine NLP techniques used to automatically retrieve MedDRA PTs from signs and symptoms extracted from FACTA+ showed suboptimal performance. GPT-3.5 achieved an accuracy of 78% in correctly assigning MedDRA PTs. Conclusion: Our approach reduced the need for manual exclusion of disproportionality signals related to listed AEFIs and may lead to better optimization of time and resources in signal management. © 2023, The Author(s).
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| 8. |
- Fällmar, David, et al.
(author)
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The extent of neuroradiological findings in COVID-19 shows correlation with blood biomarkers, Glasgow coma scale score and days in intensive care
- 2022
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In: Journal of neuroradiology. - : Elsevier. - 0150-9861 .- 1773-0406. ; 49:6, s. 421-427
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Journal article (peer-reviewed)abstract
- Background and purposeA wide range of neuroradiological findings has been reported in patients with coronavirus disease 2019 (COVID-19), ranging from subcortical white matter changes to infarcts, haemorrhages and focal contrast media enhancement. These have been descriptively but inconsistently reported and correlations with clinical findings and biomarkers have been difficult to extract from the literature. The purpose of this study was to quantify the extents of neuroradiological findings in a cohort of patients with COVID-19 and neurological symptoms, and to investigate correlations with clinical findings, duration of intensive care and biomarkers in blood.Material and methodsPatients with positive SARS-CoV-2 and at least one new-onset neurological symptom were included from April until July 2020. Nineteen patients were examined regarding clinical symptoms, biomarkers in blood and MRI of the brain. In order to quantify the MRI findings, a semi-quantitative neuroradiological severity scale was constructed a priori, and applied to the MR images by two specialists in neuroradiology.Results and conclusionsThe score from the severity scale correlated significantly with blood biomarkers of CNS injury (glial fibrillary acidic protein, total-tau, ubiquitin carboxyl-terminal hydrolase L1) and inflammation (C-reactive protein), Glasgow Coma Scale score, and the number of days spent in intensive care. The underlying radiological assessments had inter-rater agreements of 90.5%/86% (for assessments with 2/3 alternatives). Total intraclass correlation was 0.80.Previously reported neuroradiological findings in COVID-19 have been diverse and heterogenous. In this study, the extent of findings in MRI examination of the brain, quantified using a structured report, shows correlation with relevant biomarkers.
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| 9. |
- Gahrton, Caroline, et al.
(author)
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Prevalence of Viremic hepatitis C, hepatitis B, and HIV infection, and vaccination status among prisoners in Stockholm County
- 2019
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In: BMC Infectious Diseases. - : BioMed Central. - 1471-2334. ; 19:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Identification and knowledge of settings with high prevalence of hepatitis C virus (HCV) infection is important when aiming for elimination of HCV. The primary aim of this study was to estimate the prevalence of viremic HCV infection among Swedish prisoners. Secondary aims were to estimate the prevalence of hepatitis B surface antigen (HBsAg), human immunodeficiency virus (HIV), and the proportion who have received hepatitis B virus (HBV) vaccination.METHODS: A cross-sectional study of all incarcerated persons (n = 667) at all prisons (n = 9) in Stockholm County was conducted. All prisoners are routinely offered opt-in screening for HCV antibodies (anti-HCV), HCV RNA, HBsAg, anti-HBs, anti-HBc and HIV Ag/Ab at prison in Sweden. Data on the results of these tests and the number of received HBV vaccine doses were collected from the prison medical records. The parameters of HCV RNA, anti-HCV, and occurrence of testing for HCV were analysed in multiple logistic regression models in relation to age, sex and prison security class.RESULTS: The median age was 35 (IQR 26-44) years, and 93.4% were men. Seventy-one percent (n = 471) had been tested for anti-HCV, 70% (n = 465) for HBsAg and 71% (n = 471) for HIV. The prevalence of anti-HCV, HCV RNA, HBsAg and HIV Ag/Ab was 17.0, 11.5, 1.9, and 0.2%, respectively among tested persons. The proportion of prisoners who had received full HBV vaccination was 40.6% (n = 271) among all study subjects.CONCLUSIONS: The prevalence of viremic HCV infection among Swedish prisoners in Stockholm County was 11.5%, which is high in comparison to the general population. Therefore, when aiming for the WHO goal of HCV elimination, prisons could suit as a platform for identification and treatment of HCV infection. There is a need to increase testing for blood-borne viruses and to improve vaccination coverage against HBV in Swedish prisons.
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| 10. |
- Hibar, Derrek P., et al.
(author)
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Novel genetic loci associated with hippocampal volume
- 2017
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
-
Journal article (peer-reviewed)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 11. |
- Imlay, Hannah, et al.
(author)
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Consensus Definitions of BK Polyomavirus Nephropathy in Renal Transplant Recipients for Clinical Trials
- 2022
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In: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 75:7, s. 1210-1216
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Journal article (peer-reviewed)abstract
- Background BK polyomavirus (BKPyV) infection and BK polyomavirus nephropathy (BKPyVAN) are important causes of allograft dysfunction and premature allograft loss in renal transplant recipients. Results and Discussion Controlled clinical trials to evaluate new agents for prevention and treatment are needed but are hampered by the lack of outcome measures that accurately assess the effect of the intervention, are clinically relevant, and are acceptable from a regulatory perspective. Methods To facilitate consistent end points in clinical trials and to support clinical research and drug development, definitions of BKPyV infection and disease have been developed by the BK Disease Definitions Working Group of the Transplantation Associated Virus Infection Forum with the Forum for Collaborative Research, which consists of scientists, clinicians, regulators, and industry representatives. Conclusions These definitions refine established principles of "proven" BKPyV disease and introduce a "probable" disease category that could be used in clinical trials to prevent or treat BKPyVAN in renal transplant recipients. Standardized BK polyomavirus nephropathy (BKPyVAN) definitions are needed to evaluate therapeutics. We refine established criteria for "proven" BKPyVAN and introduce a "probable disease" category based on allograft dysfunction and plasma DNAemia. Plasma DNAemia thresholds for BKPyVAN are needed.
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| 12. |
- Kamal, Habiba, et al.
(author)
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Age-specific and sex-specific risks for HCC in African-born persons with chronic hepatitis B without cirrhosis
- 2023
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In: Hepatology Communications. - : Wolters Kluwer. - 2471-254X. ; 7:12
-
Journal article (peer-reviewed)abstract
- Background: The international recommendations of HCC surveillance for African-born persons with chronic hepatitis B (CHB) without cirrhosis are divergent, probably due to scarce data on incidence rate (IR) for HCC.Methods: We assembled a cohort with prospectively collected data of Swedish residents of African origin with diagnosed CHB without cirrhosis at baseline from 1990 to 2015. Data from nationwide registers were used to calculate the sex-specific IR and IR ratio (incidence rate ratios) in relation to age, comorbidities, and birth region, using a generalized linear model with a log-link function and Poisson distribution.Results: Among 3865 African-born persons with CHB without cirrhosis at baseline, 31 (0.8%; 77.4% men) developed HCC during a median of 11.1 years of follow-up, with poor survival after HCC diagnosis. The mean age at HCC diagnosis was 46.8 (SD±14.7; range 23–79) in men. HCC IR exceeded the recommended surveillance threshold of 0.2%/year at ages 54 and 59 years in men and women, respectively, and at ages 20–40 years if HCV or HDV co-infection was present. African-born men with CHB had an incidence rate ratios of 10.6 (95% CI 4.4–31.5) for HCC compared to matched African-born peers without CHB, and an incidence rate ratios of 35.3 (95% CI 16.0–88.7) compared to a matched general population.Conclusions: African-born men with CHB without cirrhosis reached an IR of 0.2%/year between 50 and 60 years, and at younger ages if HCV or HDV co-infection was present. Our findings need further confirmation, and new cost-effectiveness analyses specific for young populations are needed, to provide personalized and cost-effective HCC surveillance.
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| 13. |
- Kamal, Habiba, et al.
(author)
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Age-specific and sex-specific risks for HCC in African-born persons with chronic hepatitis B without cirrhosis
- 2023
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In: Hepatology communications. - : Wiley Periodicals Inc. on behalf of the American Association for the Study of Liver Diseases. - 2471-254X. ; 7:12
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The international recommendations of HCC surveillance for African-born persons with chronic hepatitis B (CHB) without cirrhosis are divergent, probably due to scarce data on incidence rate (IR) for HCC.METHODS: We assembled a cohort with prospectively collected data of Swedish residents of African origin with diagnosed CHB without cirrhosis at baseline from 1990 to 2015. Data from nationwide registers were used to calculate the sex-specific IR and IR ratio (incidence rate ratios) in relation to age, comorbidities, and birth region, using a generalized linear model with a log-link function and Poisson distribution.RESULTS: Among 3865 African-born persons with CHB without cirrhosis at baseline, 31 (0.8%; 77.4% men) developed HCC during a median of 11.1 years of follow-up, with poor survival after HCC diagnosis. The mean age at HCC diagnosis was 46.8 (SD±14.7; range 23-79) in men. HCC IR exceeded the recommended surveillance threshold of 0.2%/year at ages 54 and 59 years in men and women, respectively, and at ages 20-40 years if HCV or HDV co-infection was present. African-born men with CHB had an incidence rate ratios of 10.6 (95% CI 4.4-31.5) for HCC compared to matched African-born peers without CHB, and an incidence rate ratios of 35.3 (95% CI 16.0-88.7) compared to a matched general population.CONCLUSIONS: African-born men with CHB without cirrhosis reached an IR of 0.2%/year between 50 and 60 years, and at younger ages if HCV or HDV co-infection was present. Our findings need further confirmation, and new cost-effectiveness analyses specific for young populations are needed, to provide personalized and cost-effective HCC surveillance.
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| 14. |
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| 15. |
- Kamal, H., et al.
(author)
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Long-Term Study of Hepatitis Delta Virus Infection at Secondary Care Centers: The Impact of Viremia on Liver-Related Outcomes
- 2020
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In: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 72:4, s. 1177-1190
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Journal article (peer-reviewed)abstract
- Background and Aims Hepatitis delta virus (HDV) infection is associated with fast progression to liver cirrhosis and liver complications. Previous studies have, however, been mainly from tertiary care centers, with risk for referral bias toward patients with worse outcomes. Furthermore, the impact of HDV viremiaper seon liver-related outcomes is not really known outside the human immunodeficiency virus co-infection setting. We have therefore evaluated the long-term impact of HDV viremia on liver-related outcomes in a nationwide cohort of patients with hepatitis B and D co-infection, cared for at secondary care centers in Sweden. Approach and Results In total, 337 patients with anti-HDV positivity, including 233 patients with HDV RNA viremia and 91 without HDV viremia at baseline, were retrospectively studied, with a mean follow-up of 6.5 years (range, 0.5-33.1). The long-term risks for liver-related events (i.e., hepatocellular carcinoma [HCC], hepatic decompensation, or liver-related death/transplantation) were assessed, using Cox regression analysis. The risk for liver-related events and HCC was 3.8-fold and 2.6-fold higher, respectively, in patients with HDV viremia compared with those without viremia, although the latter was not statistically significant. Among patients with HDV viremia with no baseline cirrhosis, the cumulative risk of being free of liver cirrhosis or liver-related events was 81.9% and 64.0% after 5 and 10 years of follow-up, respectively. This corresponds to an incidence rate of 0.04 cases per person-year. Conclusions HDV RNA viremia is associated with a 3.8-fold higher risk for liver-related outcomes. The prognosis was rather poor for patients with HDV viremia without cirrhosis at baseline, but it was nevertheless more benign than previous estimates from tertiary centers. Our findings may be of importance when making decisions about treatment and evaluating potential outcomes of upcoming antivirals against HDV.
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| 16. |
- Kisiel, Marta, 1984-, et al.
(author)
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Patterns and predictors of sick leave among Swedish non-hospitalized healthcare and residential care workers with Covid-19 during the early phase of the pandemic
- 2021
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 16:12
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Journal article (peer-reviewed)abstract
- Healthcare and residential care workers represent two occupational groups that have, in particular, been at risk of Covid-19, its long-term consequences, and related sick leave. In this study, we investigated the predictors of prolonged sick leave among healthcare and residential workers due to non-hospitalized Covid-19 in the early period of the pandemic. This study is based on a patient register (n = 3209) and included non-hospitalized healthcare or residential care service workers with a positive RT- PCR for SARS-CoV-2 (n = 433) between March and August 2020. Data such as socio-demographics, clinical characteristics, and the length of sick leave because of Covid-19 and prior to the pandemic were extracted from the patient’s electronic health records. Prolonged sick leave was defined as sick leave ≥ 3 weeks, based on the Swedish pandemic policy. A generalized linear model was used with a binary distribution, adjusted for age, gender, and comorbidity in order to predict prolonged sick leave. Of 433 (77% women) healthcare and residential care workers included in this study, 14.8% needed longer sick leave (> 3 weeks) due to Covid-19. Only 1.4% of the subjects were on sick leave because of long Covid. The risk of sick leave was increased two-fold among residential care workers (adjusted RR 2.14 [95% CI 1.31–3.51]). Depression/anxiety (adjusted RR 2.09 [95% CI 1.31–3.34]), obesity (adjusted RR 1.96 [95% CI 1.01–3.81]) and dyspnea at symptom onset (adjusted RR 2.47 [95% CI 1.55–3.92]), sick leave prior to the pandemic (3–12 weeks) (adjusted RR 2.23 [95% CI 1.21–4.10]) were associated with longer sick leave. From a public health perspective, considering occupational category, comorbidity, symptoms at onset, and sick leave prior to the pandemic as potential predictors of sick leave in healthcare may help prevent staff shortage.
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| 17. |
- Lidström, Anna-Karin, et al.
(author)
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Work at inpatient care units is associated with an increased risk of SARS-CoV-2 infection; a cross-sectional study of 8679 healthcare workers in Sweden.
- 2020
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In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 125:4, s. 305-310
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Journal article (peer-reviewed)abstract
- BACKGROUND: During the Covid-19 pandemic, the protection of healthcare workers has been in focus throughout the world, but the availability and quality of personal protective equipment has at times and in some settings been suboptimal.MATERIALS AND METHODS: A total of 8679 healthcare workers and healthcare support staff in the county of Uppsala, north of Stockholm, were included in this cross-sectional study. All subjects were analysed for IgG anti-SARS-CoV-2, and predictors for positive serostatus were analysed in a logistic regression model including demographic parameters and self-reported employment characteristics.RESULTS: Overall, 577 (6.6%) were classified as seropositive, with no statistically significant differences between healthcare workers and support staff. Among healthcare workers, age (OR 0.987 per year, 95% CI 0.980-0.995), time to sampling (OR 1.019 per day, 95% CI 1.004-1.035), and employment at an outpatient care unit (OR 0.620, 95% CI 0.487-0.788) were statistically significantly associated with risk of infection. Covid-19 specific units were not at particular risk, compared to other units with comparable characteristics and staff demography.CONCLUSION: Our findings indicate that SARS-CoV-2 transmission is related to inpatient healthcare work, and illustrate the need for a high standard of basic hygiene routines in all inpatient care settings.
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| 18. |
- Lorant, Camilla, et al.
(author)
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Risk Factors for Developing BK Virus-Associated Nephropathy : A Single-Center Retrospective Cohort Study of Kidney Transplant Recipients
- 2022
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In: Annals of Transplantation. - 1425-9524 .- 2329-0358. ; 27
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Journal article (peer-reviewed)abstract
- BACKGROUND BK virus (BKV) infection after kidney transplantation leads to BKV-associated nephropathy (BKVAN) in up to 10% of recipients, and is associated with an increased risk of allograft dysfunction or loss. The objective of this study was to estimate the incidence of BKVAN and to analyze whether enhanced induction is associated with an increased risk of BKVAN, possibly justifying more intensive surveillance.MATERIAL AND METHODS This was a single-center retrospective cohort study. All patients who underwent kidney transplantation or simultaneous pancreas and kidney transplantation at the Uppsala University Hospital in Sweden between 2005 and 2014 were included, a period when BKV screening was not yet implemented. The effect of enhanced induction, defined as treatment with thymoglobulin, rituximab, and/or eculizumab, often in combination with IVIg and glycosorb, immunoadsorption and/or plasmapheresis/apheresis, was analyzed in a multivariable Cox proportional hazards model together with sex, age, cytomegalovirus mismatch (donor+/recipient-) and rejection treatment as co-predictors. Further, the effects of BKVAN on graft survival was analyzed in a univariable Cox proportional hazards model.RESULTS In total 44 of 928 (4.7%) patients developed a biopsy-verified BKVAN 4.8 (1.5-34.2) months after transplantation. Male sex was identified as a risk factor (HR 2.02, P=0.04) but not enhanced induction. Patients with BKVAN experienced a significantly higher risk of graft loss (HR 4.37, P<0.001).CONCLUSIONS Male sex, but not enhanced induction, was found to be a risk factor for BKVAN development after kidney transplantation. BKVAN is associated with an increased risk of graft loss.
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| 19. |
- Lorant, Camilla, et al.
(author)
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The risk factors associated with post-transplantation BKPyV nephropathy and BKPyV DNAemia : a prospective study in kidney transplant recipients
- 2024
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In: BMC Infectious Diseases. - : BioMed Central (BMC). - 1471-2334. ; 24
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Journal article (peer-reviewed)abstract
- Background: BK polyomavirus (BKPyV) infection after kidney transplantation can lead to serious complications such as BKPyV-associated nephropathy (BKPyVAN) and graft loss. The aim of this study was to investigate the incidence of BKPyVAN after implementing a BKPyV screening program, to map the distribution of BKPyV genotypes and subtypes in the Uppsala-orebro region and to identify host and viral risk factors for clinically significant events.Methods This single-center prospective cohort study included kidney transplant patients aged >= 18 years at the Uppsala University Hospital in Sweden between 2016 and 2018. BKPyV DNA was analyzed in plasma and urine every 3 months until 18 months after transplantation. Also genotype and subtype were determined. A logistic regression model was used to analyze selected risk factors including recipient sex and age, AB0 incompatibility and rejection treatment prior to BKPyVAN or high-level BKPyV DNAemia.Results: In total, 205 patients were included. Of these, 151 (73.7%) followed the screening protocol with 6 plasma samples, while184 (89.8%) were sampled at least 5 times. Ten (4.9%) patients developed biopsy confirmed BKPyVAN and 33 (16.1%) patients met criteria for high-level BKPyV DNAemia. Male sex (OR 2.85, p = 0.025) and age (OR 1.03 per year, p = 0.020) were identified as significant risk factors for developing BKPyVAN or high-level BKPyV DNAemia. BKPyVAN was associated with increased viral load at 3 months post transplantation (82,000 vs. < 400 copies/mL; p = 0.0029) and with transient, high-level DNAemia (n = 7 (27%); p < 0.0001). The most common genotypes were subtype Ib2 (n = 50 (65.8%)) and IVc2 (n = 20 (26.3%)).Conclusions: Male sex and increasing age are related to an increased risk of BKPyVAN or high-level BKPyV DNAemia. BKPyVAN is associated with transient, high-level DNAemia but no differences related to viral genotype were detected.
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| 20. |
- Nasi, A, et al.
(author)
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Reactive oxygen species as an initiator of toxic innate immune responses in retort to SARS-CoV-2 in an ageing population, consider N-acetylcysteine as early therapeutic intervention
- 2020
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In: Toxicology reports. - : Elsevier Inc.. - 2214-7500. ; 7, s. 768-771
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Journal article (peer-reviewed)abstract
- During the current COVID-19 pandemic, a need for evaluation of already available drugs for treatment of the disease is crucial. Hereby, based on literature review from the current pandemic and previous outbreaks with corona viruses we analyze the impact of the virus infection on cell stress responses and redox balance. High levels of mortality are noticed in elderly individuals infected with SARS-CoV2 and during the previous SARS-CoV1 outbreak. Elderly individuals maintain a chronic low level of inflammation which is associated with oxidative stress and inflammatory cytokine production, a condition that increases the severity of viral infections in this population. Coronavirus infections can lead to alterations of redox balance in infected cells through modulation of NAD + biosynthesis, PARP function along with altering proteasome and mitochondrial function in the cell thereby leading to enhanced cell stress responses which further exacerbate inflammation. ROS production can increase IL-6 production and lipid peroxidation resulting in cell damage. Therefore, early treatment with anti-oxidants such as NAC during COVID-19 can be a way to bypass the excessive inflammation and cell damage that lead to severe infection, thus early NAC as intervention should be evaluated in a clinical trial setting.
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| 21. |
- Nääs, Anja, et al.
(author)
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Temporal pathway analysis of cerebrospinal fluid proteome in herpes simplex encephalitis
- 2023
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In: Infectious Diseases. - : Taylor & Francis. - 2374-4235 .- 2374-4243. ; 55:10, s. 694-705
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Journal article (peer-reviewed)abstract
- ObjectivesWe examined the temporal changes of the CSF proteome in patients with herpes simplex encephalitis (HSE) during the course of the disease, in relation to anti-N-methyl-D-aspartate receptor (NMDAR) serostatus, corticosteroid treatment, brain MRI and neurocognitive performance.MethodsPatients were retrospectively included from a previous prospective trial with a pre-specified CSF sampling protocol. Mass spectrometry data of the CSF proteome were processed using pathway analysis.ResultsWe included 48 patients (110 CSF samples). Samples were grouped based on time of collection relative to hospital admission - T1: & LE; 9 d, T2: 13-28 d, T3: & GE; 68 d. At T1, a strong multi-pathway response was seen including acute phase response, antimicrobial pattern recognition, glycolysis and gluconeogenesis. At T2, most pathways activated at T1 were no longer significantly different from T3. After correction for multiplicity and considering the effect size threshold, 6 proteins were significantly less abundant in anti-NMDAR seropositive patients compared to seronegative: procathepsin H, heparin cofactor 2, complement factor I, protein AMBP, apolipoprotein A1 and polymeric immunoglobulin receptor. No significant differences in individual protein levels were found in relation to corticosteroid treatment, size of brain MRI lesion or neurocognitive performance.ConclusionsWe show a temporal change in the CSF proteome in HSE patients during the course of the disease. This study provides insight into quantitative and qualitative aspects of the dynamic pathophysiology and pathway activation patterns in HSE and prompts for future studies on the role of apolipoprotein A1 in HSE, which has previously been associated with NMDAR encephalitis.
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| 22. |
- Rystedt, Einar, et al.
(author)
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Validation of a web-based self-administered test for cognitive assessment in a Swedish geriatric setting
- 2024
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 19:2
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Journal article (peer-reviewed)abstract
- Computerized cognitive tests have the potential to cost-effectively detect and monitor cognitive impairments and thereby facilitate treatment for these conditions. However, relatively few of these tests have been validated in a variety of populations. Brain on Track, a self-administered web-based test, has previously been shown to have a good ability to differentiate between healthy individuals and patients with cognitive impairment in Portuguese populations. The objective of this study was to validate the differential ability and evaluate the usability of Brain on Track in a Swedish memory clinic setting. Brain on Track was administered to 30 patients with mild cognitive impairment/mild dementia and 30 healthy controls, all scheduled to perform the test from home after one week and after three months. To evaluate the usability, the patient group was interviewed after completion of the testing phase. Patients scored lower than healthy controls at both the first (median score 42.4 vs 54.1, p<0.001) and the second test (median score 42.3 vs 55.0, p<0.001). The test-retest intra-class correlation was 0.87. A multiple logistic regression model accounting for effects of age, gender and education rendered an ability of Brain on Track to differentiate between the groups with an area under the receiver operation characteristics curve of 0.90 for the first and 0.88 for the second test. In the subjective evaluation, nine patients left positive comments, nine were negative whereas five left mixed comments regarding the test experience. Sixty percent of patients had received help from relatives to log on to the platform. In conclusion, Brain on Track performed well in differentiating healthy controls from patients with cognitive impairment and showed a high test-retest reliability, on par with results from previous studies. However, the substantial proportion of patients needing help to log in could to some extent limit an independent use of the platform.
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| 23. |
- Satizabal, Claudia L., et al.
(author)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Journal article (peer-reviewed)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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| 24. |
- Skog, Erik, et al.
(author)
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An oseltamivir-resistant avian H1N1 influenza A virus can transmit from mallards to chickens similarly to a wild-type strain : implications for the risk of resistance transmission to humans
- 2023
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In: Journal of General Virology. - : Microbiology Society. - 0022-1317 .- 1465-2099. ; 104:4
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Journal article (peer-reviewed)abstract
- The neuraminidase inhibitor (NAI) oseltamivir is stockpiled globally as part of influenza pandemic preparedness. However, oseltamivir carboxylate (OC) resistance develops in avian influenza virus (AIV) infecting mallards exposed to environmental-like OC concentrations, suggesting that environmental resistance is a real concern. Herein we used an in vivo model to investigate if avian influenza H1N1 with the OC-resistant mutation NA-H274Y (51833/H274Y) as compared to the wild-type (wt) strain (51833 /wt) could transmit from mallards, which would potentially be exposed to environmentally contaminated environments, to and between chickens, thus posing a potential zoonotic risk of antiviral-resistant AIV. Regardless of whether the virus had the OC-resistant mutation or not, chickens became infected both through experimental infection, and following exposure to infected mallards. We found similar infection patterns between 51833/wt and 51833/H274Y such that, one chicken inoculated with 51833/wt and three chickens inoculated with 51833/H274Y were AIV positive in oropharyngeal samples more than 2 days consecutively, indicating true infection, and one contact chicken exposed to infected mallards was AIV positive in faecal samples for 3 consecutive days (51833/wt) and another contact chicken for 4 consecutive days (51833/H274Y). Importantly, all positive samples from chickens infected with 51833/H274Y retained the NA-H274Y mutation. However, none of the virus strains established sustained transmission in chickens, likely due to insufficient adaptation to the chicken host. Our results demonstrate that an OC-resistant avian influenza virus can transmit from mallards and replicate in chickens. NA-H274Y does not constitute a barrier to interspecies transmission per se, as the resistant virus did not show reduced replicative capacity compared to the wild-type counterpart. Thus, responsible use of oseltamivir and surveillance for resistance development is warranted to limit the risk of an OC-resistant pandemic strain.
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| 25. |
- Söllvander, Sofia, et al.
(author)
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Increased Number of Plasma B Cells Producing Autoantibodies Against A beta(42) Protofibrils in Alzheimer's Disease
- 2015
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 48:1, s. 63-72
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Journal article (peer-reviewed)abstract
- The Alzheimer's disease (AD)-related peptide amyloid-beta (A beta) has a propensity to aggregate into various assemblies including toxic soluble A beta protofibrils. Several studies have reported the existence of anti-A beta antibodies in humans. However, it is still debated whether levels of anti-A beta antibodies are altered in AD patients compared to healthy individuals. Formation of immune complexes with plasma A beta makes it difficult to reliably measure the concentration of circulating anti-A beta antibodies with certain immunoassays, potentially leading to an underestimation. Here we have investigated anti-A beta antibody production on a cellular level by measuring the amount of anti-A beta antibody producing cells instead of the plasma level of anti-A beta antibodies. To our knowledge, this is the first time the anti-A beta antibody response in plasma has been compared in AD patients and age-matched healthy individuals using the enzyme-linked immunospot (ELISpot) technique. Both AD patients and healthy individuals had low levels of B cells producing antibodies binding A beta(40) monomers, whereas the number of cells producing antibodies toward A beta(42) protofibrils was higher overall and significantly higher in AD compared to healthy controls. This study shows, by an alternative and reliable method, that there is a specific immune response to the toxic A beta protofibrils, which is significantly increased in AD patients.
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