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  • Public defence: 2024-03-19 13:00 Enghoffsalen, Uppsala
    Ostrowska, Bozena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Risk factors for incident heart failure and atrial fibrillation in an elderly population: The role of cardiac conduction and heart rate variability2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Heart failure (HF) and atrial fibrillation (AF) are epidemic diseases, frequently coexisting, sharing risk factors and conferring poor prognosis. Identification of individuals at high risk of HF and AF may enable early treatment and improve the prognosis. Reliable prediction models for daily clinical practice are lacking. Early modification and treatment of risk factors may reduce the incidence of AF and HF. Because atrial structure and function abnormalities increase the risk of AF, ECG indices reflecting atrial pathology may prove useful in predicting AF and HF.

    The main objectives were to evaluate whether:

    • P-wave duration (Pdur) and PR-interval in V1 predicted incident HF and incident AF (Paper I-II)
    • low frequency/high frequency (L-F/H-F) ratio, a marker of autonomic balance, predicted incident HF (Paper IV)
    • combining selected ECG variables or the L-F/H-F ratio with traditional risk factors improved the performance of the traditional HF prediction model (Paper III-IV).

    The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) with 15 years of follow-up was used for all four studies. After applying the exclusion criteria, 836 subjects were evaluated for incident HF (Paper I, III-IV) and 877 subjects for incident AF (Paper II). Cox proportional hazard analysis related ECG-derived variables to incident HF and incident AF. Study III used machine learning to determine which ECG variables correlated to incident HF. C-statistic was used to test whether adding selected ECG variables to traditional HF risk factors improved the performance of the HF prediction model.

    Short Pdur was significantly associated with incident HF (Paper I) and incident AF (Paper II). Of 134 ECG variables, high R-wave amplitude variation (SD Ramp) had the highest predictive value for HF (Paper III). A decreased L-F/H-F ratio significantly predicted HF (Paper IV). Adding eight selected ECG variables (Paper III) and the L-F/H-F ratio (Paper IV) to the traditional risk factors significantly improved HF predictive performance by 11.7% and 3.3%, respectively.

    In conclusion, the ECG may prove useful for predicting incident HF and AF beyond the traditional risk factors. An autonomic imbalance may precede the development of HF.

    List of papers
    1. A short P-wave duration is associated with incident heart failure in the elderly: a 15 years follow-up cohort study
    Open this publication in new window or tab >>A short P-wave duration is associated with incident heart failure in the elderly: a 15 years follow-up cohort study
    2022 (English)In: Journal of Geriatric Cardiology, ISSN 1671-5411, Vol. 19, no 9, p. 643-650Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Early identification of patients at risk of congestive heart failure (HF) may alter their poor prognosis. The aim was therefore to test whether simple electrocardiographic variables, the P-wave and PR-interval, could predict incident HF.

    METHODS: The PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study (1016 individuals all aged 70 years, 50% women) was used to identify predictors of HF. Subjects with prevalent HF, QRS duration z >= 130 ms, atrial tachyarrhythmias, implanted pacemaker/defibrillator, second- and third-degree atrioventricular block or delta waves at baseline were excluded. Cox proportional hazard analysis was used to relate the PR interval, P-wave duration (Pdur) and amplitude (Pamp), measured in lead V1, to incident HF. Adjustment was performed for gender, RR-interval, beta-blocking agents, systolic blood pressure, body mass index and smoking.

    RESULTS: Out of 836 subjects at risk, 107 subjects were diagnosed with HF during a follow-up of 15 years. In the multivariate analysis, there was a strong U-shaped correlation between Pdur in lead V1 and incident HF (P= 0.0001) which was significant for a Pdur < 60 ms [HR = 2.75; 95% CI: 1.87-4.06, at Pdur 40 ms] but not for prolonged Pdur. There was no significant relationship between incident HF and the PR-interval or the Pamp. A Pdur < 60 ms improved discrimination by 3.7% when added to the traditional risk factors including sex, RR-interval, beta-blocking agents, systolic blood pressure, BMI and smoking (P= 0.048).

    CONCLUSIONS: A short Pdur, an easily measured parameter on the ECG, may potentially be a useful marker of future HF, enabling its early detection and prevention, thus improving outcomes.

    Place, publisher, year, edition, pages
    Science Press, 2022
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:uu:diva-490898 (URN)10.11909/j.issn.1671-5411.2022.09.008 (DOI)000890664500002 ()36284675 (PubMedID)
    Available from: 2022-12-19 Created: 2022-12-19 Last updated: 2024-01-09Bibliographically approved
    2. Short P-Wave Duration Is Associated with Incident Atrial Fibrillation: A Registry-Based Cohort Study
    Open this publication in new window or tab >>Short P-Wave Duration Is Associated with Incident Atrial Fibrillation: A Registry-Based Cohort Study
    2022 (English)In: International Heart Journal, ISSN 1349-2365, E-ISSN 1349-3299, Vol. 63, no 4, p. 700-707Article in journal (Refereed) Published
    Abstract [en]

    Atrial fibrillation (AF) is common and increases the risk for stroke and heart failure (HF). The early identification of patients at risk may prevent the development of AF and improve prognosis. This study, therefore, aimed to test the effect of the association between P-wave and PR-interval on the ECG and incident AF. The PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study (1016 individuals all aged 70 years; 50% women) was used to identify whether the ECG variables P-wave duration (Pdur) and PR-duration in lead V1 were related to new-onset AF. Exclusion criteria were prevalent AF, QRS-duration >= 130 milliseconds (msec), atrial tachyarrhythmias and implanted pacemaker/defibrillator. Cox proportional-hazards models were used for analyses. Adjustments were made for gender, RR-interval, beta-blocking agents, systolic blood pressure, body mass index, and smoking. Of 877 subjects at risk, 189 individuals developed AF during a 15-year follow-up. There was a U-shaped relationship between the Pdur and incident AF (P = 0.017) following multiple adjustment. Values below 60 msec were significantly associated with incident AF, with a hazard ratio of 1.55 (95% confidence interval 1.15-2.09) for a Pdur <= 42 msec. There was no significant relationship between incident AF and the PR-interval. A short Pdur derived from the ECG in V1 may be a useful marker for new-onset AF, enabling the early identification of at-risk patients.

    Place, publisher, year, edition, pages
    INT HEART JOURNAL ASSOC, 2022
    Keywords
    Short P-wave as predictor, P-wave in atrial fibrillation, P-wave indices, New-onset atrial fibrillation
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:uu:diva-483749 (URN)10.1536/ihj.21-797 (DOI)000838185800008 ()35831146 (PubMedID)
    Available from: 2022-09-05 Created: 2022-09-05 Last updated: 2024-01-09Bibliographically approved
    3. High variability of the R-wave amplitude predicts incident heart failure in the elderly: a cohort study using machine learning
    Open this publication in new window or tab >>High variability of the R-wave amplitude predicts incident heart failure in the elderly: a cohort study using machine learning
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Aims: Early identification of individuals at risk for heart failure (HF) may improve their poor prognosis. The aim was to test if a prediction model of ECG variables added to traditional risk factors could improve the prediction of incident HF versus traditional risk factors alone.

    Methods and Results: The PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study (1016 individuals aged 70 years) was used for analysis of 23 ECG variables measured in 6 precordial leads. Out of 6 machine learning models used in a training dataset, the one with the best accuracy was used for the testing dataset. 

    During 15 years of follow-up, 107 of 836 included individuals at risk were diagnosed with HF. Adding the 8 best ECG variables, identified by random forest in the training dataset, to traditional risk factors resulted in an improvement of the area under the ROC curve by 11.7% (p=0.0043) compared to the traditional risk factor model alone. A high beat-to-beat variation of the R amplitude (SD Ramp) in V1 was the most powerful predictive ECG variable. A decreased low Frequency/high frequency ratio, a heart rate variability index, was correlated to a high SD Ramp in V1 (p=0.002). 

    Conclusion: Adding ECG variables to traditional cardiovascular risk factors were valuable for prediction of incident HF in an elderly population. The improvement in C statistics by adding the 8 identified ECG variables was quite substantial, which if reproduced in other populations, might be used as a screening tool for HF risk in clinical practice.

     

           

    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:uu:diva-518486 (URN)
    Available from: 2023-12-19 Created: 2023-12-19 Last updated: 2024-01-09
    4. An association between heart rate variability and incident heart failure in an elderly cohort.
    Open this publication in new window or tab >>An association between heart rate variability and incident heart failure in an elderly cohort.
    2024 (English)In: Clinical Cardiology, ISSN 0160-9289, E-ISSN 1932-8737Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Research subject
    Cardiology
    Identifiers
    urn:nbn:se:uu:diva-523878 (URN)10.1002/clc.24241 (DOI)
    Available from: 2024-02-25 Created: 2024-02-25 Last updated: 2024-02-27
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  • Public defence: 2024-03-21 09:00 H:son Holmdahlsalen, Uppsala
    Lenell, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    Traumatic brain injury in elderly patients2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The increase of elderly traumatic brain injury (TBI) patients constitutes a considerable challenge. The aim was therefore to specifically study elderly TBI patients with respect to patient characteristics, neurointensive care (NIC) and outcome, and to identify age specific features, which may be important for selection of patients and optimization of NIC in the elderly. Data from the Uppsala TBI-registry and collected physiological monitoring data from the NIC unit were analysed.

    Between 1996–1997 and 2008–2009, patients ≥60 years had doubled from 16% to 30%. Despite the increase of elderly an overall favorable outcome was maintained at around 75% between the two periods and the elderly showed favorable outcome in slightly more than 50%.

    Analysis of characteristics and outcome between 2008–2010 showed that fall accidents and acute subdural hematoma were more common in the elderly ≥65 years. Admission status and NIC treatment did not differ depending on age, except that a larger proportion of the elderly had surgery. Elderly ≥65 years showed a favorable outcome in 51% compared to 72% in the young.

    Studies of patients ≥60 years treated 2008–2014 showed that high age, multiple injuries, low Glasgow coma motor score on admission and the use of mechanical ventilation were negative prognostic factors.

    Elderly had different secondary insult patterns with a higher percentage of good monitoring time (%GMT) with high cerebral perfusion pressure (CPP), high mean arteria blood pressure (MAP) and high systolic blood pressure (SBP) and less %GMT with high intracranial pressure (ICP), low CPP and low MAP. On the contrary to the young, high %GMT with SBP>180 was associated with favorable outcome in the elderly, indicating that blood pressure probably should be treated differently in the elderly.

    Elderly had worse pressure autoregulation (higher values of PRx) and spent longer time with higher PRx. Elderly also had higher optimal CPP and spent lower %GMT with CPP close to optimal CPP. High PRx correlated with mortality in elderly but pressure autoregulation influenced outcome less in the elderly.

    Overall, the results show that elderly TBI patients differ in many aspects and more studies are warranted to increase knowledge and optimize NIC.

    List of papers
    1. Updated periodic evaluation of standardized neurointensive care shows that it is possible to maintain a high level of favorable outcome even with increasing mean age
    Open this publication in new window or tab >>Updated periodic evaluation of standardized neurointensive care shows that it is possible to maintain a high level of favorable outcome even with increasing mean age
    2015 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 157, no 3, p. 417-425Article in journal (Refereed) Published
    Abstract [en]

    Periodic evaluation of neurointensive care (NIC) is important. There is a risk that quality of daily care declines and there may also be unrecognized changes in patient characteristics and management. The aim of this work was to investigate the characteristics and outcome for traumatic brain injury (TBI) patients in the period 2008-2009 in comparison with 1996-1997 and to some extent also with earlier periods. TBI patients 16-79 years old admitted from 2008 to 2009 were selected for the study. Glasgow Coma Scale Motor score at admission (GCS M), radiology, surgery, and outcome (Glasgow Outcome Extended Scale) were collected from Uppsala Traumatic Brain Injury Register. The study included 148 patients (mean age, 45 years). Patients > 60 years old increased from 16 % 1996-1997 to 30 % 2008-2009 (p < 0.01). The proportion of GCS M 4-6 were similar, 92 vs. 93 % (NS). In 1996-1997 patients, 73 % had diffuse injury (Marshall classification) compared to 77 % for the 2008-2009 period (NS). More patients underwent surgery during 2008-2009 (43 %) compared to 1996-1997 (32 %, p < 0.05). Good recovery increased and mortality decreased substantially from 1980-1981 to 1987-1988 and to 1996-1997, but then the results were unchanged in the 2008-2009 period, with 73 % favorable outcome and 11 % mortality. Mortality increased in GCS M 6-4, from 2.8 % in 1996-1997 to 10 % in 2008-2009 (p < 0.05); most of the patients that died had aggravating factors, e.g., high age, malignancy. A large-proportion favorable outcome was maintained despite that patients > 60 years with poorer prognosis doubled, indicating that the quality of NIC has increased or at least is unchanged. More surgery may have contributed to maintaining the large proportion of favorable outcome. For future improvements, more knowledge about TBI management in the elderly is required.

    Keywords
    Traumatic brain injury, Standardized neurosurgical intensive care, Periodic evaluation, Outcome, Quality register
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-248427 (URN)10.1007/s00701-014-2329-9 (DOI)000350027700009 ()25591801 (PubMedID)
    Available from: 2015-04-10 Created: 2015-03-30 Last updated: 2024-02-01Bibliographically approved
    2. Promising clinical outcome of elderly with TBI after modern neurointensive care
    Open this publication in new window or tab >>Promising clinical outcome of elderly with TBI after modern neurointensive care
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    2016 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 158, no 1, p. 125-133Article in journal (Refereed) Published
    Abstract [en]

    The increasing number of elderly patients with traumatic brain injury (TBI) leads to specific neurointensive care (NIC) challenges. Therefore, elderly subjects with TBI need to be further studied. In this study we evaluated the demographics, management and outcome of elderly TBI patients receiving modern NIC. Patients referred to our NIC unit between 2008 and 2010 were included. Patients were divided in two age groups, elderly (E) a parts per thousand yen65 years and younger (Y) 64-15 years. Parameters studied were the dominant finding on CT scans, neurological motor skills and consciousness, type of monitoring, neurosurgical procedures/treatments and Glasgow Outcome Scale Extended score at 6 months after injury. Sixty-two E (22 %) and 222 Y (78 %) patients were included. Falls were more common in E (81 %) and vehicle accidents were more common in Y patients (37 %). Acute subdural hematoma was significantly more common in E (50 % of cases) compared to Y patients (18 %). Intracranial pressure was monitored in 44 % of E and 57 % of Y patients. Evacuation of significant mass lesions was performed more common in the E group. The NIC mortality was similar in both groups (4-6 %). Favorable outcome was observed in 72 % of Y and 51 % of E patients. At the time of follow-up 25 % of E and 7 % of Y patients had died. The outcome of elderly patients with TBI was significantly worse than in younger patients, as expected. However, as much as 51 % of the elderly patients showed a favorable outcome after NIC. We believe that these results encourage modern NIC in elderly patients with TBI. We need to study how secondary brain injury mechanisms differ in the older patients and to identify specific outcome predictors for elderly patients with TBI.

    Keywords
    Traumatic brain injury, Outcome, Elderly, Neurointensive care, Secondary injury
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-274421 (URN)10.1007/s00701-015-2639-6 (DOI)000366975000016 ()
    Funder
    Swedish Research Council
    Available from: 2016-01-21 Created: 2016-01-21 Last updated: 2024-02-01Bibliographically approved
    3. Clinical outcome and prognostic factors in elderly traumatic brain injury patients receiving neurointensive care
    Open this publication in new window or tab >>Clinical outcome and prognostic factors in elderly traumatic brain injury patients receiving neurointensive care
    2019 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 161, no 6, p. 1243-1254Article in journal (Refereed) Published
    Abstract [en]

    Background: The probability of favorable outcome after traumatic brain injury (TBI) decreases with age. Elderly,≥60 years, are an increasing part of our population. Recent studies have shown an increase of favorable outcome in elderly over time. However,the optimal patient selection and neurointensive care (NIC) treatments may differ in the elderly and the young. The aims of this study were to examine outcome in a larger group of elderly TBI patients receiving NIC and to identify demographic and treatmentrelated prognostic factors.

    Methods: Patients with TBI≥60 years receiving NIC at our department between 2008 and 2014 were included. Demographics, co-morbidity, admission characteristics, and type of treatments were collected. Clinical outcome at around 6 months was assessed. Potential prognostic factors were included in univariate and multivariate regression analysis with favorable outcomeas dependent variable.

    Results: Two hundred twenty patients with mean age 70 years (median 69; range 60–87) were studied. Overall, favorable outcome was 46% (Extended Glasgow Outcome Scale (GOSE) 5–8), unfavorable outcome 27% (GOSE 2–4), and mortality 27% (GOSE 1). Significant independent negative prognostic variables were high age (p< 0.05), multiple injuries (p<0.05),GCSM≤3 on admission (p< 0.05), and mechanical ventilation (p<0.001).

    Conclusions: Overall, the elderly TBI patients> 60 years receiving modern NIC in this study had a fair chance of favorable outcome without large risks for severe deficits and vegetative state, also in patients over 75 years of age. High age, multiple injuries, GCS M≤3 on admission, and mechanical ventilation proved to be independent negative prognostic factors. The results underline that a selected group of elderly with TBI should have access to NIC

    Place, publisher, year, edition, pages
    SPRINGER WIEN, 2019
    Keywords
    Traumatic brain injury, Elderly, Outcome, Quality register, Neurointensive care, Prognostic factors
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-385969 (URN)10.1007/s00701-019-03893-6 (DOI)000468224800028 ()30980243 (PubMedID)
    Available from: 2019-06-18 Created: 2019-06-18 Last updated: 2024-02-01Bibliographically approved
    4. Neurointensive care of traumatic brain injury in the elderly: age-specific secondary insult levels and optimal physiological levels to target need to be defined
    Open this publication in new window or tab >>Neurointensive care of traumatic brain injury in the elderly: age-specific secondary insult levels and optimal physiological levels to target need to be defined
    2022 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 164, no 1, p. 117-128Article in journal (Refereed) Published
    Abstract [en]

    Background

    Elderly patients with traumatic brain injury increase. Current targets and secondary insult definitions during neurointensive care (NIC) are mostly based on younger patients. The aim was therefore to study the occurrence of predefined secondary insults and the impact on outcome in different ages with particular focus on elderly.

    Methods

    Patients admitted to Uppsala 2008–2014 were included. Patient characteristics, NIC management, monitoring data, and outcome were analyzed. The percentage of monitoring time for ICP, CPP, MAP, and SBP above-/below-predefined thresholds was calculated.

    Results

    Five hundred seventy patients were included, 151 elderly ≥ 65 years and 419 younger 16–64 years. Age ≥ 65 had significantly higher percentage of CPP > 100, MAP > 120, and SBP > 180 and age 16–64 had higher percentage of ICP ≥ 20, CPP ≤ 60, and MAP ≤ 80. Age ≥ 65 contributed independently to the different secondary insult patterens. When patients in all ages were analyzed, low percentage of CPP > 100 and SBP > 180, respectively, was significant predictors of favorable outcome and high percentage of ICP ≥ 20, CPP > 100, SBP ≤ 100, and SBP > 180, respectively, was predictors of death. Analysis of age interaction showed that patients ≥ 65 differed and had a higher odds for favorable outcome with large proportion of good monitoring time with SBP > 180.

    Conclusions

    Elderly ≥ 65 have different patterns of secondary insults/physiological variables, which is independently associated to age. The finding that SBP > 180 increased the odds of favorable outcome in the elderly but decreased the odds in younger patients may indicate that blood pressure should be treated differently depending on age.

    Place, publisher, year, edition, pages
    Springer Nature, 2022
    Keywords
    Traumatic brain injury, Elderly, Outcome, Secondary insults, Geriatric neurointensive care, Neurointensive care monitoring
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-464152 (URN)10.1007/s00701-021-05047-z (DOI)000716840500002 ()34757477 (PubMedID)
    Funder
    Uppsala University
    Available from: 2022-01-13 Created: 2022-01-13 Last updated: 2024-02-01Bibliographically approved
    5. Cerebrovascular reactivity (PRx) and optimal cerebral perfusion pressure in elderly with traumatic brain injury
    Open this publication in new window or tab >>Cerebrovascular reactivity (PRx) and optimal cerebral perfusion pressure in elderly with traumatic brain injury
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    2024 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 166, no 1, article id 62Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE: Cerebral perfusion pressure (CPP) guidance by cerebral pressure autoregulation (CPA) status according to PRx (correlation mean arterial blood pressure (MAP) and intracranial pressure (ICP)) and optimal CPP (CPPopt = CPP with lowest PRx) is promising but little is known regarding this approach in elderly. The aim was to analyze PRx and CPPopt in elderly TBI patients.

    METHODS: A total of 129 old (≥ 65 years) and 342 young (16-64 years) patients were studied using monitoring data for MAP and ICP. CPP, PRx, CPPopt, and ΔCPPopt (difference between actual CPP and CPPopt) were calculated. Logistic regression analyses with PRx and ΔCPPopt as explanatory variables for outcome. The combined effects of PRx/CPP and PRx/ΔCPPopt on outcome were visualized as heatmaps.

    RESULTS: The elderly had higher PRx (worse CPA), higher CPPopt, and different temporal patterns. High PRx influenced outcome negatively in the elderly but less so than in younger patients. CPP close to CPPopt correlated to favorable outcome in younger, in contrast to elderly patients. Heatmap interaction analysis of PRx/ΔCPPopt in the elderly showed that the region for favorable outcome was centered around PRx 0 and ranging between both functioning and impaired CPA (PRx range - 0.5-0.5), and the center of ΔCPPopt was - 10 (range - 20-0), while in younger the center of PRx was around - 0.5 and ΔCPPopt closer to zero.

    CONCLUSIONS: The elderly exhibit higher PRx and CPPopt. High PRx influences outcome negatively in the elderly but less than in younger patients. The elderly do not show better outcome when CPP is close to CPPopt in contrast to younger patients.

    Place, publisher, year, edition, pages
    Springer Nature, 2024
    Keywords
    Cerebral autoregulation, Elderly, Neurointensive care monitoring, Optimal cerebral perfusion pressure, Pressure reactivity index, Traumatic brain injury
    National Category
    Neurology
    Research subject
    Neurosurgery
    Identifiers
    urn:nbn:se:uu:diva-522380 (URN)10.1007/s00701-024-05956-9 (DOI)001154580300001 ()38305993 (PubMedID)
    Available from: 2024-02-04 Created: 2024-02-04 Last updated: 2024-03-06Bibliographically approved
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  • Public defence: 2024-03-21 13:15 Sal IV, universitetshuset, Uppsala
    Kaltsouni, Elisavet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Science for Life Laboratory (SciLifeLab.
    Neuroimaging progesterone receptor modulation in patients with premenstrual dysphoric disorder: Is it just in your head?2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Premenstrual dysphoric disorder (PMDD) is a menstrually related mood disorder affecting about 5% of women during their reproductive years. The disorder is cyclic, with the symptomatology namely occurring at the luteal phase of a menstrual cycle, for most ovulatory menstrual cycles and entails a series of mood and physical symptoms. A neural susceptibility to regular hormonal fluctuations is hypothesized as the neuropathophysiological mechanism. While treatment options, such as selective serotonin reuptake inhibitors and hormonal interventions, are available, the neural mechanisms underlying symptom relief remain largely unclear. In this series of studies, a multimodal neuroimaging design was approach was used to reveal the neural correlates of three-month, low-dose selective progesterone receptor modulator (SPRM) treatment in comparison to a placebo. This treatment has been demonstrated to be effective in alleviating psychological symptoms associated with PMDD. Thirty-five women with fulfilling the criteria of a PMDD diagnosis were randomized to treatment with SPRM or placebo, with structural and functional MRI scans conducted before and after randomization. Findings indicated enhanced fronto-cingulate activity during a reactive aggression task in the SPRM treatment group compared to placebo, along with a negative association between aggressive responding and brain activity in the placebo group. Resting state functional connectivity was additionally altered after treatment with SPRM in fronto-visual, temporo-insular, and temporo-cerebellar regions. Additionally, a positive correlation was observed between the reduction in cortisol levels and the decrease in temporo-insular connectivity. No treatment effects were observed on brain structure, including grey and white matter volume, as well as cortical surface architecture. Lastly, White matter microstructure integrity did not differ longitudinally but showed cross-sectional differences. In conclusion, the effects of SPRM treatment were primarily observed in brain function, specifically in terms of enhanced cognitive control processing in the context of reactive aggression and resting state functional connectivity in regions relevant to cognitive and sensorimotor processing, with no significant structural alterations noted. Taken together, these findings confirm that the fluctuations rather than absolute levels of ovarian hormones are primary contributing to premenstrual symptomatology, potentially through hormonal-state dependent functional correlates. 

    List of papers
    1. Brain reactivity during aggressive response in women with premenstrual dysphoric disorder treated with a selective progesterone receptor modulator
    Open this publication in new window or tab >>Brain reactivity during aggressive response in women with premenstrual dysphoric disorder treated with a selective progesterone receptor modulator
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    2021 (English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 46, no 8, p. 1460-1467Article in journal (Refereed) Published
    Abstract [en]

    Premenstrual dysphoric disorder (PMDD) is a psychiatric condition characterized by late luteal phase affective, cognitive, and physical impairment. The disorder causes significant suffering in about 5% of women in their reproductive age. Altered sensitivity of cognitive-affective brain circuits to progesterone and its downstream metabolite allopregnanolone is suggested to underlie PMDD symptomatology. Core mood symptoms include irritability and anger, with aggression being the behavioral outcome of these symptoms. The present study sought to investigate the neural correlates of reactive aggression during the premenstrual phase in women with PMDD, randomized to a selective progesterone receptor modulator (SPRM) or placebo. Self-reports on the Daily Record of Severity of Problems were used to assess PMDD symptoms and gonadal hormone levels were measured by liquid chromatography tandem mass spectrometry. Functional magnetic resonance imaging was performed in 30 women with PMDD, while performing the point subtraction aggression paradigm. Overall, a high SPRM treatment response rate was attained (93%), in comparison with placebo (53.3%). Women with PMDD randomized to SPRM treatment had enhanced brain reactivity in the dorsal anterior cingulate cortex and dorsomedial prefrontal cortex during the aggressive response condition. The fronto-cingulate reactivity during aggressive responses depended on treatment, with a negative relationship between brain reactivity and task-related aggressiveness found in the placebo but not the SPRM group. The findings contribute to define the role of progesterone in PMDD symptomatology, suggesting a beneficial effect of progesterone receptor antagonism, and consequent anovulation, on top-down emotion regulation, i.e., greater fronto-cingulate activity in response to provocation stimuli.

    Place, publisher, year, edition, pages
    Springer NatureSpringer Nature, 2021
    National Category
    Psychiatry Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-454148 (URN)10.1038/s41386-021-01010-9 (DOI)000645584400001 ()33927343 (PubMedID)
    Funder
    Swedish Research Council, 201601439Swedish Research Council, 2020-01801Swedish Research Council, 2015-00495EU, FP7, Seventh Framework Programme, INCA 600398
    Note

    These authors contributed equally: Erika Comasco, Inger Sundström-Poromaa

    Available from: 2021-09-27 Created: 2021-09-27 Last updated: 2024-01-30Bibliographically approved
    2. Grey matter morphology in women with premenstrual dysphoric disorder treated with a selective progesterone receptor modulator.
    Open this publication in new window or tab >>Grey matter morphology in women with premenstrual dysphoric disorder treated with a selective progesterone receptor modulator.
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    2022 (English)In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 65, p. 35-43Article in journal (Refereed) Published
    Abstract [en]

    Premenstrual dysphoric disorder (PMDD) is characterized by severe cyclic mood symptoms emerging in the luteal phase of the menstrual cycle. The variation in progesterone levels and its metabolites during the luteal phase seems critical to the occurrence of PMDD symptoms. Notably, the efficacy of selective progesterone receptor modulator (SPRM) treatment on the mental symptoms of PMDD has been recently demonstrated. In the present study, structural magnetic resonance imaging was used to assess the effects of SPRM treatment, compared with placebo, on grey matter morphology in women with PMDD. In total, 35 women were scanned during the luteal phase, before and after three months of treatment with SPRM or placebo. Symptom severity was assessed using the Daily Record of Severity of Problems (DRSP), while gonadal hormone levels were measured by liquid chromatography-tandem mass spectrometry. Region-of-interest and whole-brain approaches were employed to perform voxel-based morphometry analyses, subcortical volumetric analyses, and surface-based morphometry analyses. No interaction or main effects of treatment and time were observed on grey matter volume and cortical surface measures (cortical thickness, gyrification index, sulcal depth, and fractal dimension). The relationship between change in brain morphology and symptom severity was also explored but no treatment-dependant grey matter structure change was related to symptom severity change. These findings suggest that SPRM treatment does not impart macrostructural changes onto grey matter structure, at least in the short term.

    Place, publisher, year, edition, pages
    Elsevier, 2022
    Keywords
    Brain, Grey matter, Magnetic resonance imaging, Premenstrual dysphoric disorder, Progesterone, Surface-based morphometry, Voxel-based morphometry, Women
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-488093 (URN)10.1016/j.euroneuro.2022.10.002 (DOI)000892055600002 ()36343426 (PubMedID)
    Funder
    Swedish Research Council, 2016-01439Swedish Research Council, 2020-01801Swedish Research Council, 2015-00495Swedish Society of Medicine, SLS-573171Swedish Society of Medicine, SLS-597211Swedish Society of Medicine, SLS-789101The Swedish Brain Foundation, 2020-0255EU, FP7, Seventh Framework Programme, INCA 600398Science for Life Laboratory, SciLifeLab
    Note

    De två sista författarna delar sistaförfattarskapet.

    Available from: 2022-11-09 Created: 2022-11-09 Last updated: 2024-01-30Bibliographically approved
    3. White matter integrity upon progesterone antagonism in individuals with premenstrual dysphoric disorder: a randomized placebo-controlled diffusion tensor imaging study
    Open this publication in new window or tab >>White matter integrity upon progesterone antagonism in individuals with premenstrual dysphoric disorder: a randomized placebo-controlled diffusion tensor imaging study
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Premenstrual dysphoric disorder (PMDD) is a depressive disorder triggered by fluctuations of progesterone and estradiol during the luteal phase of the menstrual cycle. Selective progesterone receptor modulation (SPRM), while exerting an antagonistic effect on progesterone and maintaining the estradiol on moderate levels, has shown beneficial effects on the mental symptoms of PMDD. Progesterone is also known for its neuroprotective effects, while synthetic progestins have been suggested to promote myelination. However, the impact of this treatment on white matter neuroanatomy is unexplored. Diffusion tensor imaging was used to collect data on white matter integrity in patients with PMDD, before and after treatment with ulipristal acetate (an SPRM) or placebo, as part of a double-blind randomized controlled-trial. Tract based spatial statistics were performed to investigate SPRM treatment vs. placebo longitudinal effects on fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) on the whole white matter skeleton. Voxel-wise analyses indicated no change over time in any white matter microstructure metrics in individuals treated with SPRM versus placebo. Improvement in PMDD symptoms did not correlate with changes in white matter microstructure. In secondary, cross-sectional comparisons during treatment, the SPRM group displayed lower FA and higher MD, RD, and AD in several tracts. The main findings suggest that SPRM treatment did not impact white matter microstructure. However, the between-group differences after treatment call for further investigation on the tracts potentially impacted by progesterone antagonism.  

    Keywords
    brain; DTI; fractional anisotropy; ovarian hormones; PMDD; progesterone; white matter
    National Category
    Medical and Health Sciences Neurosciences Radiology, Nuclear Medicine and Medical Imaging Obstetrics, Gynecology and Reproductive Medicine
    Research subject
    Neuroscience; Obstetrics and Gynaecology
    Identifiers
    urn:nbn:se:uu:diva-521576 (URN)
    Available from: 2024-01-25 Created: 2024-01-25 Last updated: 2024-03-13
    4. White matter volume and treatment with selective progesterone receptor modulator in patients with premenstrual dysphoric disorder
    Open this publication in new window or tab >>White matter volume and treatment with selective progesterone receptor modulator in patients with premenstrual dysphoric disorder
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    2024 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, p. 106977-106977, article id 106977Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences Neurosciences Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-521592 (URN)10.1016/j.psyneuen.2024.106977 (DOI)
    Funder
    Swedish Research CouncilSwedish Society of MedicineScience for Life Laboratory, SciLifeLab
    Available from: 2024-01-25 Created: 2024-01-25 Last updated: 2024-02-19
    5. Selective progesterone receptor modulation and brain activity at rest in patients with premenstrual dysphoric disorder
    Open this publication in new window or tab >>Selective progesterone receptor modulation and brain activity at rest in patients with premenstrual dysphoric disorder
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Ovarian hormones have been indicated to impact brain connectivity and mood. However, there is no consistent evidence on hormone-dependent functional connectivity and mental health. Alterations in resting state networks have been suggested as markers of affective disorders, but only preliminary evidence is provided on premenstrual dysphoric disorder, in which symptoms occur upon fluctuations of ovarian hormones. Recently, three-month low-dose selective progesterone receptor modulator (SPRM) administration has been associated with symptom relief and altered task-based brain reactivity during a reactive aggression condition. The present study sought to investigate the effect of this treatment on resting state functional connectivity (rs-FC) in patients with PMDD. Seed-based analyses were conducted, including including seeds from the classic resting state networks along with the functional cluster affected by SPRM treatment. Within previously identified networks related with emotional processing, rs-FC was compared between individuals with PMDD during the symptomatic luteal phase before randomization to treatment or placebo and during the end of the last treatment cycle. Seed-based rs-FC analyses yielded significant treatment by time effects on rs-FC between the left posterior superior temporal gyrus and the right insula cortex, between the posterior cerebellum and the left temporal pole, and between the right lateral visual network and left superior frontal gyrus. Visuo-frontal luteal phase connectivity decreased for the SPRM group and was positively correlated with changes in mood symptom severity in the placebo group. Cerebellar and temporal connectivity increased for the SPRM treatment group, while temporo-insular connectivity decreased and was positively correlated with cortisol levels. These findings indicate that SPRM treatment influenced rs-FC, which could be a relevant mechanism behind symptom alleviation.

    Keywords
    brain; functional connectivity hormones; premenstrual dysphoric disorder; progesterone; resting-state; seed-based; symptoms; women;
    National Category
    Psychiatry Neurosciences Pharmacology and Toxicology Radiology, Nuclear Medicine and Medical Imaging Endocrinology and Diabetes
    Research subject
    Neuroscience; Obstetrics and Gynaecology
    Identifiers
    urn:nbn:se:uu:diva-521575 (URN)
    Available from: 2024-01-25 Created: 2024-01-25 Last updated: 2024-03-13
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  • Public defence: 2024-03-22 09:00 Rudbecksalen, Uppsala
    Petkova, Milena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University.
    Cell-autonomous and paracrine mechanisms underlying Pik3ca-driven vascular malformations2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Vascular malformation is a benign overgrowth of blood or lymphatic vessels leading to life-threatening consequences for affected patients. Activating mutations in the TIE2 receptor cause the majority of venous malformations (VMs), while somatic activating mutations in PIK3CA, leading to the overactivation of the PI3K-AKT pathway, cause both VMs and lymphatic malformations (LMs). Although molecular inhibitors targeting the PI3K-AKT-mTOR pathway, such as rapamycin, have shown beneficial effects, they are not curative. This thesis aimed to explore the endothelial cell-autonomous and paracrine mechanisms underlying Pik3ca-driven pathological vascular growth to identify a rationale for improved and curative therapies for vascular malformations.

    In Paper I, we reported that one of the most common causative mutations, PIK3CAH1047R, gives rise to two distinct LM subtypes known as macrocystic and microcystic LM in humans. Using a transgenic mouse model with temporally controlled LEC-specific activation of Pik3caH1047R, we found that the growth of microcystic LM is dependent on both the upstream pro-lymphangiogenic VEGF-C-VEGFR3 and the downstream AKT-mTOR signalling. Combination treatment targeting both signalling pathways led to effective inhibition of lesion growth in mice, suggesting a novel therapeutic approach for LM patients. In Paper II, we explored further the endothelial cell-autonomous and paracrine mechanisms underlying microcystic LM growth in mice. Using single-cell RNA sequencing, we identified a new immune-interacting subtype of dermal lymphatic capillary endothelial cells, termed iLECs. We showed that in Pik3ca mutant mice, iLECs produce factors that recruit pro-lymphangiogenic VEGF-C-producing macrophages. Macrophage depletion, inhibition of their recruitment, and anti-inflammatory COX-2 treatment resulted in decreased lymphatic growth, indicating a critical role of paracrine signalling between iLECs and immune cells in the pathogenesis of microcystic LM. In Paper III, we described distinct lymphatic vessel responses to oncogenic PI3K activation in different organs. We observed that while lymphatic vessels in the skin form microcystic LM through vessel sprouting, in certain other organs, they form large cysts reminiscent of macrocystic LM. Finally, we used mice with a BEC-specific activation of Pik3caH1047R to compare disease mechanisms in VM to those in LM in Paper II and to focus further on the former in Paper IV.

    List of papers
    1. Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation
    Open this publication in new window or tab >>Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation
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    2020 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 11, no 1, article id 2869Article in journal (Refereed) Published
    Abstract [en]

    Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CA(H1047R) mutation, resulting in constitutive activation of the p110 alpha PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CA(H1047R)-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110 alpha activation determining the LM subtype. In the postnatal vasculature, PIK3CA(H1047R) promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways. Lymphatic malformation (LM) is a debilitating often incurable vascular disease. Using a mouse model of LM driven by a disease-causative PIK3CA mutation, the authors show that vascular growth is dependent on the upstream lymphangiogenic VEGF-C signalling, permitting effective therapeutic intervention.

    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-418954 (URN)10.1038/s41467-020-16496-y (DOI)000541703300002 ()32513927 (PubMedID)
    Funder
    Swedish Cancer Society, CAN 2016/535EU, European Research Council, ERC-2014-CoG-646849Knut and Alice Wallenberg Foundation, 2015.0030Swedish Research Council, 542-2014-3535EU, Horizon 2020, 814316EU, Horizon 2020, 749731
    Note

    Shared first authorship: Ines Martinez-Corral, Yan Zhang.

    Available from: 2020-09-10 Created: 2020-09-10 Last updated: 2024-01-26Bibliographically approved
    2. Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation
    Open this publication in new window or tab >>Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation
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    2023 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 220, no 4, article id e20220741Article in journal (Refereed) Published
    Abstract [en]

    Oncogenic mutations in PIK3CA, encoding p110 alpha-PI3K, are a common cause of venous and lymphatic malformations. Vessel type-specific disease pathogenesis is poorly understood, hampering development of efficient therapies. Here, we reveal a new immune-interacting subtype of Ptx3-positive dermal lymphatic capillary endothelial cells (iLECs) that recruit pro-lymphangiogenic macrophages to promote progressive lymphatic overgrowth. Mouse model of Pik3ca(H1047R)-driven vascular malformations showed that proliferation was induced in both venous and lymphatic ECs but sustained selectively in LECs of advanced lesions. Single-cell transcriptomics identified the iLEC population, residing at lymphatic capillary terminals of normal vasculature, that was expanded in Pik3ca(H1047R) mice. Expression of pro-inflammatory genes, including monocyte/macrophage chemokine Ccl2, in Pik3ca(H1047R)-iLECs was associated with recruitment of VEGF-C-producing macrophages. Macrophage depletion, CCL2 blockade, or anti-inflammatory COX-2 inhibition limited Pik3ca(H1047R)-driven lymphangiogenesis. Thus, targeting the paracrine crosstalk involving iLECs and macrophages provides a new therapeutic opportunity for lymphatic malformations. Identification of iLECs further indicates that peripheral lymphatic vessels not only respond to but also actively orchestrate inflammatory processes.

    Place, publisher, year, edition, pages
    Rockefeller University Press, 2023
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-496585 (URN)10.1084/jem.20220741 (DOI)000919807400001 ()36688917 (PubMedID)
    Funder
    Swedish Research Council, 2018-05973Swedish Research Council, SNIC 2022/23-461Swedish Research Council, SNIC 2022/22-133Swedish Research Council, 2020.0057Knut and Alice Wallenberg Foundation, 2020-0269Knut and Alice Wallenberg Foundation, 2018.0218Swedish Cancer Society, 19 0220 PjSwedish Cancer Society, 19 0219 UsEU, European Research Council, ERC-2014-CoG-646849EU, Horizon 2020, 814316EU, Horizon 2020, ALTF 86-2017Uppsala UniversityGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology
    Available from: 2023-02-17 Created: 2023-02-17 Last updated: 2024-01-26Bibliographically approved
    3. Organ-specific mechanisms of Pik3ca-driven lymphatic malformation
    Open this publication in new window or tab >>Organ-specific mechanisms of Pik3ca-driven lymphatic malformation
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    PI3K, PI3KCA, vascular malformations, lymphatic malformations, H1047R
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:uu:diva-521579 (URN)
    Note

    De två första författarna delar förstaförfattarskapet

    Available from: 2024-01-26 Created: 2024-01-26 Last updated: 2024-01-29Bibliographically approved
    4. Venous-specific autocrine signalling promotes PIK3CA-driven vascular malformations
    Open this publication in new window or tab >>Venous-specific autocrine signalling promotes PIK3CA-driven vascular malformations
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    PI3K, PI3KCA, Venous malformations, H1047R
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-521580 (URN)
    Available from: 2024-01-26 Created: 2024-01-26 Last updated: 2024-01-29Bibliographically approved
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  • Public defence: 2024-03-22 09:15 Lecture hall B21, Uppsala
    Edelbroek, Bart
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology and Immunology.
    Function and Evolution of Small Regulatory RNAs and their Associated Proteins: A Journey from Genome to Proteome2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Organisms throughout the tree of life have evolved distinct ways to regulate gene expression. Some of these processes involve non-coding RNAs (ncRNAs), which are not translated but functional nonetheless. These ncRNAs are of utmost importance, with dysregulation of some causing severe developmental effects or even being lethal.

    In order to get a better fundamental understanding of gene regulation, and the ncRNAs that evolved to regulate gene expression, we study this in Amoebozoa. Members of this taxon vary greatly in lifestyle and organismal complexity. Some are strictly unicellular, free-living, whereas others, such as the social amoeba Dictyostelium discoideum can transition between unicellular and multicellular lifestyles. 

    D. discoideum features a variety of small ncRNAs. Among these are the microRNAs. microRNAs have mostly been studied in plants and animals, where they are believed to have evolved convergently, and hypothesized to have played a role when these taxa evolved multicellular lifestyles. At what point the D. discoideum microRNAs evolved, how they function, and if they are involved in its multicellular lifestyle are fundamental questions addressed in this thesis. 

    Here, we studied the evolution and function of microRNAs in a broad set of species belonging to Amoebozoa. We could identify microRNAs in all studied amoebae, and concluded that they are probably not involved in the evolution of multicellularity. To in detail investigate the evolution of microRNAs, we performed comparative genomics using D. discoideum and the close relative Dictyostelium firmibasis. For this, we sequenced, assembled and annotated the genome of the latter. At this point, our findings suggest that the microRNAs evolved several times in Amoebozoa, although we cannot rule out if they have a deep evolutionary history.

    The Class I RNAs are another type of ncRNAs. These, on the other hand, are only present in the social amoebae. They are hypothesized to regulate the transition from unicellular to multicellular in these species, potentially in a post-transcriptional manner. In order to investigate this, it is essential to understand to what extent the proteome and transcriptome correlate. Hence, we performed paired transcriptomics and proteomics in a time-series during multicellular development. By including a strain in which a specific Class I RNA is knocked out, we have initiated studies of its role during the transition to multicellularity.

    In conclusion, we were able to answer broad evolutionary and functional questions about gene regulation and ncRNAs by studying Amoebozoa from genome to proteome. 

    List of papers
    1. Evolution of microRNAs in Amoebozoa and implications for the origin of multicellularity
    Open this publication in new window or tab >>Evolution of microRNAs in Amoebozoa and implications for the origin of multicellularity
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Evolutionary Biology Microbiology
    Identifiers
    urn:nbn:se:uu:diva-522125 (URN)
    Available from: 2024-02-01 Created: 2024-02-01 Last updated: 2024-02-01
    2. Chromosome-level genome assembly and annotation of the social amoeba Dictyostelium firmibasis  
    Open this publication in new window or tab >>Chromosome-level genome assembly and annotation of the social amoeba Dictyostelium firmibasis  
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Genetics Evolutionary Biology Microbiology
    Identifiers
    urn:nbn:se:uu:diva-522157 (URN)
    Available from: 2024-02-01 Created: 2024-02-01 Last updated: 2024-02-01
    3. Multi-omics analysis of aggregative multicellularity
    Open this publication in new window or tab >>Multi-omics analysis of aggregative multicellularity
    (English)Manuscript (preprint) (Other academic)
    National Category
    Bioinformatics and Systems Biology Developmental Biology
    Identifiers
    urn:nbn:se:uu:diva-522158 (URN)
    Available from: 2024-02-01 Created: 2024-02-01 Last updated: 2024-02-01
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  • Public defence: 2024-03-22 09:15 Polhemssalen, Uppsala
    Lundström, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Structural Chemistry.
    Exploring Reaction Pathways in Li-ion Batteries with Operando Gas Analysis2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The reliance on Li-ion batteries is increasing as we transition from fossil fuels to renewable energy sources. Despite their widespread use, a gap remains in understanding certain processes within these batteries, especially regarding the solid electrolyte interphase (SEI) and the impact of side reactions on Li-ion batteries. A custom-made Online Electrochemical Mass Spectrometry (OEMS) instrument was designed to explore these aspects. The OEMS instrument was validated through the study of gas-evolving reactions in the classic LiCoO2 | Graphite system. In-depth studies focusing on the reaction pathways of ethylene carbonate, the archetype Li-ion battery electrolyte solvent, identified the specific reaction pathways contributing to SEI formation. Moreover, ethylene carbonate’s interaction with residual contaminants like OH from H2O reduction was explored. It was revealed that the integrity of the SEI can be compromised by minor amounts of contaminants, establishing a competitive dynamic at the negative electrode surface between ethylene carbonate and residual contaminants such as H2O and HF. Additionally, the roles of additives like vinylene carbonate and lithium bis(oxolato) borate in SEI formation were explored. Vinylene carbonate was shown to form a layer on the negative electrode, but also scavenge protons and H2O, revealing that it is a multi-functional additive. Lithium bis(oxolato) borate on the other hand formed an SEI layer before H2O reduction, blocking the residual contaminant and ethylene carbonate from reaching the electrode surface. By providing insights into the negative electrode’s interphase and SEI formation through a custom-made OEMS instrument, this research underscores the complexity of reaction pathways and the necessity of considering both major and minor, as well as, primary and secondary reactions for a holistic understanding of Li-ion batteries.

    List of papers
    1. Design and validation of an online partial and total pressure measurement system for Li-ion cells
    Open this publication in new window or tab >>Design and validation of an online partial and total pressure measurement system for Li-ion cells
    2021 (English)In: Journal of Power Sources, ISSN 0378-7753, E-ISSN 1873-2755, Vol. 485, article id 229347Article in journal (Refereed) Published
    Abstract [en]

    Online Electrochemical Mass Spectrometry (OEMS) provides unparalleled access to the details of electrode/electrolyte interfacial reactions in electrochemical systems. Herein, the development and validation of an OEMS system along with detailed calibration protocols and limits of detection sensitivity are showcased. Combined partial and total pressure monitoring provides a clear advantage when detailing major and minor gas reactions as well as when determining unaccounted gases. A classical Li-ion LiCoO2/Graphite full cell is studied during overcharge to 4.9 V vs. Li+/Li at 50 degrees C at an unprecedented level of detail and the results are compared to LiCoO2/LiFePO4 and Graphite/LiFePO4 cells in order to differentiate between gases forming at the anode and cathode. The release of O-2 from LixCoO2 (x < 0.4) during both charge and discharge demonstrates that its degradation is dependent on state of charge 1-x rather than potential. The presented methodology establishes an improved experimental basis for deeper understanding of interfacial reactions in batteries and electrochemical systems alike.

    Place, publisher, year, edition, pages
    ElsevierELSEVIER, 2021
    Keywords
    Li-ion batteries, LiCoO2 decomposition, Gas evolution, Side-reactions, Online electrochemical mass spectrometry
    National Category
    Energy Engineering Inorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-434707 (URN)10.1016/j.jpowsour.2020.229347 (DOI)000607095900004 ()
    Funder
    Knut and Alice Wallenberg Foundation, 2017.0204Swedish Research Council, 2016-04069StandUp
    Available from: 2021-02-22 Created: 2021-02-22 Last updated: 2024-02-02Bibliographically approved
    2. Revisiting the Ethylene Carbonate–Propylene Carbonate Mystery with Operando Characterization
    Open this publication in new window or tab >>Revisiting the Ethylene Carbonate–Propylene Carbonate Mystery with Operando Characterization
    2022 (English)In: Advanced Materials Interfaces, ISSN 2196-7350, Vol. 9, no 8Article in journal (Refereed) Published
    Abstract [en]

    The “ethylene carbonate (EC)–propylene carbonate (PC) mystery” has puzzled electrochemists for decades. Surprisingly, the minor structural difference between PC and EC, a methyl vis-à-vis a proton, prevents PC unlike EC to form a stable solid electrolyte interphase (SEI) on carbon (C), which along with the popularity of PC has impeded the development of Li-ion batteries with many years. Despite several hypotheses, the fundamental reason remains debated largely due to the lack of sufficient experimental evidence. Herein, SEI formed as a result of EC and PC reductions are analyzed by two state-of-the-art operando techniques, online electrochemical mass spectrometry and electrochemical quartz crystal microbalance with dissipation monitoring. Although both EC- and PC-based electrolytes appear to have virtually identical reaction pathways, PC is reduced much more extensively than EC and forms a much thicker SEI. However, while the SEI derived from EC remains on the electrode, PC reduction products redissolve in the electrolyte leaving the bare C electrode behind. The presented study illustrates the complex scheme of competing electro-/chemical reactions behind SEI formation and provides further scientific details needed to eventually form a consensus of the processes governing electrode/electrolyte interphases in Li-ion batteries.

    Place, publisher, year, edition, pages
    John Wiley & SonsWiley, 2022
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-465027 (URN)10.1002/admi.202101258 (DOI)000713107100001 ()
    Funder
    Knut and Alice Wallenberg Foundation, 2017.0204
    Available from: 2022-01-17 Created: 2022-01-17 Last updated: 2024-02-02Bibliographically approved
    3. Unveiling Reaction Pathways of Ethylene Carbonate and Vinylene Carbonate in Li-ion Batteries
    Open this publication in new window or tab >>Unveiling Reaction Pathways of Ethylene Carbonate and Vinylene Carbonate in Li-ion Batteries
    (English)Manuscript (preprint) (Other academic)
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-522072 (URN)
    Available from: 2024-01-31 Created: 2024-01-31 Last updated: 2024-02-14
    4. Direct Operando Observation of Double Layer Charging and Early Solid Electrolyte Interphase Formation in Li-Ion Battery Electrolytes
    Open this publication in new window or tab >>Direct Operando Observation of Double Layer Charging and Early Solid Electrolyte Interphase Formation in Li-Ion Battery Electrolytes
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    2020 (English)In: Journal of Physical Chemistry Letters, ISSN 1948-7185, E-ISSN 1948-7185, Vol. 11, no 10, p. 4119-4123Article in journal (Refereed) Published
    Abstract [en]

    The solid electrolyte interphase (SEI) is the most critical yet least understood component to guarantee stable and safe operation of a Li-ion cell. Herein, the early stages of SEI formation in a typical LiPF6 and organic carbonate-based Li-ion electrolyte are explored by operando surface-enhanced Raman spectroscopy, on-line electrochemical mass spectrometry, and electrochemical quartz crystal microbalance. The electric double layer is directly observed to charge as Li+ solvated by ethylene carbonate (EC) progressively accumulates at the negatively charged electrode surface. Further negative polarization triggers SEI formation, as evidenced by H-2 evolution and electrode mass deposition. Electrolyte impurities, HF and H2O, are reduced early and contribute in a multistep (electro)chemical process to an inorganic SEI layer rich in LiF and Li2CO3. This study is a model example of how a combination of highly surface-sensitive operando characterization techniques offers a step forward to understand interfacial phenomena in Li-ion batteries.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2020
    National Category
    Materials Chemistry Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-417185 (URN)10.1021/acs.jpclett.0c01089 (DOI)000537432500052 ()32354215 (PubMedID)
    Funder
    Knut and Alice Wallenberg Foundation, 2017.0204StandUp
    Available from: 2020-08-27 Created: 2020-08-27 Last updated: 2024-02-02Bibliographically approved
    5. Competing Ethylene Carbonate Reactions on Carbon Electrode in Li-Ion Batteries
    Open this publication in new window or tab >>Competing Ethylene Carbonate Reactions on Carbon Electrode in Li-Ion Batteries
    2023 (English)In: Journal of the Electrochemical Society, ISSN 0013-4651, E-ISSN 1945-7111, Vol. 170, no 4, article id 040516Article in journal (Refereed) Published
    Abstract [en]

    Ethylene carbonate (EC) is the archetype solvent in Li-ion batteries. Still, questions remain regarding the numerous possible reaction pathways of EC. Although the reaction pathway involving direct EC reduction and SEI formation is most commonly discussed, EC ring-opening is often observed, but seldomly addressed, especially with respect to SEI formation. By applying Online Electrochemical Mass Spectrometry, the EC ring-opening reaction on carbon is found to start already at similar to 2.5 V vs Li+/Li as initiated by oxygenic carbon surface groups. Later, OH- generated from H2O reduction reaction at similar to 1.6 V further propagates EC to ring-open. The EC reduction reaction occurs <0.9 V but is suppressed depending on the extent of EC ring-opening at higher potentials. Electrode/electrolyte impurities and handling conditions are found to have a significant influence on both processes. In conclusion, SEI formation is shown to be governed by several kinetically competing reaction pathways whereby EC ring-opening can play a significant role.

    Place, publisher, year, edition, pages
    Electrochemical Society, 2023
    National Category
    Inorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-502503 (URN)10.1149/1945-7111/accb6e (DOI)000974236800001 ()
    Funder
    Knut and Alice Wallenberg Foundation, 2017.0204Swedish Foundation for Strategic Research, FFL18-0269StandUp
    Available from: 2023-05-29 Created: 2023-05-29 Last updated: 2024-02-02Bibliographically approved
    6. Elucidating the reduction mechanism of Lithium bis(oxalato)borate
    Open this publication in new window or tab >>Elucidating the reduction mechanism of Lithium bis(oxalato)borate
    (English)Manuscript (preprint) (Other academic)
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-522074 (URN)
    Available from: 2024-01-31 Created: 2024-01-31 Last updated: 2024-02-02
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  • Public defence: 2024-03-22 09:15 room B42, Uppsala
    Nilsson Broberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Metabolite Profiling of Drugs using Mass Spectrometry: Identification of analytical targets for doping control and improvements of the metabolite search process2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Doping is defined as the use of prohibited substances or methods by the World Anti-Doping Agency and the aim with doping control analysis is to detect the use of these illicit substances or methods. Substances that are prohibited in human or equine sports have either a positive or negative impact on the performance. Since administered drugs generally are metabolized to a varying degree and thereby not only excreted in their original form, their metabolite profiles are of high interest because drug metabolites may be present in the body for a longer time than the administered drug itself. Thereby detection of metabolites can improve the window of detection. Unfortunately, the metabolite profiles of non-approved drugs that are mainly available on the Internet, such as Selective Androgen Receptor Modulators (SARMs) are often unknown. 

    This thesis consists of four papers that all encompass drug metabolite profiling either in vivo, in vitro or in a combination, utilizing separation with liquid chromatography and detection with high resolution mass spectrometry. In paper I and II, the equine in vivo metabolite profiles of the two SARMs ACP-105 and LGD-3303 were investigated and the results showed that using drug metabolites as analytical targets can prolong the detection time. For ACP-105, the in vivo metabolite profile was compared with different incubation models such as liver microsomes, S9 fractions and the fungus Cunninghamella elegans. The in vivo and in vitro metabolite profiles showed an interesting overlap for several metabolites, demonstrating the importance and usefulness for in vitro methods in doping control, especially since microsome incubates are allowed as reference material. An optimization of microsome incubation conditions utilizing experimental design was presented in paper III and IV, showing that the optimized conditions greatly impacted the yield of drug metabolites, but also that the optimal conditions are substance dependent. In paper III, a multivariate data analysis search tool utilizing OPLS-DA was presented, which greatly simplified the in vitro drug metabolite identification process of ACP-105 and the results showed relevance in comparison with human in vivo metabolites.

    In conclusion, several new analytical targets with improved detectability for equine and human doping control have been presented, where the drug metabolite profile showed to be of great importance. All together, these new analytical targets, the optimized microsome incubation conditions for improved metabolite yield and the search tool that aids the metabolite investigation through multivariate data analysis, have made a positive contribution to the doping control area.

    List of papers
    1. Investigation of Equine In Vivo and In Vitro Derived Metabolites of the Selective Androgen Receptor Modulator (SARM) ACP-105 for Improved Doping Control
    Open this publication in new window or tab >>Investigation of Equine In Vivo and In Vitro Derived Metabolites of the Selective Androgen Receptor Modulator (SARM) ACP-105 for Improved Doping Control
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    2021 (English)In: Metabolites, ISSN 2218-1989, E-ISSN 2218-1989, Vol. 11, no 2, article id 85Article in journal (Refereed) Published
    Abstract [en]

    Selective Androgen Receptor Modulators (SARMs) have anabolic properties but less adverse effects than anabolic androgenic steroids. They are prohibited in both equine and human sports and there have been several cases of SARMs findings reported over the last few years. The aim of this study was to investigate the metabolite profile of the SARM ACP-105 (2-chloro-4-[(3-endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]-3-methylbenzonitrile) in order to find analytical targets for doping control. Oral administration of ACP-105 was performed in horses, where blood and urine samples were collected over a time period of 96 h. The in vivo samples were compared with five in vitro incubation models encompassing Cunninghamella elegans, microsomes and S9 fractions of both human and equine origin. The analyses were performed using ultra-high performance liquid chromatography coupled to high resolution Q Exactive(TM) Orbitrap(TM) mass spectrometry (UHPLC-HRMS). A total of 21 metabolites were tentatively identified from the in vivo experiments, of which several novel glucuronides were detected in plasma and urine. In hydrolyzed urine, hydroxylated metabolites dominated. The in vitro models yielded several biotransformation products, including a number of monohydroxylated metabolites matching the in vivo results. The suggested analytical target for equine doping control in plasma is a dihydroxylated metabolite with a net loss of two hydrogens. In urine, the suggested targets are two monohydroxylated metabolites after hydrolysis with beta-glucuronidase, selected both due to prolongation of the detection time and the availability of reference material from the in vitro models.

    Place, publisher, year, edition, pages
    MDPIMDPI, 2021
    Keywords
    SARM, Selective Androgen Receptor Modulator, ACP-105, mass spectrometry, doping, horse, metabolites, microsomes, Cunninghamella elegans
    National Category
    Biochemistry and Molecular Biology Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-440429 (URN)10.3390/metabo11020085 (DOI)000622773100001 ()33535528 (PubMedID)
    Available from: 2021-04-21 Created: 2021-04-21 Last updated: 2024-02-05Bibliographically approved
    2. Equine in vivo metabolite profiling of the selective androgen receptor modulator LGD-3303 for doping control
    Open this publication in new window or tab >>Equine in vivo metabolite profiling of the selective androgen receptor modulator LGD-3303 for doping control
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    2023 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 233, article id 115468Article in journal (Refereed) Published
    Abstract [en]

    LGD-3303 is a Selective Androgen Receptor Modulator (SARM) that is prohibited in both equine and human sports due to its anabolic properties. The aim of this study was to investigate the equine in vivo metabolite profile of LGD-3303 and identify drug metabolites that can be suitable as new and improved analytical targets for equine doping control. This was performed by an oral administration of 0.05 mg.kg(-1) LGD-3303 to horses, where blood and urine samples were collected up to 96 h after administration. The in vivo samples consisting of plasma, urine and hydrolyzed urine were analyzed utilizing ultra-high performance liquid chromatography hyphenated to a Q Exactive (TM) Orbitrap (TM) high resolution mass spectrometer with a heated electrospray ionization source. A total of eight metabolites of LGD-3303 were tentatively identified, including one carboxylated and several hydroxylated metabolites in combination with glucuronic acid conjugates. A monohydroxylated metabolite is suggested as an analytical target for doping control analysis of plasma and urine after hydrolysis with beta-glucuronidase, due to the high intensity and prolonged detection time in comparison to parent LGD-3303.

    Place, publisher, year, edition, pages
    Elsevier, 2023
    Keywords
    Mass spectrometry, Selective androgen receptor modulator, LGD-3303, Doping control, Metabolites, Equine
    National Category
    Analytical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-507451 (URN)10.1016/j.jpba.2023.115468 (DOI)001008240000001 ()37224728 (PubMedID)
    Available from: 2023-07-07 Created: 2023-07-07 Last updated: 2024-02-05Bibliographically approved
    3. A multivariate data analysis approach for the investigation of in vitro derived metabolites of ACP-105 in comparison with human in vivo metabolites
    Open this publication in new window or tab >>A multivariate data analysis approach for the investigation of in vitro derived metabolites of ACP-105 in comparison with human in vivo metabolites
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    2023 (English)In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 1231, article id 123927Article in journal (Refereed) Published
    Abstract [en]

    Selective androgen receptor modulators (SARMs) such as ACP-105 are prohibited in sports due to their anabolic properties. ACP-105 has in previous equine studies shown to undergo extensive metabolism, which makes its metabolite profile important to investigate in humans, since the metabolism is unknown in this species. The aims of the study were to systematically optimize in vitro microsome incubations for improved metabolite yield and to utilize a multivariate data analysis (MVDA) approach to aid the metabolite discovery. Microsomes together with S9 fractions were used at optimal conditions, both with and without phase II additives. Furthermore, the relevance of the in vitro derived metabolites was evaluated as analytical targets in doping control by comparison with results from a human post-administration urine sample collected after a single dose of 100 µg ACP-105. All samples were analyzed with liquid chromatography - Orbitrap mass spectrometry.

    The use of the systematical optimization and MVDA greatly simplified the search and a total of 18 in vitro metabolites were tentatively identified. The yield of the two main monohydroxylated isomers increased by 24 and 10 times, respectively. In the human urine sample, a total of seven metabolites of ACP-105, formed by a combination of hydroxylations and glucuronic acid conjugations, were tentatively identified. The main metabolites were two monohydroxylated forms that are suggested as analytical targets for human doping control after hydrolysis. All the in vivo metabolites could be detected with the MVDA approach on the in vitro models, demonstrating its usefulness for prediction of the in vivo metabolite profile.

    Place, publisher, year, edition, pages
    Elsevier, 2023
    Keywords
    ACP-105, Doping control, MVDA, Metabolites in vivo and in vitro, Microsomes, UHPLC-HRMS
    National Category
    Analytical Chemistry Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-517780 (URN)10.1016/j.jchromb.2023.123927 (DOI)001112393600001 ()37972465 (PubMedID)
    Available from: 2023-12-12 Created: 2023-12-12 Last updated: 2024-02-05Bibliographically approved
    4. Optimization of In Vitro Microsome Incubations for Improved Drug Metabolite Yield Utilizing Experimental Design
    Open this publication in new window or tab >>Optimization of In Vitro Microsome Incubations for Improved Drug Metabolite Yield Utilizing Experimental Design
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Analytical Chemistry Pharmaceutical Sciences
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-521780 (URN)
    Available from: 2024-01-31 Created: 2024-01-31 Last updated: 2024-02-05
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  • Public defence: 2024-03-22 13:00 room A1:107a, Uppsala
    Wang, Mengqi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Advanced molecular tools for diagnostic analyses of RNA and antibodies in situ and in solution2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Advanced molecular diagnostics uses in vitro biological assays to detect nucleic acids or proteins even in low concentrations across samples, allowing for the identification of biomarkers, monitoring the course of the disease over time, and selection of appropriate therapy. In this thesis, I focus on development and early applications of several molecular tools of expected value in research, and eventually also clinically. 

    In papers I and II, proximity extension assay (PEA) was for the first time modified to measure specific antibody responses, rather than protein levels as in the standard PEA. We call the method AbPEA and the technique was used to sensitively measure antibody responses to the spike protein or the nucleocapsid of SARS-CoV-2. We demonstrated that AbPEA has high specificity, sensitivity, and broad dynamic range, along with multiplexing potential, offering performance similar to that of other methods for antibody measurements. We demonstrated utilization of blood and saliva samples in paper I and paper II, respectively, which further establish that our approach has great potential for large-scale screening and biobanking. 

    In paper III, we aimed to investigate how the protein composition of extracellular vesicles (EVs) differed among blood samples collected from healthy individual or ones with either mild or severe COVID-19. Proximity barcoding assay was applied to obtain a comprehensive overview of the protein composition of large numbers of individual EVs, demonstrating interesting differences. 

    In paper IV, we enhanced padlock-RCA-based RNA genotyping in situ by using another newly developed technology for highly selective detection of DNA or RNA sequence variants, referred to as super RCA (sRCA). Our analysis showed that this approach can improve the selectivity for sequence variants during in situ detection of mutant or wild-type transcripts, and the signals representing superRCA reaction products are prominent and easily distinguished from any background.

    List of papers
    1. Detection of SARS-CoV-2 antibodies in serum and dried blood spot samples of vaccinated individuals using a sensitive homogeneous proximity extension assay
    Open this publication in new window or tab >>Detection of SARS-CoV-2 antibodies in serum and dried blood spot samples of vaccinated individuals using a sensitive homogeneous proximity extension assay
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    2022 (English)In: New Biotechnology, ISSN 1871-6784, E-ISSN 1876-4347, Vol. 72, p. 139-148Article in journal (Refereed) Published
    Abstract [en]

    A homogeneous PCR-based assay for sensitive and specific detection of antibodies in serum or dried blood spots (DBS) is presented and the method is used to monitor individuals infected with or vaccinated against SARS-CoV-2. Detection probes were prepared by conjugating the recombinant spike protein subunit 1 (S1), containing the receptor binding domain (RBD) of SARS-CoV-2, to each of a pair of specific oligonucleotides. The same was done for the nucleocapsid protein (NP). Upon incubation with serum or DBS samples, the bi- or multivalency of the antibodies (IgG, IgA or IgM) brings pairs of viral proteins with their conjugated oligonucleotides in proximity, allowing the antibodies to be detected by a modified proximity extension assay (PEA). Anti-S1 and anti-NP antibodies could be detected simultaneously from one incubation reaction. This Antibody PEA (AbPEA) test uses only 1 µl of neat or up to 100,000-fold diluted serum or one ø1.2 mm disc cut from a DBS. All 100 investigated sera and 21 DBS collected prior to the COVID-19 outbreak were negative, demonstrating a 100% specificity. The area under the curve, as evaluated by Receiver Operating Characteristic (ROC) analysis reached 0.998 (95%CI: 0.993–1) for samples taken from 11 days after symptoms onset. The kinetics of antibody responses were monitored after a first and second vaccination using serially collected DBS from 14 individuals. AbPEA offers highly specific and sensitive solution-phase antibody detection without requirement for secondary antibodies, no elution step when using DBS sample in a simple procedure that lends itself to multiplex survey of antibody responses.

    Place, publisher, year, edition, pages
    Elsevier, 2022
    Keywords
    Homogenous serological assay, PCR-based antibody detection, SARS-CoV-2 antibody, Proximity extension assay, Finger -prick dried blood spot, Multiplex immunoassay
    National Category
    Biochemistry and Molecular Biology Infectious Medicine Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-492677 (URN)10.1016/j.nbt.2022.11.004 (DOI)000896515300004 ()36423830 (PubMedID)
    Funder
    Science for Life Laboratory, SciLifeLabKnut and Alice Wallenberg Foundation, 2020.0182Swedish Foundation for Strategic Research, SB16-0046Swedish Research Council, 2020-02258
    Available from: 2023-01-10 Created: 2023-01-10 Last updated: 2024-02-01Bibliographically approved
    2. Monitoring SARS-CoV-2 IgA, IgM and IgG antibodies in blood and saliva samples using antibody proximity extension assays (AbPEA)
    Open this publication in new window or tab >>Monitoring SARS-CoV-2 IgA, IgM and IgG antibodies in blood and saliva samples using antibody proximity extension assays (AbPEA)
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    Antibody proximity extension assay, antibody isotypes, SARS-CoV-2 antibody, vaccination
    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:uu:diva-522099 (URN)
    Available from: 2024-01-31 Created: 2024-01-31 Last updated: 2024-02-01
    3. Surface protein profiles of extracellular vesicles reveal SARS-CoV-2 infection
    Open this publication in new window or tab >>Surface protein profiles of extracellular vesicles reveal SARS-CoV-2 infection
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    Proximity barcoding assay, Extracellular vesicles, Surface proteins
    National Category
    Infectious Medicine Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-521787 (URN)
    Available from: 2024-01-28 Created: 2024-01-28 Last updated: 2024-02-01
    4. Highly selective in situ detection of mutant transcripts with gap-fill padlock probes and superRCA
    Open this publication in new window or tab >>Highly selective in situ detection of mutant transcripts with gap-fill padlock probes and superRCA
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    In situ superRCA, gap-fill padlock probes, mutant transcript, cancer diagnostics
    National Category
    Medical Biotechnology
    Identifiers
    urn:nbn:se:uu:diva-521978 (URN)
    Available from: 2024-01-30 Created: 2024-01-30 Last updated: 2024-02-01
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  • Public defence: 2024-03-22 13:00 Campus Gotland, E 22, Visby
    Eiríksdóttir, Lovísa
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies. Uppsala University.
    Being at home in business education: ... with sustainability2024Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This inquiry is about business education. At first, the intention was that it would be about sustainability in business education, but the engagement with questions of sustainability left the idea of business with deep wounds that opened up for new questions of how to take care of them.

    With post-qualitative inquiry I embark on a journey, along with educators working at Stockholm School of Economics, Copenhagen Business School and Hanken School of Economics in Helsinki. These business schools have committed to be in leadership of sustainability education through PRME (Principles of Responsible Management Education). Subsequently, we together reflect on possible ways to work with business and sustainability, simultaneously, in education.

    One critical discovery in this (re)search is that most of the business educators, including myself, were educating students for something we did not want to be part of, once sustainability became a frame of mind. In thinking with sustainability, we got reminded of all the darkness of our common world through exploitation, inequity and inequality. What does it mean to educate others for something you do not what to be part of?

    Through reading the work of Hanna Arendt, in particular her notions of evil, thinking and love, I use essayistic writing and poetic inquiry to inspire for ways in which business education can co-exist with sustainability. In other words, to search for possibilities where we can educate into a common world. I argue that active attention towards the practice of thinking will help us connect differently through our education.

    This different connection I ally with a homecoming process with business education that requires an ontology of immanence; a one-world-ontology, where we become aware of our earth-bound relational existence and consequently where it becomes impossible to educate as something we fundamentally are not.

    This thesis’ aim and its contribution to the field of business studies is to lay bare and consider dangerous questions about business and its response-ability to serious sustainability troubles. Education might be the only place where those questions can thrive without the anxiety of needing to know in advance what the alternative should be.

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  • Public defence: 2024-03-22 13:15 Sal IX, Uppsala
    Lillo Cea, Pablo Antonio
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    The World-Class Ordination: A Field Theory Approach to the Study of Global University Rankings2024Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Using Pierre Bourdieu’s field theory, this thesis explores the idea of a “world-class university” by analysing the narratives and dynamics that shape this classification in the context of global university rankings. It uses a combination of methods, including historical studies, bibliometrics, multiple correspondence analysis, and social network analysis to examine the socio-historical factors determining world-class status in higher education.

    The research reinterprets the rise and evolution of global university rankings, framing it as a process of field formation. Influential entities like the IREG Observatory and the Center for World-Class Universities have been instrumental in fostering a global discourse that encourages competition among higher education institutions, leading to the establishment of a worldwide system for evaluating academic excellence.

    A comparative analysis of institutions, nations, and regions based on ranking results over two decades spotlights the enduring dominance of U.S. and U.K. institutions amidst the rising presence of Chinese. Focusing on 2022 data from the Academic Ranking of World Universities, QS World University Ranking, and Times Higher Education World University Ranking using Multiple Correspondence Analysis. It finds that prestige, heavily influenced by private reputation surveys, outweighs performance or internationalisation metrics in these rankings. The analysis also reveals a contrast between international recruitment and a domestic orientation, with English-speaking institutions attracting more international students and faculty. A dichotomy in scientific recognition emerges, opposing older institutions with award-winning alumni and staff to younger universities excelling in citations per faculty. Euclidean clustering supports these findings, identifying distinct groups of institutions, such as domestically focused Asian institutions and well-rounded Anglo-Saxon universities.

    Lastly, the thesis examines patterns of academic collaboration using social network analysis, with a focus on Swedish, English, and German higher education institutions. It observes a shift in partnerships from American to Asian counterparts, indicating Asia’s ascending role in the global academic landscape and reflecting changes in global university rankings. Overall, this study enhances our comprehension of higher education from a global perspective, uncovering the pervasive dominance of the Anglo-Saxon educational model in university evaluations, where the quantification of reputation is misrecognised as academic excellence.

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    UUThesis_P-Lillo-Cea-2024
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  • Public defence: 2024-03-25 09:00 lecture room Sonja Lyttkens, Uppsala
    Sánchez Martín, Darío
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Nanotechnology and Functional Materials.
    Visual and magnetic detection of antimicrobial resistance genes using nanoparticles and isothermal amplification2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Antibiotic resistance is becoming an increasing concern, necessitating new ways to diagnose and treat it rapidly and accurately. One proposed solution is the use of nucleic acid amplification tests, capable of detecting resistance in just a few hours, as opposed to the several days that traditional testing methods may require. One concept for such a test involves the volume-amplified magnetic nanobead detection assay (VAM-NDA), which combines rolling circle amplification (RCA), an isothermal amplification method, with magnetic nanoparticles (MNPs) for the detection of the RCA products.

    In this thesis, improvements have been made to the VAM-NDA. Coupling of RCA products with microparticles allowed a greater hydrodynamic increase of the MNPs when bound to these products, facilitating the detection of shorter products. Moreover, circle-to-circle amplification (C2CA) was performed, a technique comprising two RCA reactions, increasing the sensitivity of the assay and leading to a 1 attomole limit of detection. 

    Optimization of several reaction parameters has allowed for increased sensitivity. Of highest relevance are the changes made to the length of padlock probes, oligonucleotides used for target recognition. These changes resulted in faster amplification. Equally important is the work conducted on phi29 DNA polymerase. Different manufacturers and mutants of this enzyme were tested, resulting in an improved and faster amplification. However, a previously undiscovered feature of this enzyme was also investigated, where phi29 amplification is competitively inhibited by the presence of ssDNA oligonucleotides, regardless of whether digestion of those is possible or not.

    Finally, a novel detection method for RCA products was developed, where nanoparticles were made to aggregate with the DNA products, resulting in aggregates visible to the naked eye. This method was further optimized, and integrated with C2CA, as well as substituting MNPs for coloured polystyrene nanoparticles. The result is a fast assay that can detect down to 100 zeptomoles of target DNA visually, in less than two hours. The use of coloured nanoparticles also allowed multiplexing using two sets of nanoparticles with different colours, and two targets were detected in a single sample.

    In conclusion, this thesis brings a DNA detection method one step closer to its use in the identification of antimicrobial resistance. The improvements to VAM-NDA and magnetic detection, advances on padlock probe design, the discovery of a novel behaviour of phi29 DNA polymerase, and the potential for naked-eye detection and multiplexing are of high relevance for future basic and translational research.

    List of papers
    1. Evaluating the performance of a magnetic nanoparticle-based detection method using circle-to-circle amplification
    Open this publication in new window or tab >>Evaluating the performance of a magnetic nanoparticle-based detection method using circle-to-circle amplification
    2021 (English)In: Biosensors, ISSN 2079-6374, Vol. 11, no 6, article id 173Article in journal (Refereed) Published
    Abstract [en]

    This work explores several issues of importance for the development of a diagnostic method based on circle-to-circle amplification (C2CA) and oligonucleotide-functionalized magnetic nanoparticles. Firstly, the performance of the detection method was evaluated in terms of sensitivity and speed. Synthetic target sequences for Newcastle disease virus and Salmonella were used as model sequences. The sensitivity of the C2CA assay resulted in detection of 1 amol of starting DNA target with a total amplification time of 40 min for both target sequences. Secondly, the functionalization of the nanoparticles was evaluated in terms of robustness and stability. The functionalization was shown to be very robust, and the stability test showed that 92% of the oligos were still attached on the particle surface after three months of storage at 4 degrees C. Altogether, the results obtained in this study provide a strong foundation for the development of a quick and sensitive diagnostic assay.

    Place, publisher, year, edition, pages
    MDPI, 2021
    National Category
    Nano Technology
    Research subject
    Engineering Science with specialization in Nanotechnology and Functional Materials
    Identifiers
    urn:nbn:se:uu:diva-445225 (URN)10.3390/bios11060173 (DOI)000665581100001 ()34071179 (PubMedID)
    Funder
    Swedish Research Council Formas, 221-2014-574Swedish Foundation for Strategic Research Stiftelsen Olle Engkvist Byggmästare, 194-0644
    Available from: 2021-06-11 Created: 2021-06-11 Last updated: 2024-02-01Bibliographically approved
    2. Formation of Visible Aggregates between Rolling Circle Amplification Products and Magnetic Nanoparticles as a Strategy for Point-of-Care Diagnostics
    Open this publication in new window or tab >>Formation of Visible Aggregates between Rolling Circle Amplification Products and Magnetic Nanoparticles as a Strategy for Point-of-Care Diagnostics
    2021 (English)In: ACS Omega, E-ISSN 2470-1343, Vol. 6, no 48, p. 32970-32976Article in journal (Refereed) Published
    Abstract [en]

    Visual detection of rolling circle amplification products (RCPs) has been achieved by specific aggregation with magnetic nanoparticles. The method presented here reliably generates aggregates in 1.5 h; these are visible to the naked eye in samples containing at least 0.4 fmol of RCPs. In addition, alternate current susceptometry and absorbance spectroscopy have also been used to quantify the amplified products. The specificity of the detection method was tested, and no non-specific aggregation was detected in samples containing up to 20 fmol of non-complementary amplified DNA. This method is a versatile tool for detecting pathogenic DNA in point-of-care diagnostics, with no readout equipment required. However, chips and automated assays can be used in conjugation with the developed method since detection and quantification can be achieved by commercially available readout instruments.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS)American Chemical Society (ACS), 2021
    National Category
    Nano Technology
    Research subject
    Engineering Science with specialization in Nanotechnology and Functional Materials; Engineering Science with specialization in Nanotechnology and Functional Materials
    Identifiers
    urn:nbn:se:uu:diva-461606 (URN)10.1021/acsomega.1c05047 (DOI)000749695800058 ()34901648 (PubMedID)
    Funder
    Swedish Research Council Formas, 221-2014-574Swedish Foundation for Strategic Research , FLU-IDOlle Engkvists stiftelse, 1940644
    Available from: 2021-12-16 Created: 2021-12-16 Last updated: 2024-02-01Bibliographically approved
    3. Naked-eye detection of antibiotic resistance gene sul1 based on aggregation of magnetic nanoparticles and DNA amplification products
    Open this publication in new window or tab >>Naked-eye detection of antibiotic resistance gene sul1 based on aggregation of magnetic nanoparticles and DNA amplification products
    2022 (English)In: Biosensors and Bioelectronics: X, ISSN 2590-1370, Vol. 12, article id 100277Article in journal (Refereed) Published
    Abstract [en]

    The continued spread of antimicrobial resistance is a global problem. In fact, the WHO has declared antimicrobial resistance one of the top 10 global public health threats facing humanity. Molecular methods offer a faster means of characterizing resistant strains than phenotypic drug susceptibility testing. We have developed a molecular detection method that generates visible aggregates from DNA amplified products and functionalized magnetic nanoparticles. The amplification and detection procedure take less than 2 h. In this study we also investigated the factors behind the aggregation and confirmed that the size of the padlock probe is a relevant parameter for the amplification efficiency. We compared a 92 and a 69 nt long padlock probe and found the latter to perform over 4 times better than the 92 nt padlock probe. This effect was related to a higher quantity of amplification products produced by the shorter padlock probe. Consequently, the quantity of amplified DNA products affects the aggregation in a positive way, and thanks to it, a better assay sensitivity was achieved. Finally, using our developed method, we could detect as little as 1 amol of the antibiotic-resistance gene sul1 from a sample containing a multiresistance plasmid. We were also able to quantify the amount of plasmid DNA through absorbance spectroscopy and AC susceptometry. The presented results form the foundation of future development of an ultrasensitive and cheap detection approach that could be used in point of care settings.

    Place, publisher, year, edition, pages
    Elsevier, 2022
    National Category
    Nano Technology
    Research subject
    Engineering Science with specialization in Nanotechnology and Functional Materials
    Identifiers
    urn:nbn:se:uu:diva-488041 (URN)10.1016/j.biosx.2022.100277 (DOI)
    Available from: 2022-11-08 Created: 2022-11-08 Last updated: 2024-02-01Bibliographically approved
    4. Rolling Circle Amplification on a Bead: Improving the Detection Time for a Magnetic Bioassay
    Open this publication in new window or tab >>Rolling Circle Amplification on a Bead: Improving the Detection Time for a Magnetic Bioassay
    2023 (English)In: ACS Omega, E-ISSN 2470-1343, Vol. 8, no 4, p. 4391-4397Article in journal (Refereed) Published
    Abstract [en]

    Detection of pathogens has become increasingly important, especially in the face of outbreaks and epidemics all over the world. Nucleic acid detection techniques provide a solid base to detect and identify pathogens. In recent years, magnetic sensors and magnetic labels have become of more interest due to their simplicity of use, low cost, and versatility. In this work, we have used the isothermal DNA amplification technique of rolling circle amplification (RCA) in combination with oligo-functionalized magnetic nanoparticles. Detection of RCA products takes place through specific binding between magnetic nanoparticles and RCA products. Upon binding, the relaxation frequency of the nanoparticle changes. This change was measured using an AC susceptometer. We showcase that the RCA time can be reduced for a quicker assay when performing the RCA on the surface of micrometer-sized beads, which consequently increases the hydrodynamic volume of the RCA products. This, in turn, increases the Brownian relaxation frequency shift of the nanoparticles upon binding. We performed optimization work to determine the ideal quantity of micrometer-sized particles, oligo-functionalized nanoparticles, and the amplification time of the RCA. We show that the detection of 0.75 fmol of preamplification synthetic target is possible with only 20 min of amplification time. Finally, we showcase the high specificity of the assay, as the functionalized nanoparticles are unable to bind to amplified DNA that does not match their labels. Overall, this paves the way for a simple bioassay that can be used without expensive laboratory equipment for detection of pathogens in outbreak settings and clinics around the world.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2023
    National Category
    Nano Technology
    Research subject
    Engineering Science with specialization in Nanotechnology and Functional Materials
    Identifiers
    urn:nbn:se:uu:diva-497741 (URN)10.1021/acsomega.2c07992 (DOI)000928233600001 ()36743032 (PubMedID)
    Funder
    Swedish Research Council Formas, 221-2014-574Swedish Foundation for Strategic Research, FLU-ID
    Available from: 2023-03-02 Created: 2023-03-02 Last updated: 2024-02-01Bibliographically approved
    5. Reduced amplification by phi29 DNA polymerase in the presence of unbound oligos during reaction in RCA
    Open this publication in new window or tab >>Reduced amplification by phi29 DNA polymerase in the presence of unbound oligos during reaction in RCA
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Synthetic single-stranded oligonucleotides play crucial roles in DNA amplification reactions for various applications, such as serving as primers, enabling magnetic separation, and generating dsDNA for subsequent digestion. Typically, these oligos are added in excess to ensure rapid binding to their intended targets. However, while performing rolling circle amplification (RCA) using phi29 DNA polymerase, we observed a decrease in amplification efficiency when oligos were present in the reaction. This phenomenon was consistently observed in two separate laboratories, prompting this study to delve into the root causes responsible for the decline in RCA efficiency. The lowered efficiency was consistent regardless of the manufacturer or any mutations in the phi29 polymerase. We identified several variables that influenced RCA efficiency, mainly the length of the oligos used and the presence of modifications, particularly those obstructing 3’ end digestion. This strongly suggests that the exonuclease domain of phi29 DNA polymerase is responsible for the competition-based inhibition. Our investigation shows that even picomole quantities of oligos can significantly reduce total DNA production during the phi29 DNA polymerase-mediated amplification process. Conversely, the addition of oligos to the reaction did not impede the efficiency of Bst 3.0 polymerase, likely due to the lack of an exonuclease domain of said polymerase. While increasing the quantity of phi29 DNA polymerase in the reaction partially alleviated the adverse effects of excess oligos, we believe it is crucial to carefully optimize the oligo quantities to achieve maximum amplification of the desired targets.

    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-521571 (URN)
    Available from: 2024-01-25 Created: 2024-01-25 Last updated: 2024-02-01
    6. Sensitive multiplex visual detection of DNA targets using colored polystyrene nanoparticles and circle-to-circle amplification.
    Open this publication in new window or tab >>Sensitive multiplex visual detection of DNA targets using colored polystyrene nanoparticles and circle-to-circle amplification.
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Antibiotic resistance poses a significant threat to public health, acknowledged by the World Health Organization as a foremost global concern. The detection of pathogens and the determination of antibiotic resistance are critical for effective treatment. In a previous study, we introduced a DNA detection method capable of producing visible aggregates from DNA-amplified products and functionalized magnetic nanoparticles. This current research focuses on optimizing key parameters of the amplification protocol to develop a point-of-care detection method. Circle-to-circle amplification has been employed to enhance sensitivity. Through systematic adjustments to sample volumes, reaction times, padlock probe design and length, polymerase selection, and nanoparticle types, we achieved a visual limit of detection of 100 zeptomoles for a synthetic DNA target. This represents to a 10-fold improvement over our previously reported LOD.

    Noteworthy is the utilization of phi29-XT, a novel phi29 DNA polymerase mutant, for PLP amplification and diagnostic assay development. Additionally, we successfully demonstrated multiplexed detection of two DNA targets within a single sample, employing colored polystyrene nanoparticles. Each target was identified by a distinct nanoparticle color (red or blue), achieving an LOD of 500 zeptomoles.

    Lastly, we explored a method for end-point analysis of multiplexed samples using smartphone camera images and image analysis with ImageJ, albeit in an early development state. These advancements underscore the potential for our optimized methods to contribute significantly to the field of antibiotic resistance detection and diagnosis, paving the way for more effective and tailored treatments.

    National Category
    Diagnostic Biotechnology
    Identifiers
    urn:nbn:se:uu:diva-521572 (URN)
    Available from: 2024-01-25 Created: 2024-01-25 Last updated: 2024-02-01
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  • Public defence: 2024-04-05 09:15 Polhemsalen, Uppsala
    Gogoi, Neeha
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Structural Chemistry.
    Elucidating Chemical and Electrochemical Side-Reaction Mechanisms in Li-ion Batteries2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Lithium-ion batteries constitute a leading technology that plays a major role in the transition towards sustainable transportation and power generation. The stability of modern batteries relies on a passivation layer formed on the negative electrode known as the solid electrolyte interphase (SEI). Despite concerted efforts to comprehend the various processes taking place during SEI formation, monitoring the reaction pathways in real-time is still very challenging. This is due to the complex interactions within the multicomponent electrochemical system, aggravated by the wide range of electrolyte compositions, electrode materials, and operating conditions.

    In this thesis, operando surface enhanced Raman spectroscopy is explored to elucidate the progressive formation of the SEI on the negative electrode surface when the electrode is negatively polarised in a spectro-electrochemical cell. Complementary online-electrochemical mass spectrometry is employed to identify the associated gaseous products formed during the process. The work illustrates that the electrolyte as well as contaminants, such as O2, CO2, and H2O, contribute in electro-/chemical processes that build up the SEI. The thesis then explores reaction pathways involving a SEI-forming electrolyte additive, namely vinylene carbonate (VC), emphasizing its role as a H2O scavenging agent. In comparison to the conventional electrolyte solvent ethylene carbonate, VC exhibits a faster reaction with water impurities, particularly in presence of hydroxide ions. This results in the formation of products that are less likely to impact cell performance.

    In the later part, the thesis delves into understanding the stability of electrolyte in an environment of Lewis bases (LB) typically found in the SEI. For that, individual LB (e.g., OH- and OCH3-) are mixed with typical carbonate-based solvents and the products formed as a result of the reaction are analysed. Furthermore, tris(trimethylsilyl)phosphate (TMSPa), a representative of the silyl-functionalised electrolyte additive and known for its reactivity, especially towards fluorides, is used as a means to chemically probe its reactivity towards several LB residues. This investigation aims to establish a more simplified and generally applicable reaction mechanism thereof. The products that are soluble in the electrolyte have been investigated by nuclear magnetic resonance spectroscopy and those in the gas phase is characterised by mass spectrometry. The work highlights that the residues that remain active even after the SEI formation may lead to unwanted side-reactions.

    The thesis contributes to a deeper fundamental understanding of the myriad of processes that take place in batteries during SEI formation providing insights crucial for designing next-generation battery materials.

    List of papers
    1. Elucidating the Step‐Wise Solid Electrolyte Interphase Formation in Lithium‐Ion Batteries with Operando Raman Spectroscopy
    Open this publication in new window or tab >>Elucidating the Step‐Wise Solid Electrolyte Interphase Formation in Lithium‐Ion Batteries with Operando Raman Spectroscopy
    2022 (English)In: Advanced Materials Interfaces, ISSN 2196-7350, Vol. 9, no 22, article id 2200945Article in journal (Refereed) Published
    Abstract [en]

    The solid electrolyte interphase (SEI) is arguably one of the most critical components of the Li-ion cell. Despite decades of studies of the SEI, its intrinsic complexity and the lack of suitable characterization tools still prevent a real consensus on the governing mechanisms to be reached. Herein, operando Raman spectroscopy supported by complimentary online electrochemical mass spectrometry is employed to study the SEI formation on Au in a model electrolyte based on LiClO4 in ethylene carbonate (EC). Both the electrolyte itself and cell contaminants, such as O2, CO2, and H2O, contribute in stepwise electro-/chemical processes to the build-up of the SEI. Effects associated with electrode/electrolyte double-layer charging, electrode adsorbate polarization (stark effect), and SEI dissolution are discerned. Lithium carbonate and lithium oxide are identified as major products formed already ≈2 V versus Li+/Li. Although Raman spectroscopy provides deeper insights into the underlying mechanisms, complementary techniques are necessary to support spectral interpretations. Classical challenges in the field of surface science, such as contaminations, have to be systematically addressed if the puzzle of the SEI ever will be completed.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2022
    Keywords
    interphases, Li-ion batteries, operando, Raman, solid electrolyte interphase, SERS
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-480332 (URN)10.1002/admi.202200945 (DOI)000823854500001 ()
    Funder
    Swedish Research Council, 2016‐04069Knut and Alice Wallenberg Foundation, 2017.0204Swedish Foundation for Strategic Research, FFL18-0269StandUp
    Available from: 2022-07-09 Created: 2022-07-09 Last updated: 2024-02-14Bibliographically approved
    2. Base-driven Ring-Opening Reactions of Vinylene Carbonate
    Open this publication in new window or tab >>Base-driven Ring-Opening Reactions of Vinylene Carbonate
    (English)Manuscript (preprint) (Other academic)
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-523096 (URN)
    Available from: 2024-02-14 Created: 2024-02-14 Last updated: 2024-02-14
    3. Unveiling Reaction Pathways of Ethylene Carbonate and Vinylene Carbonate in Li-ion Batteries
    Open this publication in new window or tab >>Unveiling Reaction Pathways of Ethylene Carbonate and Vinylene Carbonate in Li-ion Batteries
    (English)Manuscript (preprint) (Other academic)
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-522072 (URN)
    Available from: 2024-01-31 Created: 2024-01-31 Last updated: 2024-02-14
    4. Silyl-Functionalized Electrolyte Additives and Their Reactivity toward Lewis Bases in Li-Ion Cells
    Open this publication in new window or tab >>Silyl-Functionalized Electrolyte Additives and Their Reactivity toward Lewis Bases in Li-Ion Cells
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    2022 (English)In: Chemistry of Materials, ISSN 0897-4756, E-ISSN 1520-5002, Vol. 34, no 8, p. 3831-3838Article in journal (Refereed) Published
    Abstract [en]

    Silyl groups are included in a wide range of electrolyte additives to enhance the performance of state-of-the-art Li-ion batteries. A recognized representative thereof is tris-(trimethylsilyl)phosphate (TMSPa) which, along with the similarly structured phosphite, has been at the center of numerous electrolyte studies. Even though the silyl group has already been widely reported to be specifically reactive towards fluorides, herein, a reactivity towards several Lewis bases typically found in Li-ion cells is postulated and investigated with the aim to establish a more simplified and generally applicable reaction mechanism thereof. Both gaseous and electrolyte soluble reactants and products are monitored by combining nuclear magnetic resonance and injection cell-coupled mass spectrometry. Experimental observations are supported by computational models. The results clearly demonstrate that the silyl groups react with water, hydroxide, and methoxide and thereby detach in a stepwise fashion from the central phosphate in TMSPa. Intermolecular interaction between TMSPa and the reactants likely facilitates dissolution and lowers the free energy of reaction. Lewis bases are well known to trigger side reactions involving both the Li-ion electrode and electrolyte. By effectively scavenging these, the silyl group can be explained to lower cell impedance and prolong the lifetime of modern Li-ion batteries.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS)American Chemical Society (ACS), 2022
    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-474784 (URN)10.1021/acs.chemmater.2c00345 (DOI)000795962300023 ()
    Funder
    Swedish Research Council, 2016-04069Knut and Alice Wallenberg Foundation, 2017.0204Swedish Foundation for Strategic Research, FFL18-0269StandUpeSSENCE - An eScience CollaborationSwedish National Infrastructure for Computing (SNIC)
    Available from: 2022-05-23 Created: 2022-05-23 Last updated: 2024-02-14Bibliographically approved
    5. Reactivity of Organosilicon Additives with Water in Li-ion Batteries
    Open this publication in new window or tab >>Reactivity of Organosilicon Additives with Water in Li-ion Batteries
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    2024 (English)In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 128, no 4, p. 1654-1662Article in journal (Refereed) Published
    Abstract [en]

    Introducing small volumes of organosilicon-containing additives as part of lithium-ion battery (LIB) electrolyte engineering has been getting a lot of attention owing to these additives’ multifunctional properties. Tris(trimethylsilyl)phosphate (TMSPa) is a prominent member of this class of additives and scavenges Lewis bases such as water, although the rate at which the reaction occurs and the fate of the resultant product in the battery system still remain unknown. Herein, we have employed complementary nuclear magnetic resonance and gas chromatography–mass spectrometry to systematically study the reactivity of TMSPa with water in conventional organic carbonate solvents mimicking the Li-ion cell environment. The reaction products are identified, and a working reaction pathway is proposed by following the chemical evolution of the products over varying time and temperatures. We found that the main reaction products are trimethylsilanol (TMSOH) and phosphoric acid (H3PO4); however, various P–O–Si-containing intermediates were also found. Similar to water, the Lewis base TMSOH can undergo reaction with TMSPa at room temperature to form hexamethyldisiloxane and can also activate ethylene carbonate (EC) ring-opening reactions at elevated temperatures (≥80 °C), yielding a TMS derivative with ethylene glycol (TMS-EG). While the formation of TMS-EG at the expense of EC is in principle an unwanted parasitic reaction, it should be noted that this reaction is only activated at elevated temperatures in comparison to EC ring-opening by H2O, which takes place at ≥40 °C. Thus, the study underlines the advantages of organo-silicon compounds as electrolyte additives. Elucidating the reaction mechanism in model systems like this is important for future studies of similar additives in order to improve the accuracy of additive exploration in LIBs.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2024
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-522242 (URN)10.1021/acs.jpcc.3c07505 (DOI)001156038200001 ()
    Funder
    Swedish Research Council, 2016-04069Knut and Alice Wallenberg Foundation, 2017.0204Swedish Foundation for Strategic Research, FFL18-0269
    Available from: 2024-02-01 Created: 2024-02-01 Last updated: 2024-03-06Bibliographically approved
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  • Public defence: 2024-04-05 10:15 Geijersalen, sal 6-1023, Uppsala
    Elfström, Johan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Theology, Department of Theology.
    Reconceiving Public Reason: Neutrality, Civility, and the Self-Defeat Objection2024Doctoral thesis, monograph (Other academic)
    Abstract [en]

    How should we live together? The question is at the heart of social ethics and it is an as urgent political question as ever. In this thesis, one particularly attractive reply to this central issue is analysed—John Rawls’s theory of public reason, and three different objections that have been put against it. Rawls’s theory is an approach to democratic decision-making. According to it, the exercise of political power should be neutral. Secondly, the exercise of political power should restrict the reasons that have justificatory force in political decision-making procedures to reasons that do not rely on any particular worldview. Finally, the exercise of political power is legitimate only if it is in accordance with terms of cooperation that all reasonable and rational persons can accept.

    The objections each target one of these components. Cécile Laborde has challenged the conception of neutrality espoused by egalitarian liberals generally. Egalitarian liberal understandings of neutrality do not take sufficient account of all relevant dimensions of our worldviews and often confuse neutral policies with what conforms to the status quo. Jeffrey Stout, in turn, targets the constraints on public discourse and argues that imposing such constraints is unfair to religious citizens because it distributes the burdens of cooperation to their disadvantage. Finally, Steven Wall argues that the requirement that the legitimate exercise of political power be acceptable to citizens ends up defeating itself.

    These arguments are tested and I consider the alternative approaches that are presented by each of the three critics. I propose that neutrality should be rejected, as equality better captures the end pursued by demanding neutral treatment of different worldviews. I then go on to revise the constraints that Rawls impose. Although many of Stout’s arguments are persuasive, Rawls’s constraints on political discourse are introduced for very good reasons. Finally, I argue that Wall’s self-defeat argument fails and that Rawls’s principle of legitimacy need not be revised, but is defendable in its current form. 

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    UUThesis_J-Elfström-2024
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  • Public defence: 2024-04-05 10:15 Häggsalen, Ångströmlaboratoriet, Uppsala
    Södergren, Simon
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Microsystems Technology.
    Miniaturized fluid system for high-pressure analytics2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    High-pressure chemistry can be used to determine the contents of blood or water samples and to discover new chemistries. However, working with chemistry at pressures of many tens, or even hundreds, of bars often requires expensive and stationary equipment, such as autoclaves or chromatographic systems like high-performance liquid chromatography (HPLC).

    Since the introduction of microfluidics in the '90s, researchers have attempted to develop microfluidic chips as microreactors to speed up synthesis with faster mass and heat transfer. Other researchers have made efforts to create microfluidic chip-based HPLC to reduce the cost, increase the separation quality, speed up the analysis, and even enable portable systems for on-site medical or environmental analysis. Still, fully integrated systems have not yet been realized due to a lack of fluidic control components.

    This thesis presents novel methods for on-chip regulation and monitoring of pressure, flow, and temperature. Papers I and II specifically suggest a method for regulating backpressure and stabilizing pressure and flows using thermally controlled restrictors. Furthermore, a collaboration was made where a pressure-regulating chip was connected to an on-chip HPLC. The purpose of this was to activate sample plugs and therefore reduce the requirement for expensive surrounding equipment and enable portability, Paper III. Paper IV explores the use of a pressurized capsule to generate high-pressure flows that are coupled to a pressure-regulating chip to stabilize and regulate the pressure. Finally, an approach for integrating pressure sensors into high-pressure tolerant microchannels has been proposed, Paper V.

    The work conducted has provided new insights into fluid dynamics. The regulating method employed in Paper I-IV utilizes a restrictor that alters the pressure drop as temperature changes, hence changing the viscosity of the fluid. Although this technology has been known since before, new understandings have emerged regarding how the compressibility of incompressible fluids must be considered at higher pressures. Additionally, the concept of buffer capacitance is presented, which is central when working with high-pressure microfluidics.

    Through this thesis, discoveries of high-pressure microfluidics have been accomplished, which enable micro-total-analysis systems that could serve as portable HPLC equipment.

    List of papers
    1. Thermally controlled microfluidic back pressure regulator
    Open this publication in new window or tab >>Thermally controlled microfluidic back pressure regulator
    2022 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, no 1, article id 569Article in journal (Refereed) Published
    Abstract [en]

    By using the temperature dependence of viscosity, we introduce a novel type of microfluidic lab-on-a-chip back pressure regulator (BPR) that can be integrated into a micro-total-analysis-system. A BPR is an important component used to gain pressure control and maintain elevated pressures in e.g. chemical extractions, synthesis, and analyses. Such applications have been limited in microfluidics, since the back pressure regularly has been attained by passive restrictors or external large-scale BPRs. Herein, an active microfluidic BPR is presented, consisting of a glass chip with integrated thin-film heaters and thermal sensors. It has no moving parts but a fluid restrictor where the flow resistance is controlled by the change of viscosity with temperature. Performance was evaluated by regulating the upstream pressure of methanol or water using a PID controller. The developed BPR has the smallest reported dead volume of 3 nL and the thermal actuation has time constants of a few seconds. The pressure regulation were reproducible with a precision in the millibar range, limited by the pressure sensor. The time constant of the pressure changes was evaluated and its dependence of the total upstream volume and the compressibility of the liquids is introduced.

    Place, publisher, year, edition, pages
    NATURE PORTFOLIO, 2022
    Keywords
    SUPERCRITICAL-FLUID: CHROMATOGRAPHY; LIQUID-CHROMATOGRAPHY: FLOWSYSTEM: HPLC; SEPARATION
    National Category
    Other Electrical Engineering, Electronic Engineering, Information Engineering
    Identifiers
    urn:nbn:se:uu:diva-466637 (URN)10.1038/s41598-021-04320-6 (DOI)000742155800057 ()35022424 (PubMedID)
    Available from: 2022-01-31 Created: 2022-01-31 Last updated: 2024-02-18Bibliographically approved
    2. Microfluidic active pressure and flow stabiliser
    Open this publication in new window or tab >>Microfluidic active pressure and flow stabiliser
    2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, article id 22504Article in journal (Refereed) Published
    Abstract [en]

    In microfluidics, a well-known challenge is to obtain reproducible results, often constrained by unstable pressures or flow rates. Today, there are existing stabilisers made for low-pressure microfluidics or high-pressure macrofluidics, often consisting of passive membranes, which cannot stabilise long-term fluctuations. In this work, a novel stabilisation method that is able to handle high pressures in microfluidics is presented. It is based on upstream flow capacitance and thermal control of the fluid's viscosity through a PID controlled restrictor-chip. The stabiliser consists of a high-pressure-resistant microfluidic glass chip with integrated thin films, used for resistive heating. Thereby, the stabiliser has no moving parts. The quality of the stabilisation was evaluated with an ISCO pump, an HPLC pump, and a Harvard pump. The stability was greatly improved for all three pumps, with the ISCO reaching the highest relative precision of 0.035% and the best accuracy of 8.0 ppm. Poor accuracy of a pump was compensated for in the control algorithm, as it otherwise reduced the capacity to stabilise longer times. As the dead volume of the stabiliser was only 16 nL, it can be integrated into micro-total-analysis- or other lab-on-a-chip-systems. By this work, a new approach to improve the control of microfluidic systems has been achieved.

    Place, publisher, year, edition, pages
    Springer NatureSpringer Nature, 2021
    National Category
    Fluid Mechanics and Acoustics
    Identifiers
    urn:nbn:se:uu:diva-461143 (URN)10.1038/s41598-021-01865-4 (DOI)000720520100014 ()34795333 (PubMedID)
    Funder
    The Kamprad Family Foundation
    Note

    De två första författarna delar förstaförfattarskapet.

    Available from: 2021-12-13 Created: 2021-12-13 Last updated: 2024-02-18Bibliographically approved
    3. Coupling microchip pressure regulators with chipHPLC as a step toward fully portable analysis system
    Open this publication in new window or tab >>Coupling microchip pressure regulators with chipHPLC as a step toward fully portable analysis system
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    2023 (English)In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 385, article id 133732Article in journal (Refereed) Published
    Abstract [en]

    Herein the coupling of a miniaturized, nanoliter scaled, pressure regulator (chipPR), and a chipHPLC device is introduced. The active temperature based flow control of the chipPR is able to generate rapid pressure changes and therefore enables on-chip pinched injection and flow gradients with reduced instrumental effort and minimal dead volumes. The functionality of the chipPR empowered chipHLPC device was demonstrated with high-speed HPLC-separations applying fluorescence and electrospray mass spectrometry (ESI-MS) detection. The system shows excellent long-term stability of chromatography integrity (retention times with RSD of 0.44-0.91%) due to the integration of a PID feedback regulation. This first chip-based HPLC device equipped with chipPRs enables precise flow control with significantly reduced technical effort compared to the state-of-the-art.

    Place, publisher, year, edition, pages
    Elsevier, 2023
    Keywords
    Lab-on-a-chip, ChipHPLC, Thermal actuation, Microfluidics, Pressure regulation
    National Category
    Other Electrical Engineering, Electronic Engineering, Information Engineering Analytical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-502526 (URN)10.1016/j.snb.2023.133732 (DOI)000977773900001 ()
    Funder
    The Kamprad Family Foundation, 20170169
    Available from: 2023-05-26 Created: 2023-05-26 Last updated: 2024-02-18Bibliographically approved
    4. Portable high-pressure pump system for HPLC combining pressurized gas and on-chip pressure regulation
    Open this publication in new window or tab >>Portable high-pressure pump system for HPLC combining pressurized gas and on-chip pressure regulation
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    High-pressure pumps for microfluidic systems typically require high powerand have large sizes, which hinder portability of otherwise miniaturized HPLC systems. To solve this, a battery-powered, pneumatic system for pressure-driven chromatography is presented. The system utilizes the stored energy in pressurized gas without consuming any of the gas. As the chromatography liquid flows, the gas in the pressure container expands and its pressure reduces. To compensate for this, a solution is presented with an on-chip microfluidic pressure regulator. The chip contains a microfluidic restrictor where fluid is heated by Joule heating to decrease viscosity, and thus reduce the pressure drop over the restrictor. An 18 V battery driven system with 50 ml N2 at 51 bar could provide a water flow rate of 55 µl/min at 32 bar for 67 min with a mean power consumption of 0.2 W. With the regulating microfluidic chip, the pressure stability was 2 mbar, i.e., on pair with high-quality high-pressure syringe pumps. The required gas volume, and hence the total size, is scalable with the desired liquid volume, which makes it suitable for miniaturized systems.

    National Category
    Other Materials Engineering Fluid Mechanics and Acoustics
    Research subject
    Engineering Science with specialization in Microsystems Technology
    Identifiers
    urn:nbn:se:uu:diva-523406 (URN)
    Available from: 2024-02-18 Created: 2024-02-18 Last updated: 2024-02-19Bibliographically approved
    5. In-line small high-pressure sensors in anodically bonded microfluidic restrictors
    Open this publication in new window or tab >>In-line small high-pressure sensors in anodically bonded microfluidic restrictors
    2023 (English)In: Sensors and Actuators A-Physical, ISSN 0924-4247, E-ISSN 1873-3069, Vol. 356, article id 114345Article in journal (Refereed) Published
    Abstract [en]

    High-pressure microflow chemistry is advancing due to its potential advantages of being rapid, inexpensive, and accessible. However, as microfluidic devices gain popularity in areas such as synthesis and analysis, there is still a lack of control over thermodynamic parameters during high-pressure processes. This is an effect of existing external sensors causing an excessive increase in the system's internal and dead volumes. To avoid this, more sensors need to be integrated into high-pressure-resistant microfluidic channels. Herein, a proposed approach for integrating an in-line pressure-flow-temperature sensor is provided, where the flow is calculated from the pressure drop over a restrictor. An anodically bonded Si-glass microfluidic chip was constructed with wet-etched glass channels, boron-doped piezoresistors, and dry-etched diaphragms. The pressure sensors showed a precision of +/- 0.07% of full scale (70 bar) and the chip can withstand more than 210 bar. The internal volume was 25 nL and the diaphragms measured 72 x 108 mu m. With this work, improved control of high-pressure microfluidics has been accomplished.

    Place, publisher, year, edition, pages
    ELSEVIER SCIENCE SA, 2023
    Keywords
    High-pressure microfluidics, Diaphragm pressure sensor, Piezoresestivity, Micro total analysis system, Process control
    National Category
    Energy Engineering
    Identifiers
    urn:nbn:se:uu:diva-506963 (URN)10.1016/j.sna.2023.114345 (DOI)001002776000001 ()
    Funder
    The Kamprad Family Foundation, 20170169
    Available from: 2023-07-04 Created: 2023-07-04 Last updated: 2024-02-18Bibliographically approved
  • Public defence: 2024-04-09 13:15 room A1:111a, Uppsala
    Wang, Han
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Structural Decorations in Viruses: Unraveling Acquired Functional Structures in Icosahedral RNA Virus Capsids2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Viruses have a profound impact worldwide, posing challenges to animal welfare, agriculture, human health, and the ecosystem. This thesis examines the realm of non-enveloped icosahedral double-stranded (ds)RNA and single-stranded (ss)RNA viruses through three studies. In Paper I, we employed a reverse genetics approach to generate recombinant dsRNA totivirus-like viruses—which negatively impact fisheries and the economy—unraveling the intricate relationships between viral genes and life cycles. Our reverse genetic method has proven essential for generating infectious totivirus-like virus particles, allowing for a nuanced exploration of viral behaviors. Understanding these behaviors has the potential to help in developing effective virus control approaches. In Paper II, we elucidated the previously unknown capsid structure, uncovering the intriguing acquired features of a dsRNA megabirnavirus—Rosellinia necatrix megabirnavirus 1-W779 (RnMBV1)—through cryogenic electron microscopy single-particle analysis. RnMBV1, a fungal virus, has potential applications in controlling white root rot, a plant disease that causes substantial economic losses. Insights into this viral structural information can enhance our ability to leverage this fungal virus for economic and agricultural benefits. In Paper III, we obtained the capsid atomic models of a Marnaviridae ssRNA virus: Chaetoceros socialis forma radians RNA virus 1. Additionally, we generated a structure-based phylogeny using viral protein structures predicted by AlphaFold2; this was done to enhance our understanding of algal virus-host specificity. As harmful algal blooms (HABs) pose global threats to ecology and the economy, Chaetoceros algae have emerged as a contributing factor. Certain Marnaviridae viruses exhibit specific infection patterns in Chaetoceros, thereby influencing the occurrence and mitigation of HABs. Studies on Marnaviridae viruses collectively provide insights into the interactions between algal viruses and their hosts, paving the way for utilizing marine algal viruses to address HAB-related challenges. Together, our functional and structural analyses will contribute to a broader understanding of both dsRNA and ssRNA viruses, their behaviors, and their potential applications in addressing economic, agricultural, ecological, and healthcare issues.

    List of papers
    1. A full-length infectious cDNA clone of a dsRNA totivirus-like virus
    Open this publication in new window or tab >>A full-length infectious cDNA clone of a dsRNA totivirus-like virus
    2022 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 576, p. 127-133Article in journal (Refereed) Published
    Abstract [en]

    Totivirus-like viruses are a group of non-segmented double-stranded (ds)RNA viruses with two open reading frames, which were recently discovered and provisionally assigned to the Totiviridae family. Unlike yeast and protozoan Totiviridae viruses, these totivirus-like viruses infect a diverse spectrum of metazoan hosts and currently have enormous impacts on fisheries and agriculture. We developed the first infectious full-length cDNA clone of a totivirus-like virus, the Omono River virus (OmRV), and produced infectious particles using an RNA -transcript-based method. Compared with the parent wild-type particles from nature, the infectious-cloning OmRV particles have presented strong cytopathic effects, infectivity and similar morphology. Thus far, the established system is one of the few reported systems for generating a non-segmented dsRNA virus cDNA clone.

    Place, publisher, year, edition, pages
    Elsevier, 2022
    Keywords
    dsRNA virus, Totivirus, OmRV, Mosquito, Infectious clone, Reverse genetics
    National Category
    Microbiology
    Identifiers
    urn:nbn:se:uu:diva-490903 (URN)10.1016/j.virol.2022.09.010 (DOI)000888431800001 ()36242926 (PubMedID)
    Funder
    Swedish Research Council, 2018- 03387Swedish Research Council Formas, 2018-00421The Royal Swedish Academy of Sciences, BS2018-0053
    Available from: 2022-12-19 Created: 2022-12-19 Last updated: 2024-02-14Bibliographically approved
    2. Capsid structure of a fungal dsRNA megabirnavirus reveals its previously unidentified surface architecture
    Open this publication in new window or tab >>Capsid structure of a fungal dsRNA megabirnavirus reveals its previously unidentified surface architecture
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    2023 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 19, no 2, article id e1011162Article in journal (Refereed) Published
    Abstract [en]

    Rosellinia necatrix megabirnavirus 1-W779 (RnMBV1) is a non-enveloped icosahedral double-stranded (ds)RNA virus that infects the ascomycete fungus Rosellinia necatrix, a causative agent that induces a lethal plant disease white root rot. Herein, we have first resolved the atomic structure of the RnMBV1 capsid at 3.2 Å resolution using cryo-electron microscopy (cryo-EM) single-particle analysis. Compared with other non-enveloped icosahedral dsRNA viruses, the RnMBV1 capsid protein structure exhibits an extra-long C-terminal arm and a surface protrusion domain. In addition, the previously unrecognized crown proteins are identified in a symmetry-expanded cryo-EM model and are present over the 3-fold axes. These exclusive structural features of the RnMBV1 capsid could have been acquired for playing essential roles in transmission and/or particle assembly of the megabirnaviruses. Our findings, therefore, will reinforce the understanding of how the structural and molecular machineries of the megabirnaviruses influence the virulence of the disease-related ascomycete fungus.

    Author summary

    A fungal plant soil-borne pathogen, Rosellinia necatrix, which can cause devastating disease white root rot in many highly valued fruit trees, is difficult to be controlled with conventional approaches such as fungicide applications. Rosellinia necatrix megabirnavirus 1-W779 (RnMBV1) is a dsRNA virus isolated from the R. necatrix field strain, W779, and this virus can be a viro-control candidate to confer hypovirulence in its host R. necatrix. To make use of RnMBV1 in the white root rot disease control, more molecular and structural investigations will offer us more insights. Here, we have performed cryo-electron microscopy (cryo-EM) single-particle analysis, to obtain the first atomic models of RnMBV1 particles. Based on the atomic structures, we found unique both surface and interior features. In addition, we found a previously unidentified protein on the viral surface. These aforementioned structural features might play important roles in the viral life cycles, and will encourage us to apply this fungal virus as a viro-control approach.

    Place, publisher, year, edition, pages
    Public Library of Science (PLoS), 2023
    National Category
    Structural Biology Microbiology
    Identifiers
    urn:nbn:se:uu:diva-501867 (URN)10.1371/journal.ppat.1011162 (DOI)000942039200002 ()36848381 (PubMedID)
    Funder
    Swedish Research Council, 2018-03387Swedish Research Council Formas, 2018-00421The Royal Swedish Academy of Sciences, BS2018-0053
    Available from: 2023-05-17 Created: 2023-05-17 Last updated: 2024-02-14Bibliographically approved
    3. Structural Insights into Common and Host-Specific Receptor-Binding Mechanisms in Algal Picorna-like Viruses
    Open this publication in new window or tab >>Structural Insights into Common and Host-Specific Receptor-Binding Mechanisms in Algal Picorna-like Viruses
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    2022 (English)In: Viruses, E-ISSN 1999-4915, Vol. 14, no 11, article id 2369Article in journal (Refereed) Published
    Abstract [en]

    Marnaviridae viruses are abundant algal viruses that regulate the dynamics of algal blooms in aquatic environments. They employ a narrow host range because they merely lyse their algal host species. This host-specific lysis is thought to correspond to the unique receptor-binding mechanism of the Marnaviridae viruses. Here, we present the atomic structures of the full and empty capsids of Chaetoceros socialis forma radians RNA virus 1 built-in 3.0 &Aring; and 3.1 &Aring; cryo-electron microscopy maps. The empty capsid structure and the structural variability provide insights into its assembly and uncoating intermediates. In conjunction with the previously reported atomic model of the Chaetoceros tenuissimus RNA virus type II capsid, we have identified the common and diverse structural features of the VP1 surface between the Marnaviridae viruses. We have also tested the potential usage of AlphaFold2 for structural prediction of the VP1s and a subsequent structural phylogeny for classifying Marnaviridae viruses by their hosts. These findings will be crucial for inferring the host-specific receptor-binding mechanism in Marnaviridae viruses.

    Place, publisher, year, edition, pages
    MDPI, 2022
    Keywords
    Marnaviridae, algal bloom, algal viruses, icosahedral viruses, ssRNA viruses
    National Category
    Structural Biology
    Identifiers
    urn:nbn:se:uu:diva-487745 (URN)10.3390/v14112369 (DOI)000881549600001 ()36366467 (PubMedID)
    Funder
    Swedish Research Council, 2018-03387The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), JA2014-5721Swedish Research Council Formas, 2018-00421The Royal Swedish Academy of Sciences, BS2018-0053
    Available from: 2022-11-01 Created: 2022-11-01 Last updated: 2024-02-14Bibliographically approved
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  • Public defence: 2024-04-10 09:00 Rudbecksalen, Uppsala
    Zhang, Hanzhao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Role of MYCN in retinoblastoma: From carcinogenesis to tumor progression2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Retinoblastoma, a pediatric malignancy of the retina, is primarily driven by the bi-allelic inactivation of the RB1gene. However, a subset of cases are characterized by proficient RB1 functions but with MYCN copy number mutations, suggesting an alternative oncogenic mechanism in the absence of RB1 mutations. The aim of this thesis is to investigate the intricate molecular and cellular pathways implicated in retinoblastoma, with a particular focus on the role of MYCN expression and its interplay with the cell cycle and apoptotic pathways.

    In Paper I, we explored the regulatory mechanisms underpinning MYCN-induced retinoblastoma using aRB1-proficient MYCN-overexpressing in vivo model in embryonic chicken retina and MYCN-transformed cells in culture. Our findings revealed that MYCN overexpression led to a significant upregulation of E2F levels, thereby dysregulating the cell cycle and mimicking the mechanistic phenotype of RB1-deficient tumors. Inhibition on E2f DNA-binding activity efficiently normalized growth and apoptosis in MYCN-transformed cells in culture. Despite RB1 proficiency, the elevated E2F levels induced a neoplastic behavior in retinal cells, indicating a novel mechanism of retinoblastoma carcinogenesis independent of RB1 inactivation.

    Paper II employed single-cell RNA sequencing to dissect the cellular composition of MYCN-driven retinoblastoma in chicken in vivo model, revealing a predominant origin in cone photoreceptor progenitors. This finding suggested a cell-type-specific vulnerability to MYCN-induced transformation. The research further identifies a notable heterogeneity within the MYCN-transformed cells, with a subset of cells exhibiting non-cone photoreceptor features but features of other neurons like ganglion cells. A cluster was also identified withelevated expression of genes related to malignancy and tumor progression, including UBE2C and TOP2A. This suggested a link between MYCN overexpression and tumor development, potentially mediated through the E2F pathway.

    In Paper III, the focus shifted to the interplay between MYCN expression, E2f activity, and the p53 pathway in human retinoblastoma cell lines exhibiting both RB1 deficiency and MYCN amplification. By modulating E2f and p53 pathway activities using chemical inhibitors, we demonstrated the essential role of MYCN expression level in mediating p53-driven growth inhibition and highlighted the independent effects of E2f inhibition and p53 activation by a Mdm2 inhibitor.

    Together, these studies illuminate the intricate molecular pathways involved in MYCN-amplified retinoblastoma, emphasizing the pivotal role of MYCN in disrupting cell cycle regulation and promoting tumorigenesis. These insights not only advance our understanding of retinoblastoma pathogenesis but also provide potential therapeutic targets within the MYCN-E2F axis, offering novel treatment strategies in MYCN-amplified retinoblastoma.

    List of papers
    1. Inhibition of high level E2F in a RB1 proficient MYCN overexpressing chicken retinoblastoma model normalizes neoplastic behaviour.
    Open this publication in new window or tab >>Inhibition of high level E2F in a RB1 proficient MYCN overexpressing chicken retinoblastoma model normalizes neoplastic behaviour.
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    2023 (English)In: Cellular Oncology, ISSN 2211-3428, E-ISSN 2211-3436Article in journal (Refereed) Epub ahead of print
    Abstract [en]

    PURPOSE: Retinoblastoma, a childhood cancer, is most frequently caused by bi-allelic inactivation of RB1 gene. However, other oncogenic mutations such as MYCN amplification can induce retinoblastoma with proficient RB1. Previously, we established RB1-proficient MYCN-overexpressing retinoblastoma models both in human organoids and chicken. Here, we investigate the regulatory events in MYCN-induced retinoblastoma carcinogenesis based on the model in chicken.

    METHODS: MYCN transformed retinal cells in culture were obtained from in vivo MYCN electroporated chicken embryo retina. The expression profiles were analysed by RNA sequencing. Chemical treatments, qRT-PCR, flow cytometry, immunohisto- and immunocytochemistry and western blot were applied to study the properties and function of these cells.

    RESULTS: The expression profile of MYCN-transformed retinal cells in culture showed cone photoreceptor progenitor signature and robustly increased levels of E2Fs. This expression profile was consistently observed in long-term culture. Chemical treatments confirmed RB1 proficiency in these cells. The cells were insensitive to p53 activation but inhibition of E2f efficiently induced cell cycle arrest followed by apoptosis.

    CONCLUSION: In conclusion, with proficient RB1, MYCN-induced high level of E2F expression dysregulates the cell cycle and contributes to retinoblastoma carcinogenesis. The increased level of E2f renders the cells to adopt a similar mechanistic phenotype to a RB1-deficient tumour.

    Keywords
    Animal model, Chicken, E2F, Intraocular cancer, MYCN, RB1 proficient, Retinoblastoma
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-522867 (URN)10.1007/s13402-023-00863-0 (DOI)37606819 (PubMedID)
    Available from: 2024-02-12 Created: 2024-02-12 Last updated: 2024-02-21
    2. Single-cell RNA sequencing reveals cellular properties and carcinogenesis of a RB1-proficient MYCN-overexpressing retinoblastoma model from embryonic chicken retina
    Open this publication in new window or tab >>Single-cell RNA sequencing reveals cellular properties and carcinogenesis of a RB1-proficient MYCN-overexpressing retinoblastoma model from embryonic chicken retina
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-523113 (URN)
    Available from: 2024-02-14 Created: 2024-02-14 Last updated: 2024-02-21
    3. Characterization of MYCN amplified retinoblastoma lines with respect to effects of E2f and p53 activity
    Open this publication in new window or tab >>Characterization of MYCN amplified retinoblastoma lines with respect to effects of E2f and p53 activity
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-523107 (URN)
    Available from: 2024-02-14 Created: 2024-02-14 Last updated: 2024-02-21
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  • Public defence: 2024-04-10 09:15 Sal IX, Uppsala
    Bärkås, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Participatory eHealth and Health Data Research Group.
    Patients’ Access to Their Mental Health Records: Understanding Policy, Access, and Patient Experiences2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    ORA is the concept of patients' access to clinical information, which has become more widespread worldwide. When patients are provided online record access (ORA) to their health records, concerns have been raised by healthcare professionals, especially when it comes to patients with mental health diagnoses. In the general population, positive aspects appear to outweigh the negative, yet limited research has so far explored the impact of ORA in mental healthcare. 

    The overall aim of this thesis was to explore how patients experience ORA in mental healthcare through four studies: 1) a literature review aimed to explore the current literature on the experiences of ORA among mental healthcare patients, care partners, and healthcare professionals, 2) a document analysis combined with key stakeholder email interviews that aimed to explore to what extent ORA in mental healthcare has been implemented in Sweden including national and local policy regulations, 3) an online patient survey study aimed to understand mental healthcare patients' experiences with ORA in Sweden, Estonia, Finland, and Norway, and 4) an online patient survey study aimed to understand if and how patients with mental health conditions experiences of ORA differs from patients in other healthcare settings. 

    More patients reported positive experiences with ORA in mental healthcare than negative experiences. Common benefits of ORA included, among others, a greater sense of control over their care, improved understanding of their mental health diagnosis, and better adherence to appointments. Despite patients' predominant positive experiences, only 17 out of 21 regions in Sweden offered ORA in mental healthcare in 2021. Additionally, many patients experienced errors and omissions and felt offended by the content of their health records. Mental healthcare patients experienced this at a higher rate than patients in other healthcare settings.

    In conclusion, mental healthcare patients have higher rates of negative experiences of ORA compared to patients in other healthcare settings. However, patients' experiences of ORA are still predominantly positive among both patient groups. Yet, in 2021, only 17 regions offered patients ORA in mental healthcare. Denying mental healthcare patients ORA to protect them from negative experiences could instead increase stigma in this patient group.

    List of papers
    1. Sharing Clinical Notes and Electronic Health Records With People Affected by Mental Health Conditions: Scoping Review
    Open this publication in new window or tab >>Sharing Clinical Notes and Electronic Health Records With People Affected by Mental Health Conditions: Scoping Review
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    2021 (English)In: JMIR Mental Health, E-ISSN 2368-7959, Vol. 8, no 12, article id e34170Article in journal (Refereed) Published
    Abstract [en]

    Background: Electronic health records (EHRs) are increasingly implemented internationally, whereas digital sharing of EHRs with service users (SUs) is a relatively new practice. Studies of patient-accessible EHRs (PAEHRs)-often referred to as open notes-have revealed promising results within general medicine settings. However, studies carried out in mental health care (MHC) settings highlight several ethical and practical challenges that require further exploration.

    Objective: This scoping review aims to map available evidence on PAEHRs in MHC. We seek to relate findings with research from other health contexts, to compare different stakeholders' perspectives, expectations, actual experiences with PAEHRs, and identify potential research gaps.

    Methods: A systematic scoping review was performed using 6 electronic databases. Studies that focused on the digital sharing of clinical notes or EHRs with people affected by mental health conditions up to September 2021 were included. The Mixed Methods Appraisal Tool was used to assess the quality of the studies. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Extension for Scoping Reviews guided narrative synthesis and reporting of findings.

    Results: Of the 1034 papers screened, 31 were included in this review. The studies used mostly qualitative methods or surveys and were predominantly published after 2018 in the United States. PAEHRs were examined in outpatient (n=29) and inpatient settings (n=11), and a third of all research was conducted in Veterans Affairs Mental Health. Narrative synthesis allowed the integration of findings according to the different stakeholders. First, SUs reported mainly positive experiences with PAEHRs, such as increased trust in their clinician, health literacy, and empowerment. Negative experiences were related to inaccurate notes, disrespectful language use, or uncovering of undiscussed diagnoses. Second, for health care professionals, concerns outweigh the benefits of sharing EHRs, including an increased clinical burden owing to more documentation efforts and possible harm triggered by reading the notes. Third, care partners gained a better understanding of their family members' mental problems and were able to better support them when they had access to their EHR. Finally, policy stakeholders and experts addressed ethical challenges and recommended the development of guidelines and trainings to better prepare both clinicians and SUs on how to write and read notes.

    Conclusions: PAEHRs in MHC may strengthen user involvement, patients' autonomy, and shift medical treatment to a coproduced process. Acceptance issues among health care professionals align with the findings from general health settings. However, the corpus of evidence on digital sharing of EHRs with people affected by mental health conditions is limited. Above all, further research is needed to examine the clinical effectiveness, efficiency, and implementation of this sociotechnical intervention.

    Place, publisher, year, edition, pages
    JMIR Publications, 2021
    Keywords
    electronic health records, open notes, psychiatry, mental health, user involvement, patient advocacy, patient portal
    National Category
    Psychiatry Other Medical Sciences not elsewhere specified
    Research subject
    Medical Informatics; Psychology
    Identifiers
    urn:nbn:se:uu:diva-462043 (URN)10.2196/34170 (DOI)000739100300011 ()34904956 (PubMedID)
    Projects
    NORDeHEALTHBeyond Implementation of eHealth
    Funder
    NordForsk, 100477Forte, Swedish Research Council for Health, Working Life and Welfare, 2020-01229
    Available from: 2021-12-19 Created: 2021-12-19 Last updated: 2024-02-20Bibliographically approved
    2. Patients’ Access to Their Psychiatric Notes: Current Policies and Practices in Sweden
    Open this publication in new window or tab >>Patients’ Access to Their Psychiatric Notes: Current Policies and Practices in Sweden
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    2021 (English)In: International Journal of Environmental Research and Public Health, ISSN 1661-7827, E-ISSN 1660-4601, Vol. 18, no 17, article id 9140Article in journal (Refereed) Published
    Abstract [en]

    Patients’ access to electronic health records (EHRs) is debated worldwide, and access to psychiatry records is even more criticized. There is a nationwide service in Sweden which offers all citizens the opportunity to read their EHR, including clinical notes. This study aims to explore Swedish national and local policy regulations regarding patients’ access to their psychiatric notes and describe to what extent patients currently are offered access to them. The rationale behind the study is that current policies and current practices may differ between the 21 self-governing regions, although there is a national regulation. We gathered web-based information from policy documents and regulations from each region’s website. We also conducted key stakeholder interviews with respondents from the regions and cross-regional private care providers, using a qualitative approach. The results show that 17 of 21 regions share psychiatric notes with patients, where forensic psychiatric care was the most excluded psychiatric care setting. All private care providers reported that they mainly follow the regions’ guidelines. Our findings show that regional differences concerning sharing psychiatric notes persist, despite Swedish regulations and a national policy that stipulates equal care for everyone. The differences, however, appear to have decreased over time, and we report evidence that the regions are moving toward increased transparency for psychiatry patients.

    Place, publisher, year, edition, pages
    MDPI, 2021
    Keywords
    mental health, psychiatry, psychiatric record, psychiatric notes, patient accessible electronic health record, PAEHR, open notes, policies
    National Category
    Health Care Service and Management, Health Policy and Services and Health Economy
    Research subject
    Medical Informatics
    Identifiers
    urn:nbn:se:uu:diva-452386 (URN)10.3390/ijerph18179140 (DOI)000694051800001 ()34501730 (PubMedID)
    Projects
    NORDeHEALTH
    Funder
    NordForsk, 100477
    Available from: 2021-09-06 Created: 2021-09-06 Last updated: 2024-02-20Bibliographically approved
    3. Experiences from Patients in Mental Healthcare Accessing their Electronic Health Records: Results from a Cross-National Survey in Estonia, Finland, Norway, and Sweden
    Open this publication in new window or tab >>Experiences from Patients in Mental Healthcare Accessing their Electronic Health Records: Results from a Cross-National Survey in Estonia, Finland, Norway, and Sweden
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Health Sciences
    Research subject
    Medical Informatics
    Identifiers
    urn:nbn:se:uu:diva-522716 (URN)
    Available from: 2024-02-08 Created: 2024-02-08 Last updated: 2024-02-20
    4. Errors, Omissions, and Offenses in the Health Record of Mental Health Care Patients: Results from a Nationwide Survey in Sweden
    Open this publication in new window or tab >>Errors, Omissions, and Offenses in the Health Record of Mental Health Care Patients: Results from a Nationwide Survey in Sweden
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    2023 (English)In: Journal of Medical Internet Research, E-ISSN 1438-8871, Vol. 25Article in journal (Refereed) Published
    Abstract [en]

    Background: Previous research reports that patients with mental health conditions experience benefits, for example, increased empowerment and validation, from reading their patient-accessible electronic health records (PAEHRs). In mental health care (MHC), PAEHRs remain controversial, as health care professionals are concerned that patients may feel worried or offended by the content of the notes. Moreover, existing research has focused on specific mental health diagnoses, excluding the larger PAEHR userbase with experience in MHC. Objective: The objective of this study is to establish if and how the experiences of patients with and those without MHC differ in using their PAEHRs by (1) comparing patient characteristics and differences in using the national patient portal between the 2 groups and (2) establishing group differences in the prevalence of negative experiences, for example, rates of errors, omissions, and offenses between the 2 groups. Methods: Our analysis was performed on data from an online patient survey distributed through the Swedish national patient portal as part of our international research project, NORDeHEALTH. The respondents were patient users of the national patient portal 1177, aged 15 years or older, and categorized either as those with MHC experience or with any other health care experience (nonmental health care [non-MHC]). Patient characteristics such as gender, age, education, employment, and health status were gathered. Portal use characteristics included frequency of access, encouragement to read the record, and instances of positive and negative experiences. Negative experiences were further explored through rates of error, omission, and offense. The data were summarized through descriptive statistics. Group differences were analyzed through Pearson chi-square. Results: Of the total sample (N=12,334), MHC respondents (n=3131) experienced errors (1586/3131, 50.65%, and non-MHC 3311/9203, 35.98%), omissions (1089/3131, 34.78%, and non-MHC 2427/9203, 26.37%) and offenses (1183/3131, 37.78%, and non-MHC 1616/9203, 17.56%) in the electronic health record at a higher rate than non-MHC respondents (n=9203). Respondents reported that the identified error (MHC 795/3131, 50.13%, and non-MHC 1366/9203, 41.26%) and omission (MHC 622/3131, 57.12%, and non-MHC 1329/9203, 54.76%) were “very important,” but most did nothing to correct them (MHC 792/3131, 41.29%, and non-MHC 1838/9203, 42.17%). Most of the respondents identified as women in both groups. Conclusions: About 1 in 2 MHC patients identified an error in the record, and about 1 in 3 identified an omission, both at a much higher rate than in the non-MHC group. Patients with MHC also felt offended by the content of the notes more commonly (1 in 3 vs 1 in 6). These findings validate some of the worries expressed by health care professionals about providing patients with MHC with PAEHRs and highlight challenges with the documentation quality in the records.

    Keywords
    electronic health records, EHR, mental health, mental health care, national survey, online records access, open notes, ORA, patient-accessible electronic health record, PAEHR, patients, user experiences
    National Category
    Health Care Service and Management, Health Policy and Services and Health Economy
    Research subject
    Medical Informatics
    Identifiers
    urn:nbn:se:uu:diva-515506 (URN)10.2196/47841 (DOI)
    Funder
    NordForsk, 100477
    Available from: 2023-11-03 Created: 2023-11-03 Last updated: 2024-02-20
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