| 1. |
- Wiberg, Nana, et al.
(författare)
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Infant outcome at four years of age after intrapartum sampling of scalp blood lactate for fetal assessment. A cohort study
- 2018
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- Objective To correlate the value of lactate in fetal scalp blood at delivery and the outcomes of the offspring at four years of age. Methods Cases where scalp blood lactate was taken within sixty minutes before delivery were identified from the randomized trial "Determination of pH or lactate in fetal scalp blood in management of intrapartum fetal distress”. Data were grouped according to the generally accepted cutoffs for normality, pre-acidemia, acidemia and concentrations above mean +2 SD during the second stage. The outcome measures included gross-/fine motor function, vision, hearing, speaking and cognitive disorders, signs of central motor damage and referral to specialized pediatric services. Results 307 cases were available for final analyse. With normal scalp lactate concentration, the number of children with a diagnosed disorder was lower compared to the pre-acidemic/ acidemic groups, although the findings were only significant for fine motor dysfunction (p = 0.036). Elevated lactate values were significantly associated with increased risk for a poorer capacity of attention and understanding of instructions (OR 1.37, 95% CI 1.07–1.74), and for fine motor dysfunction (OR 1.22, 95% CI 1.00–1.49) at the age of four. Conclusion Higher levels of lactate in fetal scalp blood seems to be associated with increased risk of an aberrant developmental outcome at four years of age in some areas.
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| 2. |
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| 3. |
- Blennow Nordström, Erik, et al.
(författare)
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Neuropsychological outcome after cardiac arrest : results from a sub-study of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) trial
- 2023
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Ingår i: Critical Care. - : BioMed Central (BMC). - 1364-8535 .- 1466-609X. ; 27:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cognitive impairment is common following out-of-hospital cardiac arrest (OHCA), but the nature of the impairment is poorly understood. Our objective was to describe cognitive impairment in OHCA survivors, with the hypothesis that OHCA survivors would perform significantly worse on neuropsychological tests of cognition than controls with acute myocardial infarction (MI). Another aim was to investigate the relationship between cognitive performance and the associated factors of emotional problems, fatigue, insomnia, and cardiovascular risk factors following OHCA.METHODS: This was a prospective case-control sub-study of The Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Eight of 61 TTM2-sites in Sweden, Denmark, and the United Kingdom included adults with OHCA of presumed cardiac or unknown cause. A matched non-arrest control group with acute MI was recruited. At approximately 7 months post-event, we administered an extensive neuropsychological test battery and questionnaires on anxiety, depression, fatigue, and insomnia, and collected information on the cardiovascular risk factors hypertension and diabetes.RESULTS: Of 184 eligible OHCA survivors, 108 were included, with 92 MI controls enrolled. Amongst OHCA survivors, 29% performed z-score ≤ - 1 (at least borderline-mild impairment) in ≥ 2 cognitive domains, 14% performed z-score ≤ - 2 (major impairment) in ≥ 1 cognitive domain while 54% performed without impairment in any domain. Impairment was most pronounced in episodic memory, executive functions, and processing speed. OHCA survivors performed significantly worse than MI controls in episodic memory (mean difference, MD = - 0.37, 95% confidence intervals [- 0.61, - 0.12]), verbal (MD = - 0.34 [- 0.62, - 0.07]), and visual/constructive functions (MD = - 0.26 [- 0.47, - 0.04]) on linear regressions adjusted for educational attainment and sex. When additionally adjusting for anxiety, depression, fatigue, insomnia, hypertension, and diabetes, executive functions (MD = - 0.44 [- 0.82, - 0.06]) were also worse following OHCA. Diabetes, symptoms of anxiety, depression, and fatigue were significantly associated with worse cognitive performance.CONCLUSIONS: In our study population, cognitive impairment was generally mild following OHCA. OHCA survivors performed worse than MI controls in 3 of 6 domains. These results support current guidelines that a post-OHCA follow-up service should screen for cognitive impairment, emotional problems, and fatigue.TRIAL REGISTRATION: ClinicalTrials.gov, NCT03543371. Registered 1 June 2018.
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| 4. |
- Blennow Nordström, Erik, et al.
(författare)
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Neuropsychological outcome after cardiac arrest : A prospective case control sub-study of the Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest trial (TTM2)
- 2020
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: This study is designed to provide detailed knowledge on cognitive impairment after out-of-hospital cardiac arrest (OHCA) and its relation to associated factors, and to validate the neurocognitive screening of the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest trial (TTM2-trial), assessing effectiveness of targeted temperature management after OHCA. Methods: This longitudinal multi-center clinical study is a sub-study of the TTM2-trial, in which a comprehensive neuropsychological examination is performed in addition to the main TTM2-trial neurocognitive screening. Approximately 7 and 24 months after OHCA, survivors at selected study sites are invited to a standardized assessment, including performance-based tests of cognition and questionnaires of emotional problems, fatigue, executive function and insomnia. At 1:1 ratio, a matched control group from a cohort of acute myocardial infarction (MI) patients is recruited to perform the same assessment. We aim to include 100 patients per group. Potential differences between the OHCA patients and the MI controls at 7 and 24 months will be analyzed with a linear regression, using composite z-scores per cognitive domain (verbal, visual/constructive, working memory, episodic memory, processing speed, executive functions) as primary outcome measures. Results from OHCA survivors on the main TTM2-trial neurocognitive screening battery will be compared with neuropsychological test results at 7 months, using sensitivity and specificity analyses. Discussion: In this study we collect detailed information on cognitive impairment after OHCA and compare this to a control group of patients with acute MI. The validation of the TTM2 neurocognitive screening battery could justify its inclusion in routine follow-up. Our results may have a potential to impact on the design of future follow-up strategies and interventions after OHCA. Trial registration: ClinicalTrials.gov, NCT03543371. Registered 1 June 2018
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| 6. |
- Blennow Nordström, Erik, et al.
(författare)
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Serum neurofilament light levels are correlated to long-term neurocognitive outcome measures after cardiac arrest
- 2022
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Ingår i: Brain Injury. - : Informa UK Limited. - 0269-9052 .- 1362-301X. ; 36:6, s. 800-809
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Tidskriftsartikel (refereegranskat)abstract
- Objective To explore associations between four methods assessing long-term neurocognitive outcome after out-of-hospital cardiac arrest and early hypoxic-ischemic neuronal brain injury assessed by the biomarker serum neurofilament light (NFL), and to compare the agreement for the outcome methods. Methods An explorative post-hoc study was conducted on survivor data from the international Target Temperature Management after Out-of-hospital Cardiac Arrest trial, investigating serum NFL sampled 48/72-hours post-arrest and neurocognitive outcome 6 months post-arrest. Results Among the long-term surviving participants (N = 457), serum NFL (n = 384) was associated to all outcome instruments, also when controlling for demographic and cardiovascular risk factors. Associations between NFL and the patient-reported Two Simple Questions (TSQ) were however attenuated when adjusting for vitality and mental health. NFL predicted results on the outcome instruments to varying degrees, with an excellent area under the curve for the clinician-report Cerebral Performance Category (CPC 1-2: 0.90). Most participants were classified as CPC 1 (79%). Outcome instrument correlations ranged from small (Mini-Mental State Examination [MMSE]-TSQ) to strong (CPC-MMSE). Conclusions The clinician-reported CPC was mostly related to hypoxic-ischemic brain injury, but with a ceiling effect. These results may be useful when selecting methods and instruments for clinical follow-up models.
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| 7. |
- Blennow Nordström, Erik, et al.
(författare)
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Validity of the IQCODE-CA : An informant questionnaire on cognitive decline modified for a cardiac arrest population
- 2017
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Ingår i: Resuscitation. - : Elsevier. - 0300-9572 .- 1873-1570. ; 118, s. 8-14
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To examine the psychometric properties of a modified version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), for a cardiac arrest population (IQCODE-CA). Methods: The IQCODE-CA, a 26-item observer-reported questionnaire, was completed by informants, defined as relatives or close friends, of 268 out-of-hospital cardiac arrest (OHCA) survivors who participated in the Target Temperature Management trial in a scheduled follow-up 180 +/- 14 days after OHCA. Survivors completed the Mini Mental State Examination (MMSE), the Rivermead Behavioural Memory Test (RBMT) and the Hospital Anxiety and Depression Scale (HADS). An exploratory factor analysis was performed. Associations between IQCODE-CA results and demographic variables along with other instruments were calculated. Area under the curve (AUC) ratios were evaluated to examine discrimination. Results: The IQCODE-CA measured one factor, global cognitive decline, with high internal consistency (ordinal alpha = 0.95). Age, gender or education did not influence the IQCODE-CA score. Associations with performance-based measures of global cognitive function as well as anxiety and depression ranged from small to moderate (rs = -0.29 to 0.38). AUC ratios ranged from fair to good (0.72-0.81). According to the MMSE and RBMT, the optimal cut-off score to identify cognitive decline on the IQCODE-CA was 3.04. Using this value, 53% of the survivors were under the cut-off. Conclusions: The IQCODE-CA identified a large amount of survivors with possible cognitive problems, making it useful when screening for cognitive decline post-CA. Due to lower AUC ratios than desired, additional performance-based measures should be used to improve the overall screening methodology. (C) 2017 Elsevier B.V. All rights reserved.
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| 8. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 9. |
- Bratt, Ola, 1963, et al.
(författare)
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Population-based Organised Prostate Cancer Testing: Results from the First Invitation of 50-year-old Men
- 2023
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Ingår i: European Urology. - 0302-2838 .- 1873-7560.
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Tidskriftsartikel (refereegranskat)abstract
- Background: The European Union recently recommended evaluation of the feasibility of organised prostate cancer screening. In Sweden, regional population-based organised prostate cancer testing (OPT) programmes were introduced in 2020. Objective: To describe initial participation rates and diagnostic outcomes. Design, setting, and participants: The three most populated Swedish regions invited all men aged 50 yr to OPT by a letter in 2020–2022. Men with prostate-specific antigen (PSA) ≥3 ng/ml were referred for prostate magnetic resonance imaging (MRI). PSA assays differed across regions. Men with Prostate Imaging Reporting and Data System (PI-RADS) 1–3 and PSA density ≥0.15 ng/ml/cm3 or PI-RADS 4–5 were referred for a biopsy. Data were obtained from the Swedish Register for Organised Prostate Cancer Testing. Outcome measurements and statistical analysis: Overall and regional participation rates, PSA distributions, PI-RADS score distributions, cancer detection, and treatment were evaluated. Results and limitations: A total of 23 855 (35%) of 68 060 invited men participated; 696 (2.9%) had PSA ≥3 ng/ml, and of them, 306 (44%) had a biopsy indication and 221 (32%) had a biopsy. On biopsy, 93 (42%) had Gleason grade group ≥2 (0.39% of PSA-tested men) and 44 (20%) Gleason grade group 1 cancer. Most men with cancer had treatment with curative intent (70%) or were under active surveillance (28%). Across regions, proportions of men with PSA ≥3 ng/ml ranged from 2.3% to 4.0%, and those with PI-RADS score 4–5 ranged from 12% to 21%. A limitation is that results are applicable only to first testing of men in their early 50s. Conclusions: The OPT programmes are feasible with good compliance to the diagnostic pathway. The use of MRI and PSA density avoided a biopsy for over half of the men with PSA ≥3 ng/ml. Inter-regional differences in diagnostic outcomes show a need for standardisation of the diagnostic pathway's components. Patient summary: We report the diagnostic outcomes of inviting 68 000 50-yr-old men to organised prostate cancer testing.
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| 10. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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