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  • 201. Ahsan, Murshidul
    et al.
    Hasan, Badrul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Algotsson, Magnus
    Sarenbo, Sirkku
    Handling and Welfare of Bovine Livestock at Local Abattoirs in Bangladesh2014In: Journal of Applied Animal Welfare Science, ISSN 1088-8705, E-ISSN 1532-7604, Vol. 17, no 4, p. 340-353Article in journal (Refereed)
    Abstract [en]

    The World Organization for Animal Health (OIE) allows rope casting and the tying of legs for nonhuman animals laughter without stunning. The handling and welfare of bovine livestock (Bosindicus and Bubalus bubalis) were studied in 8 local abattoirs in 5 districts of Bangladesh. A total of 302 animals were evaluated. At the local abattoirs, approximately 1/3 of the cattle and water buffalo were eithere maciated orinjured/sick. The size and vigor of the animals determined the casting method. Small and weak animals were cast on concrete floors by lifting a foreleg followed by pushing, or simply by twisting the head of the animal and then binding the legs with rope. Vigorous animals such as buffalo were castusing ropes and human force. Bleeding was slow and flaying was sometimes initiated before the animals were unconscious. Pulling and tearing of the trachea and pouring of water into the exposed trache a shortly after cutting were also observed in some cases.The over all animal handling was unnecessarily rough and he OIE standards were not implemented. Animals are subjected to considerable mistreatment, and there is an urgent need for the training nde ducation of the staff in a battoirs concerning humanes laughtering practices as well as a need to build moderns laughtering plants in Bangladesh.

  • 202. Aili, K
    et al.
    Nyman, T
    Svartengren, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Hillert, L
    Sleep as a predictive factor for the onset and resolution of multi-site pain: A 5-year prospective study2015In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 19, no 3, p. 341-349Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Disturbed sleep and pain often co-exist and the relationship between the two conditions is complex and likely reciprocal. This 5-year prospective study examines whether disturbed sleep can predict the onset of multi-site pain, and whether non-disturbed sleep can predict the resolution of multi-site pain.

    METHODS: The cohort (n = 1599) was stratified by the number of self-reported pain sites: no pain, pain from 1-2 sites and multi-site pain (≥3 pain sites). Sleep was categorized by self-reported sleep disturbance: sleep A (best sleep), sleep B and sleep C (worst sleep). In the no-pain and pain-from-1-2 sites strata, the association between sleep (A, B and C) and multi-site pain 5 years later was analysed. Further, the prognostic value of sleep for the resolution of multi-site pain at follow-up was calculated for the stratum with multi-site pain at baseline. In the analyses, gender, age, body mass index, smoking, physical activity and work-related exposures were treated as potential confounders.

    RESULTS: For individuals with no pain at baseline, a significantly higher odds ratio for multi-site pain 5 years later was seen for the tertile reporting worst sleep [odds ratio (OR) 4.55; 95% confidence interval (CI) 1.28-16.12]. Non-disturbed (or less disturbed) sleep had a significant effect when predicting the resolution of multi-site pain (to no pain) (OR 3.96; 95% CI 1.69-9.31).

    CONCLUSION: In conclusion, sleep could be relevant for predicting both the onset and the resolution of multi-site pain. It seems to be a significant factor to include in research on multi-site pain and when conducting or evaluating intervention programmes for pain.

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  • 203.
    Aili, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine. Department of Health and Sport, School of Health and Welfare, Halmstad University.
    Hellman, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Svartengren, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Danielsson, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Psychiatry.
    Including a Three-Party Meeting Using the Demand and Ability Protocol in an Interdisciplinary Pain Rehabilitation Programme for a Successful Return to Work Process2022In: International Journal of Environmental Research and Public Health, ISSN 1661-7827, E-ISSN 1660-4601, Vol. 19, no 24, article id 16614Article in journal (Refereed)
    Abstract [en]

    The Demand and Ability Protocol (DAP) is used in three-party meetings involving an employee, an employer, and a representative from the rehabilitation team. The aim of this study is to investigate the inclusion of an intervention using the DAP in an interdisciplinary pain rehabilitation programme (IPRP) compared to usual care. This non-randomised controlled trial included patients assigned to an IPRP in Sweden. The intervention group received a DAP intervention targeting their work situation in addition to the usual care provided by the IPRP. The control group received IPRP only. Outcome measures were collected from the Swedish Quality Registry for Pain Rehabilitation. Results demonstrated improvements in both groups regarding self-reported anxiety, depression and EQ5D. Sleep was improved in the intervention group but not in the control group. No statistical differences in outcomes were observed between the groups. In conclusion, adding the DAP intervention to IPRP seemed to have the potential to improve sleep among the patients, which may indicate an overall improvement regarding health outcomes from a longer perspective. The results were less clear, however, regarding the work-related outcomes of sickness absence and workability.

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  • 204. Aili, Katarina
    et al.
    Nyman, Teresia
    Hillert, Lena
    Svartengren, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Sleep disturbances predict future sickness absence among individuals with lower back or neck-shoulder pain: A 5-year prospective study2015In: Scandinavian Journal of Public Health, ISSN 1403-4948, E-ISSN 1651-1905, Vol. 43, no 3, p. 315-323Article in journal (Refereed)
    Abstract [en]

    Background: Musculoskeletal pain is one of the most common causes of sickness absence. Sleep disturbances are often co-occurring with pain, but the relationship between sleep and pain is complex. Little is known about the importance of self-reported sleep, when predicting sickness absence among persons with musculoskeletal pain. This study aims to study the association between self-reported sleep quality and sickness absence 5 years later, among individuals stratified by presence of lower back pain (LBP) and neck and shoulder pain (NSP). Methods: The cohort (n = 2286) in this 5-year prospective study (using data from the MUSIC-Norrtalje study) was stratified by self-reported pain into three groups: no LBP or NSP, solely LBP or NSP, and oncurrent LBP and NSP. Odds ratios (ORs) for the effect of self-reported sleep disturbances at baseline on sickness absence (> 14 consecutive days), 5 years later, were calculated. Results: Within all three pain strata, individuals reporting the most sleep problems showed a significantly higher OR for all-cause sickness absence, 5 years later. The group with the most pronounced sleep problems within the concurrent LBP and NSP stratum had a significantly higher OR (OR 2.00; CI 1.09-3.67) also for long-term sickness absence (> 90days) 5 years later, compared to the group with the best sleep. Conclusions: Sleep disturbances predict sickness absence among individuals regardless of co-existing features of LBP and/or NSP. The clinical evaluation of patients should take possible sleep disturbances into account in the planning of treatments.

  • 205.
    Aili, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine. Department of Health and Sport, School of Health and Welfare, Halmstad University, Halmstad, Sweden.
    Svartengren, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine. Department of Occupational and Environmental Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Danielsson, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Psychiatry.
    Johansson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine. Central Hospital in Karlstad, Karlstad, Sweden.
    Hellman, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine. Department of Occupational and Environmental Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Active engagement of managers in employee RTW and manager-employee relationship: managers’ experiences of participating in a dialogue using the Demand and Ability Protocol2023In: Disability and Rehabilitation, ISSN 0963-8288, E-ISSN 1464-5165, Vol. 45, no 26, p. 4394-4403Article in journal (Refereed)
    Abstract [en]

    Purpose: To describe how managers of employees on sick-leave, due to chronic pain conditions, experience participating in a three-party meeting using the Demand and Ability Protocol (DAP) in the return-to-work process.

    Materials and methods: This study is based on individual semi-structured interviews with 17 managers of employees with chronic pain. Interviews were conducted after participating in a three-party meeting including the employee, manager, and a representative from the rehabilitation team. The data were analyzed using thematic analysis with an inductive approach.

    Results: Two main themes were identified - "to converse with a clear structure and setup" and "to be involved in the employee's rehabilitation." The first theme describe experiences from the conversation, and the second theme reflected the managers' insights when being involved in the employee's rehabilitation. The themes comprise 11 sub-themes describing how the DAP conversation and the manager ' s involvement in the rehabilitation may influence the manager, the manager-employee relationship, and the organization.

    Conclusions: This study show, from a manager's perspective, how having a dialogue with a clear structure and an active involvement in the employee's rehabilitation may be beneficial for the manager-employee relationship. Insights from participating in the DAP may also be beneficial for the organization.

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  • 206.
    Aili, Katarina
    et al.
    Karolinska Inst, Inst Environm Med, Unit Occupat Med, Stockholm, Sweden..
    Åström-Paulsson, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Stoetzer, Ulrich
    Karolinska Inst, Inst Environm Med, Unit Intervent & Implementat Res, Stockholm, Sweden..
    Svartengren, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Hillert, Lena
    Karolinska Inst, Inst Environm Med, Unit Occupat Med, Stockholm, Sweden..
    Reliability of Actigraphy and Subjective Sleep Measurements in Adults: the Design of Sleep Assessments2017In: Journal of Clinical Sleep Medicine (JCSM), ISSN 1550-9389, E-ISSN 1550-9397, Vol. 13, no 1, p. 39-47Article in journal (Refereed)
    Abstract [en]

    STUDY OBJECTIVES: The aim of the study was to investigate how many nights of measurement are needed for a reliable measure of sleep in a working population including adult women and men.

    METHODS: In all, 54 individuals participated in the study. Sleep was assessed for 7 consecutive nights using actigraphy as an objective measure, and the Karolinska sleep diary for a subjective measure of quality. Using intra-class correlation and the Spearman-Brown formula, calculations of how many nights of measurements were required for a reliable measure were performed. Differences in reliability according to whether or not weekend measurements were included were investigated. Further, the correlation between objectively (actigraphy) measured sleep and subjectively measured sleep quality was studied over the different days of the week.

    RESULTS/CONCLUSIONS: The results concerning actigraphy sleep measures suggest that data from at least 2 nights are to be recommended when assessing sleep percent and at least 5 nights when assessing sleep efficiency. For actigraphy-measured total sleep time, more than 7 nights are needed. At least 6 nights of measurements are required for a reliable measure of self-reported sleep. Fewer nights (days) are required if measurements include only week nights. Overall, there was a low correlation between the investigated actigraphy sleep parameters and subjective sleep quality, suggesting that the two methods of measurement capture different dimensions of sleep.

  • 207.
    Aimo, Alberto
    et al.
    Univ Hosp Pisa, Cardiol Div, Pisa, Italy.
    Januzzi, James L., Jr.
    Massachusetts Gen Hosp, Boston, MA 02114 USA;Baim Inst Clin Res, Boston, MA USA.
    Vergaro, Giuseppe
    Scuola Super Sant Anna, Inst Life Sci, Pisa, Italy;Fdn Toscana G Monasterio, Pisa, Italy.
    Clerico, Aldo
    Scuola Super Sant Anna, Inst Life Sci, Pisa, Italy;Fdn Toscana G Monasterio, Pisa, Italy.
    Latini, Roberto
    IRCCS, Dept Cardiovasc Res, Ist Ric Farmacolog Mario Negri, Milan, Italy.
    Meessen, Jennifer
    IRCCS, Dept Cardiovasc Res, Ist Ric Farmacolog Mario Negri, Milan, Italy.
    Anand, Inder S.
    Univ Minnesota, Div Cardiovasc Med, Minneapolis, MN USA;VA Med Ctr, Dept Cardiol, Minneapolis, MN USA.
    Cohn, Jay N.
    Univ Minnesota, Div Cardiovasc Med, Minneapolis, MN USA.
    Gravning, Jorgen
    Oslo Univ Hosp, Dept Cardiol, Oslo, Norway;Univ Oslo, Ctr Heart Failure Res, Oslo, Norway.
    Ueland, Thor
    Oslo Univ Hosp, Rikshosp, Res Inst Internal Med, Oslo, Norway;Univ Oslo, Fac Med, Oslo, Norway;Univ Tromso, KG Jebsen Thrombosis Res & Expertise Ctr, Tromso, Norway.
    Nymo, Stale H.
    Oslo Univ Hosp, Rikshosp, Res Inst Internal Med, Oslo, Norway.
    Brunner-La Rocca, Hans-Peter
    Maastricht Univ, Dept Cardiol, Med Ctr, Maastricht, Netherlands.
    Bayes-Genis, Antoni
    Hosp Badalona Germans Trias & Pujol, Badalona, Barcelona, Spain.
    Lupon, Josep
    Hosp Badalona Germans Trias & Pujol, Badalona, Barcelona, Spain.
    de Boer, Rudolf A.
    Univ Med Ctr Groningen, Groningen, Netherlands.
    Yoshihisa, Akiomi
    Fukushima Med Univ, Dept Cardiovasc Med, Fukushima, Japan.
    Takeishi, Yasuchika
    Fukushima Med Univ, Dept Cardiovasc Med, Fukushima, Japan.
    Egstrup, Michael
    Copenhagen Univ Hosp, Dept Cardiol, Rigshosp, Copenhagen, Denmark.
    Gustafsson, Ida
    Copenhagen Univ Hosp, Dept Cardiol, Rigshosp, Copenhagen, Denmark.
    Gagging, Hanna K.
    Massachusetts Gen Hosp, Boston, MA 02114 USA;Baim Inst Clin Res, Boston, MA USA.
    Eggers, Kai M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Huber, Kurt
    Wilhelminenspital & Sigmund Freud Univ, Fac Internal Med, Med Sch, Vienna, Austria.
    Tentzeris, Ioannis
    Wilhelminenspital & Sigmund Freud Univ, Fac Internal Med, Med Sch, Vienna, Austria.
    Ripoli, Andrea
    Fdn Toscana G Monasterio, Pisa, Italy.
    Passino, Claudio
    Scuola Super Sant Anna, Inst Life Sci, Pisa, Italy;Fdn Toscana G Monasterio, Pisa, Italy.
    Emdin, Michele
    Scuola Super Sant Anna, Inst Life Sci, Pisa, Italy;Fdn Toscana G Monasterio, Pisa, Italy.
    Revisiting the obesity paradox in heart failure: Per cent body fat as predictor of biomarkers and outcome2019In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 26, no 16, p. 1751-1759Article in journal (Refereed)
    Abstract [en]

    Aims Obesity defined by body mass index (BMI) is characterized by better prognosis and lower plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure. We assessed whether another anthropometric measure, per cent body fat (PBF), reveals different associations with outcome and heart failure biomarkers (NT-proBNP, high-sensitivity troponin T (hs-TnT), soluble suppression of tumorigenesis-2 (sST2)). Methods In an individual patient dataset, BMI was calculated as weight (kg)/height (m) (2) , and PBF through the Jackson-Pollock and Gallagher equations. Results Out of 6468 patients (median 68 years, 78% men, 76% ischaemic heart failure, 90% reduced ejection fraction), 24% died over 2.2 years (1.5-2.9), 17% from cardiovascular death. Median PBF was 26.9% (22.4-33.0%) with the Jackson-Pollock equation, and 28.0% (23.8-33.5%) with the Gallagher equation, with an extremely strong correlation (r = 0.996, p < 0.001). Patients in the first PBF tertile had the worst prognosis, while patients in the second and third tertile had similar survival. The risks of all-cause and cardiovascular death decreased by up to 36% and 27%, respectively, per each doubling of PBF. Furthermore, prognosis was better in the second or third PBF tertiles than in the first tertile regardless of model variables. Both BMI and PBF were inverse predictors of NT-proBNP, but not hs-TnT. In obese patients (BMI >= 30 kg/m(2), third PBF tertile), hs-TnT and sST2, but not NT-proBNP, independently predicted outcome. Conclusion In parallel with increasing BMI or PBF there is an improvement in patient prognosis and a decrease in NT-proBNP, but not hs-TnT or sST2. hs-TnT or sST2 are stronger predictors of outcome than NT-proBNP among obese patients.

  • 208. Aimo, Alberto
    et al.
    Januzzi, James L
    Vergaro, Giuseppe
    Eggers, Kai M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Circulating levels and prognostic value of soluble ST2 in heart failure are less influenced by age than N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T2020In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 22, no 11, p. 2078-2088Article in journal (Refereed)
    Abstract [en]

    Aims N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT) and soluble suppression of tumorigenesis-2 (sST2) predict outcome in chronic heart failure (HF). We assessed the influence of age on circulating levels and prognostic significance of these biomarkers. Methods and results Individual data from 5301 patients with chronic HF and NT-proBNP, hs-TnT, and sST2 data were evaluated. Patients were stratified according to age: <60 years (n = 1332, 25%), 60-69 years (n = 1628, 31%), 70-79 years (n = 1662, 31%), and >= 80 years (n = 679, 13%). Patients (median age 66 years, 75% men, median left ventricular ejection fraction 28%, 64% with ischaemic HF) had median NT-proBNP 1564 ng/L, hs-TnT 21 ng/L, and sST2 29 ng/mL. Age independently predicted NT-proBNP and hs-TnT, but not sST2. The best NT-proBNP and hs-TnT cut-offs for 1-year and 5-year all-cause and cardiovascular mortality and 1- to 12-month HF hospitalization increased with age, while the best sST2 cut-offs did not. When stratifying patients according to age- and outcome-specific cut-offs, this stratification yielded independent prognostic significance over NT-proBNP levels only, or the composite of NT-proBNP and hs-TnT, and improved risk prediction for most endpoints. Finally, absolute NT-proBNP, hs-TnT, and sST2 levels predicted outcomes independent of age, sex, left ventricular ejection fraction category, ethnic group, and other variables. Conclusions Soluble ST2 is less influenced by age than NT-proBNP or hs-TnT; all these biomarkers predict outcome regardless of age. The use of age- and outcome-specific cut-offs of NT-proBNP, hs-TnT and sST2 allows more accurate risk stratification than NT-proBNP alone or the combination of NT-proBNP and hs-TnT.

  • 209.
    Aimo, Alberto
    et al.
    Scuola Super Sant Anna, Pisa, Italy.
    Januzzi, James L
    Massachusetts Gen Hosp, Boston, MA, USA; Harvard Clin Res Inst, Boston, MA USA.
    Vergaro, Giuseppe
    Scuola Super Sant Anna, Pisa, Italy; Fdn Toscana Gabriele Monasterio, Pisa, Italy.
    Ripoli, Andrea
    Fdn Toscana Gabriele Monasterio, Pisa, Italy.
    Latini, Roberto
    IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy.
    Masson, Serge
    IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy.
    Magnoli, Michela
    IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy.
    Anand, Inder S
    Univ Minnesota, Div Cardiovasc Med, Minneapolis, MN, USA; VA Med Ctr, Dept Cardiol, Minneapolis, MN USA.
    Cohn, Jay N
    Univ Minnesota, Div Cardiovasc Med, Minneapolis, MN, USA.
    Tavazzi, Luigi
    ES Hlth Sci Fdn, GVM Hosp Care & Res, Cotignola, Italy.
    Tognoni, Gianni
    IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy.
    Gravning, Jørgen
    Oslo Univ Hosp, Dept Cardiol, Ulleval, Norway; Univ Oslo, Ctr Heart Failure Res, Oslo, Norway.
    Ueland, Thor
    Oslo Univ Hosp, Rikshosp, Internal Med Res Inst, Oslo, Norway; Univ Oslo, Fac Med, Oslo, Norway; Univ Tromso, Jebsen Thrombosis Res & Expertise Ctr, Tromso, Norway.
    Nymo, Ståle H
    Oslo Univ Hosp, Rikshosp, Internal Med Res Inst, Oslo, Norway.
    Brunner-La Rocca, Hans-Peter
    Maastricht Univ, Med Ctr, Dept Cardiol, Maastricht, Netherlands.
    Bayes-Genis, Antoni
    Hosp Badalona Germans Trias & Pujol, Badalona, Barcelona, Spain.
    Lupón, Josep
    Hosp Badalona Germans Trias & Pujol, Badalona, Barcelona, Spain.
    de Boer, Rudolf A
    Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands.
    Yoshihisa, Akiomi
    Fukushima Med Univ, Dept Cardiovasc Med, Fukushima, Japan.
    Takeishi, Yasuchika
    Fukushima Med Univ, Dept Cardiovasc Med, Fukushima, Japan.
    Egstrup, Michael
    Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, Copenhagen, Denmark.
    Gustafsson, Ida
    Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, Copenhagen, Denmark.
    Gaggin, Hanna K
    Massachusetts Gen Hosp, Boston, MA, USA; Harvard Clin Res Inst, Boston, MA, USA.
    Eggers, Kai M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Huber, Kurt
    Wilhelminenspital Stadt Wien, Fac Internal Med, Vienna, Austria; Sigmund Freud Univ, Med Sch, Vienna, Austria.
    Tentzeris, Ioannis
    Wilhelminenspital Stadt Wien, Fac Internal Med, Vienna, Austria; Sigmund Freud Univ, Med Sch, Vienna, Austria.
    Tang, Wai H.W.
    Cleveland Clin, Inst Heart & Vasc, Cleveland, OH, USA.
    Grodin, Justin
    Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX USA.
    Passino, Claudio
    Scuola Super Sant Anna, Pisa, Italy; Fdn Toscana Gabriele Monasterio, Pisa, Italy.
    Emdin, Michele
    Scuola Super Sant Anna, Pisa, Italy; Fdn Toscana Gabriele Monasterio, Pisa, Italy.
    Prognostic Value of High-Sensitivity Troponin T in Chronic Heart Failure: An Individual Patient Data Meta-Analysis2018In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 137, no 3, p. 286-297Article in journal (Refereed)
    Abstract [en]

    Background: Most patients with chronic heart failure have detectable troponin concentrations when evaluated by high-sensitivity assays. The prognostic relevance of this finding has not been clearly established so far. We aimed to assess high-sensitivity troponin assay for risk stratification in chronic heart failure through a meta-analysis approach.

    Methods: Medline, EMBASE, Cochrane Library, and Scopus were searched in April 2017 by 2 independent authors. The terms were “troponin” AND “heart failure” OR “cardiac failure” OR “cardiac dysfunction” OR “cardiac insufficiency” OR “left ventricular dysfunction.” Inclusion criteria were English language, clinical stability, use of a high-sensitivity troponin assay, follow-up studies, and availability of individual patient data after request to authors. Data retrieved from articles and provided by authors were used in agreement with the PRISMA statement. The end points were all-cause death, cardiovascular death, and hospitalization for cardiovascular cause.

    Results: Ten studies were included, reporting data on 11 cohorts and 9289 patients (age 66±12 years, 77% men, 60% ischemic heart failure, 85% with left ventricular ejection fraction <40%). High-sensitivity troponin T data were available for all patients, whereas only 209 patients also had high-sensitivity troponin I assayed. When added to a prognostic model including established risk markers (sex, age, ischemic versus nonischemic etiology, left ventricular ejection fraction, estimated glomerular filtration rate, and N-terminal fraction of pro-B-type natriuretic peptide), high-sensitivity troponin T remained independently associated with all-cause mortality (hazard ratio, 1.48; 95% confidence interval, 1.41–1.55), cardiovascular mortality (hazard ratio, 1.40; 95% confidence interval, 1.33–1.48), and cardiovascular hospitalization (hazard ratio, 1.42; 95% confidence interval, 1.36–1.49), over a median 2.4-year follow-up (all P<0.001). High-sensitivity troponin T significantly improved risk prediction when added to a prognostic model including the variables above. It also displayed an independent prognostic value for all outcomes in almost all population subgroups. The area under the curve–derived 18 ng/L cutoff yielded independent prognostic value for the 3 end points in both men and women, patients with either ischemic or nonischemic etiology, and across categories of renal dysfunction.

    Conclusions: In chronic heart failure, high-sensitivity troponin T is a strong and independent predictor of all-cause and cardiovascular mortality, and of hospitalization for cardiovascular causes, as well. This biomarker then represents an additional tool for prognostic stratification.

  • 210.
    Aimo, Alberto
    et al.
    Scuola Super Sant Anna, Pisa, Italy.
    Januzzi, James L.
    Massachusetts Gen Hosp, Harvard Clin Res Inst, Boston, MA USA.
    Vergaro, Giuseppe
    Scuola Super Sant Anna, Pisa, Italy; Fdn Toscana G Monasterio, Pisa, Italy.
    Ripoli, Andrea
    Fdn Toscana G Monasterio, Pisa, Italy.
    Latini, Roberto
    IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy.
    Masson, Serge
    IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy.
    Magnoli, Michela
    IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy.
    Anand, Inder S.
    Univ Minnesota, Div Cardiovasc Med, Minneapolis, MN USA; VA Med Ctr, Dept Cardiol, Minneapolis, MN USA.
    Cohn, Jay N
    Univ Minnesota, Div Cardiovasc Med, Minneapolis, MN USA.
    Tavazzi, Luigi
    ES Hlth Sci Fdn, GVM Hosp Care & Res, Cotignola, Italy.
    Tognoni, Gianni
    IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy.
    Gravning, Jørgen
    Oslo Univ Hosp, Dept Cardiol, Oslo, Norway; Univ Oslo, Ctr Heart Failure Res, Oslo, Norway.
    Ueland, Thor
    Oslo Univ Hosp, Res Inst Internal Med, Rikshosp, Oslo, Norway; Univ Oslo, Fac Med, Oslo, Norway; Univ Tromso, KG Jebsen Thrombosis Res & Expertise Ctr, Tromso, Norway .
    Nymo, Ståle H
    Oslo Univ Hosp, Res Inst Internal Med, Rikshosp, Oslo, Norway.
    Rocca, Hans-Peter Brunner-La
    Maastricht Univ, Med Ctr, Dept Cardiol, Maastricht, Netherland.
    Bayes-Genis, Antoni
    Hosp Badalona Germans Trias & Pujol, Barcelona, Spain.
    Lupón, Josep
    Hosp Badalona Germans Trias & Pujol, Barcelona, Spain.
    de Boer, Rudolf A.
    Univ Med Ctr Groningen, Groningen, Netherlands.
    Yoshihisa, Akiomi
    Fukushima Med Univ, Dept Cardiovasc Med, Fukushima, Japan.
    Takeishi, Yasuchika
    Fukushima Med Univ, Dept Cardiovasc Med, Fukushima, Japan.
    Egstrup, Michael
    Copenhagen Univ Hosp, Dept Cardiol, Rigshosp, Copenhagen, Denmark.
    Gustafsson, Ida
    Copenhagen Univ Hosp, Dept Cardiol, Rigshosp, Copenhagen, Denmark.
    Gaggin, Hanna K.
    Massachusetts Gen Hosp, Harvard Clin Res Inst, Boston, MA USA.
    Eggers, Kai M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Huber, Kurt
    Wilhelminenspital Stadt Wien, Fac Internal Med, Vienna, Austria; Sigmund Freud Univ, Med Sch, Vienna, Austria.
    Tentzeris, Ioannis
    Wilhelminenspital Stadt Wien, Fac Internal Med, Vienna, Austria; Sigmund Freud Univ, Med Sch, Vienna, Austria.
    Wilson Tang, W. H.
    Cleveland Clin, Heart & Vasc Inst, Cleveland, OH USA.
    Grodin, Justin L
    Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Div Cardiol, Dallas, TX USA.
    Passino, Claudio
    Scuola Super Sant Anna, Pisa, Italy; Fdn Toscana G Monasterio, Pisa, Italy.
    Emdin, Michele
    Scuola Super Sant Anna, Pisa, Italy; Fdn Toscana G Monasterio, Pisa, Italy.
    High-sensitivity troponin T, NT-proBNP and glomerular filtration rate: A multimarker strategy for risk stratification in chronic heart failure2019In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 277, p. 166-172, article id S0167-5273(18)32769-4Article in journal (Refereed)
    Abstract [en]

    Background: In a recent individual patient data meta-analysis, high-sensitivity troponin T (hs-TnT) emerged as robust predictor of prognosis in stable chronic heart failure (HF). In the same population, we compared the relative predictive performances of hs-TnT, N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP), hs-C-reactive protein (hs-CRP), and estimated glomerular filtration rate (eGFR) for prognosis.

    Methods and results: 9289 patients (66 ± 12 years, 77% men, 85% LVEF <40%, 60% ischemic HF) were evaluated over a 2.4-year median follow-up. Median eGFR was 58 mL/min/1.73 m2 (interquartile interval 46–70; n = 9220), hs-TnT 16 ng/L (8–20; n = 9289), NT-proBNP 1067 ng/L (433–2470; n = 8845), and hs-CRP 3.3 mg/L (1.4–7.8; n = 7083). In a model including all 3 biomarkers, only hs-TnT and NT-proBNP were independent predictors of all-cause and cardiovascular mortality and cardiovascular hospitalization. hs-TnT was a stronger predictor than NT-proBNP: for example, the risk for all-cause death increased by 54% per doubling of hs-TnT vs. 24% per doubling of NT-proBNP. eGFR showed independent prognostic value from both hs-TnT and NT-proBNP. The best hs-TnT and NT-proBNP cut-offs for the prediction of all-cause death increased progressively with declining renal function (eGFR ≥ 90: hs-TnT 13 ng/L and NT-proBNP 825 ng/L; eGFR < 30: hs-TnT 40 ng/L and NT-proBNP 4608 ng/L). Patient categorization according to these cut-offs effectively stratified patient prognosis across all eGFR classes.

    Conclusions: hs-TnT conveys independent prognostic information from NT-proBNP, while hs-CRP does not. Concomitant assessment of eGFR may further refine risk stratification. Patient classification according to hs-TnT and NT-proBNP cut-offs specific for the eGFR classes holds prognostic significance.

  • 211.
    Aithal, Guruprasad P.
    et al.
    Nottingham Univ Hosp NHS Trust, NIHR Nottingham Digest Dis Biomed Res Unit, Nottingham, England..
    Nicoletti, Paola
    Columbia Univ, New York, NY USA..
    Bjornsson, Einar
    Landspitali Univ Hosp, Reykjavik, Iceland..
    Lucena, M. I.
    CIBERehd, Madrid, Spain.;Univ Malaga, E-29071 Malaga, Spain..
    Andrade, Raul J.
    CIBERehd, Madrid, Spain.;Univ Malaga, E-29071 Malaga, Spain..
    Grove, Jane
    Nottingham Univ Hosp NHS Trust, NIHR Nottingham Digest Dis Biomed Res Unit, Nottingham, England..
    Stephens, C.
    Univ Malaga, E-29071 Malaga, Spain..
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Maitland-van der Zee, Anke H.
    Univ Utrecht, Utrecht, Netherlands..
    Martin, Jennifer H.
    Univ Queensland, Brisbane, Qld, Australia.;Princess Alexandra Hosp, Brisbane, Qld, Australia..
    Cascorbi, Ingolf
    Univ Hosp Schleswig Holstein, Kiel, Germany..
    Dillon, John F.
    Ninewells Hosp & Med Sch, Dundee, Scotland..
    Laitinen, Tarja
    Univ Helsinki, Cent Hosp, Helsinki, Finland..
    Larrey, Dominique G.
    Hop St Eloi, Montpellier, France..
    Molokhia, Mariam
    Univ London, Kings Coll London, London SW3 6LX, England..
    Kullak-Ublick, Gerd A.
    Univ Zurich, Zurich, Switzerland..
    Ibanez, Luisa
    Hosp Univ Vall Hebron, Barcelona, Spain..
    Pirmohamed, Munir
    Univ Liverpool, Liverpool L69 3BX, Merseyside, England..
    Qin, Shengying
    Shanghai Jiao Tong Univ, Shanghai 200030, Peoples R China..
    Sawle, Ashley
    Columbia Univ, New York, NY USA..
    Bessone, Fernando
    Univ Nacl Rosario, Fac Ciencias Med, RA-2000 Rosario, Argentina..
    Hernandez, Nelia
    Univ Republ, Mentevideo, Uruguay..
    Stolz, Andrew
    Univ So Calif, Los Angeles, CA USA..
    Chalasani, Naga P.
    Indiana Univ, Indianapolis, IN 46204 USA..
    Serrano, Jose
    Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA..
    Barnhart, Huiman X.
    Duke Clin Res Inst, Durham, NC USA..
    Fontana, Robert J.
    Univ Michigan, Ann Arbor, MI 48109 USA..
    Watkins, Paul
    Hamner UNC Inst Drug Safety Sci, Durham, NC USA..
    Urban, Thomas J.
    UNC Eshelman Sch Pharm, Chapel Hill, NC USA..
    Daly, Ann K.
    Newcastle Univ, Newcastle, NSW, Australia..
    HLA-A*33:01 is strongly associated with drug-induced liver injury (DILI) due to terbinafine and several other unrelated compounds2015In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 62, p. 325A-326AArticle in journal (Other academic)
  • 212.
    Ajeganova, Sofia
    et al.
    Karolinska Inst, Dept Med Huddinge, S-14186 Stockholm, Sweden..
    Tesfa, Daniel
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med Huddinge, S-14186 Stockholm, Sweden.;Roche AB, Med Affairs, S-10074 Stockholm, Sweden..
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Fadeel, Bengt
    Karolinska Inst, Inst Environm Med, Unit Mol Toxicol, S-17177 Stockholm, Sweden..
    Vedin, Inger
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med Huddinge, S-14186 Stockholm, Sweden..
    Zignego, Anna Linda
    Univ Florence, Ctr Syst Manifestat Hepatitis Viruses, Dept Internal Med, I-50134 Florence, Italy..
    Palmblad, Jan
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med Huddinge, S-14186 Stockholm, Sweden..
    Effect of FCGR polymorphism on the occurrence of late-onset neutropenia and flare-free survival in rheumatic patients treated with rituximab2017In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 19, article id 44Article in journal (Refereed)
    Abstract [en]

    Background: The causes and mechanisms of late-onset neutropenia (LON) following rituximab treatment in patients with rheumatic diseases are not known. In this study, we aimed to investigate the role of established Fc gamma receptor gene (FCGR) polymorphisms and B-cell-activating factor (BAFF) gene promoter polymorphisms for the development of LON and for the efficacy of rituximab in patients with rheumatic diseases. Methods: A single-center case-control retrospective study was nested in a cohort of 214 consecutive patients with rheumatic diseases treated with rituximab. Eleven patients presented with LON. Fifty non-LON control subjects were matched by diagnosis, age, sex, and treatments. Single-nucleotide polymorphisms of FCGR (FCGR2A 131H/R, FCGR2B 232I/T, FCGR3A 158V/F) and BAFF promoter polymorphism -871C/T were analyzed with polymerase chain reaction-based techniques, and serum immunoglobulin M (IgM) and BAFF levels were analyzed by enzyme-linked immunosorbent assay. Flare-free survival was related to LON occurrence and polymorphisms. Results: The FCGR3A V allele, but not other FCGR polymorphisms, correlated with the occurrence of LON; each V allele conferred a fourfold increased OR for LON (p = 0.017). FCGR3A 158V/V and presentation with LON were associated with a longer flare-free survival (p = 0.023 and p = 0.031, respectively). FCGR3A 158V/V was related to lower IgM levels (p = 0.016). Serum BAFF levels showed no relationship with LON and BAFF -871C/T promoter polymorphism. There was a tendency toward longer flare-free survival in patients with the BAFF -871T/T allotype compared with the C/T or C/C allotypes (p = 0.096). Conclusions: The results of the present study suggest that presentation with LON may be a result of the intrinsic efficacy of rituximab in patients with rheumatic diseases. LON could indicate a longer biological and therapeutic activity of rituximab modulated by a certain genotypic polymorphism: the high-affinity FCGR3A V allele. This genotype and the occurrence of LON are both related to longer flare-free survival, suggestive of common mechanisms for LON and duration of response to rituximab. The role of the BAFF -871C/T promoter polymorphism in LON occurrence is unclear.

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  • 213.
    Akaberi, Dario
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Identification of protease inhibitors against Flaviviruses and Coronaviruses2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Vector-borne flaviviruses and coronaviruses of zoonotic origins are important human pathogens and represent a serious threat to public health worldwide. Flaviviruses can be found on all continents, apart from Antarctica, where they are transmitted by arthropod vectors causing millions of infections every year. While most of the infections are mild or asymptomatic, flaviviruses like dengue and yellow fever viruses can cause potentially lethal hemorrhagic fever and shock syndrome. Neurotropic flaviviruses like West Nile, Japanese encephalitis, and Tick-borne encephalitis (TBEV) can cause meningoencephalitis with long-term symptoms.  Coronaviruses, and in particular betacoronaviruses of zoonotic origin like SARS (2003) and MERS (2012), have been periodically emerging since the early 2000s causing outbreaks of severe respiratory syndrome. The latest example is SARS-CoV-2 that after causing a cluster of infection in the Chinese city of Wuhan, spread all over the world causing at present over 6.9 million deaths. Although vaccines are essential in preventing infections or severe disease and hospitalization in the case of SARS-CoV-2, antivirals represent an extremely valuable tool for treatment and prevention of current and future flavivirus and coronavirus infections. In the work presented in this thesis we have used a combination of in silico and in vitro techniques to identify and test the activity of potential inhibitors of viral proteases. 

    In our first study (paper 1) we unexpectedly identified an HIV protease inhibitor with in vitro activity against ZIKV NS2B-NS3 protease. The inhibitor was identified by virtual screening of a library of known protease inhibitors, evaluated by molecular dynamics simulation and finally tested against recombinant ZIKV protease using a FRET-based enzymatic assay. The same combination of molecular docking and molecular dynamics simulations were also used to correctly predict the activity of a known pan-Flavivirus protease inhibitor against TBEV protease (paper 2). As a result, we were the first to report peptide-based compounds with in vitro activity against TBEV. 

    After the outbreak of the COVID-19 we switched our attention to SARS-CoV-2. We first tested the inhibitory effect of the broad-spectrum antiviral nitric oxide (NO) and found that the NO-releasing compound SNAP had a dose dependent inhibitory effect on SARS-CoV-2 replication in cell-based assays (paper 3). We speculated that SNAP could inhibit SARS-COV-2 protease by trans-nitration of the catalytic Cys145 of SARS-CoV-2 main protease and found that SNAP had a dose dependent inhibitory effect on recombinant SARS-CoV-2 Mpro protease activity in an in vitro enzymatic assay. In our last study (paper 4) we identified a new class of potent SARS-CoV-2 protease inhibitors through the affinity screening of DNA-encoded-chemical libraries containing 4.2 billion compounds. The identified compounds inhibited recombinant SARS-CoV-2 protease with IC50 as low as 25 nM and had a dose dependent antiviral effect in the low micromolar range in infected Calu-3 and Caco-2 cell lines. 

    List of papers
    1. Targeting the NS2B-NS3 protease of tick-borne encephalitis virus with pan-flaviviral protease inhibitors
    Open this publication in new window or tab >>Targeting the NS2B-NS3 protease of tick-borne encephalitis virus with pan-flaviviral protease inhibitors
    Show others...
    2021 (English)In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 190, article id 105074Article in journal (Refereed) Published
    Abstract [en]

    Tick-borne encephalitis (TBE) is a severe neurological disorder caused by tick-borne encephalitis virus (TBEV), a member of the Flavivirus genus. Currently, two vaccines are available in Europe against TBEV. However, TBE cases have been rising in Sweden for the past twenty years, and thousands of cases are reported in Europe, emphasizing the need for antiviral treatments against this virus. The NS2B-NS3 protease is essential for flaviviral life cycle and has been studied as a target for the design of inhibitors against several well-known flaviviruses, but not TBEV. In the present study, Compound 86, a known tripeptidic inhibitor of dengue (DENV), West Nile (WNV) and Zika (ZIKV) proteases, was predicted to be active against TBEV protease using a combination of in silico techniques. Further, Compound 86 was found to inhibit recombinant TBEV protease with an IC50 = 0.92 mu M in the in vitro enzymatic assay. Additionally, two more peptidic analogues were synthetized and they displayed inhibitory activities against both TBEV and ZIKV proteases. In particular, Compound 104 inhibited ZIKV protease with an IC50 = 0.25 mu M. These compounds represent the first reported inhibitors of TBEV protease to date and provides valuable information for the further development of TBEV as well as pan-flavivirus protease inhibitors.

    Place, publisher, year, edition, pages
    ElsevierELSEVIER, 2021
    Keywords
    Tick-borne encephalitis virus, Zika virus, NS2B-NS3 serine protease, Docking, MD simulations, Peptide hybrids
    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:uu:diva-447918 (URN)10.1016/j.antiviral.2021.105074 (DOI)000657783600004 ()33872674 (PubMedID)
    Funder
    Swedish National Infrastructure for Computing (SNIC), SNIC 2017/1-213Swedish National Infrastructure for Computing (SNIC), SNIC 2018/3-252Swedish National Infrastructure for Computing (SNIC), SNIC 2019/3-312
    Available from: 2021-09-02 Created: 2021-09-02 Last updated: 2024-01-15Bibliographically approved
    2. Identification of a C2-symmetric diol based human immunodeficiency virus protease inhibitor targeting Zika virus NS2B-NS3 protease
    Open this publication in new window or tab >>Identification of a C2-symmetric diol based human immunodeficiency virus protease inhibitor targeting Zika virus NS2B-NS3 protease
    Show others...
    2020 (English)In: Journal of Biomolecular Structure and Dynamics, ISSN 0739-1102, E-ISSN 1538-0254, Vol. 38, no 18, p. 5526-5536Article in journal (Refereed) Published
    Abstract [en]

    Zika virus (ZIKV) is an emerging mosquito-borne flavivirus and infection by ZIKV Asian lineage is known to cause fetal brain anomalies and Guillain-Barrés syndrome. The WHO declared ZIKV a global public health emergency in 2016. However, currently neither vaccines nor antiviral prophylaxis/treatments are available. In this study, we report the identification of a C2-symmetric diol-based Human immunodeficiency virus type-1 (HIV) protease inhibitor active against ZIKV NS2B-NS3 protease. The compound, referred to as 9b, was identified by in silico screening of a library of 6265 protease inhibitors. Molecular dynamics (MD) simulation studies revealed that compound 9b formed a stable complex with ZIKV protease. Interaction analysis of compound 9b's binding pose from the cluster analysis of MD simulations trajectories predicted that 9b mostly interacted with ZIKV NS3. Although designed as an aspartyl protease inhibitor, compound 9b was found to inhibit ZIKV serine protease in vitro with IC50 = 143.25 ± 5.45 µM, in line with the in silico results. Additionally, linear interaction energy method (LIE) was used to estimate binding affinities of compounds 9b and 86 (a known panflavivirus peptide hybrid with IC50 = 1.64 ± 0.015 µM against ZIKV protease). The LIE method correctly predicted the binding affinity of compound 86 to be lower than that of 9b, proving to be superior to the molecular docking methods in scoring and ranking compounds. Since most of the reported ZIKV protease inhibitors are positively charged peptide-hybrids, with our without electrophilic warheads, compound 9b represents a less polar and more drug-like non-peptide hit compound useful for further optimization.Communicated by Ramaswamy Sarma.

    Keywords
    In silico screening, NS2B-NS3 protease, Zika virus (ZIKV), protease inhibitors, structure-based drug discovery
    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-430553 (URN)10.1080/07391102.2019.1704882 (DOI)000504558200001 ()31880199 (PubMedID)
    Funder
    Kjell and Marta Beijer Foundation
    Available from: 2021-01-11 Created: 2021-01-11 Last updated: 2023-08-10Bibliographically approved
    3. Mitigation of the replication of SARS-CoV-2 by nitric oxide in vitro
    Open this publication in new window or tab >>Mitigation of the replication of SARS-CoV-2 by nitric oxide in vitro
    Show others...
    2020 (English)In: Redox Biology, E-ISSN 2213-2317, Vol. 37, article id 101734Article in journal (Refereed) Published
    Abstract [en]

    The ongoing SARS-CoV-2 pandemic is a global public health emergency posing a high burden on nations' health care systems and economies. Despite the great effort put in the development of vaccines and specific treatments, no prophylaxis or effective therapeutics are currently available. Nitric oxide (NO) is a broad-spectrum antimicrobial and a potent vasodilator that has proved to be effective in reducing SARS-CoV replication and hypoxia in patients with severe acute respiratory syndrome. Given the potential of NO as treatment for SARS-CoV-2 infection, we have evaluated the in vitro antiviral effect of NO on SARS-CoV-2 replication. The NO-donor S-nitroso-N-acetylpenicillamine (SNAP) had a dose dependent inhibitory effect on SARS-CoV-2 replication, while the non S-nitrosated NAP was not active, as expected. Although the viral replication was not completely abolished (at 200 μM and 400 μM), SNAP delayed or completely prevented the development of viral cytopathic effect in treated cells, and the observed protective effect correlated with the level of inhibition of the viral replication. The capacity of the NO released from SNAP to covalently bind and inhibit SARS-CoV-2 3CL recombinant protease in vitro was also tested. The observed reduction in SARS-CoV-2 protease activity was consistent with S-nitrosation of the enzyme active site cysteine.

    Place, publisher, year, edition, pages
    Elsevier, 2020
    Keywords
    3CL protease, COVID-19, FRET, Nitric oxide, SARS-CoV-2
    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:uu:diva-430554 (URN)10.1016/j.redox.2020.101734 (DOI)000605007700001 ()33007504 (PubMedID)
    Funder
    Swedish Research Council, 2017-05807Swedish Research Council, 2018-02569Knut and Alice Wallenberg FoundationScience for Life Laboratory, SciLifeLab
    Available from: 2021-01-11 Created: 2021-01-11 Last updated: 2024-01-04Bibliographically approved
    4. Identification of unique and potent inhibitors of SARS-CoV-2 main protease from DNA-encoded chemical libraries
    Open this publication in new window or tab >>Identification of unique and potent inhibitors of SARS-CoV-2 main protease from DNA-encoded chemical libraries
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    SARS-CoV-2, antivirals, protease inhibitors
    National Category
    Infectious Medicine Medicinal Chemistry
    Research subject
    Biology with specialization in Microbiology
    Identifiers
    urn:nbn:se:uu:diva-508906 (URN)
    Available from: 2023-08-10 Created: 2023-08-10 Last updated: 2023-08-14Bibliographically approved
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  • 214.
    Akaberi, Dario
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Zoonosis Sci Ctr, Uppsala, Sweden..
    Bahlstrom, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Chinthakindi, Praveen K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Nyman, Tomas
    Karolinska Inst, Dept Med Biochem & Biophys, Prot Sci Facil, Stockholm, Sweden..
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala Univ, Zoonosis Sci Ctr, Uppsala, Sweden..
    Palanisamy, Navaneethan
    Univ Freiburg, Inst Biol 2, Freiburg, Germany..
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Zoonosis Sci Ctr, Uppsala, Sweden..
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Targeting the NS2B-NS3 protease of tick-borne encephalitis virus with pan-flaviviral protease inhibitors2021In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 190, article id 105074Article in journal (Refereed)
    Abstract [en]

    Tick-borne encephalitis (TBE) is a severe neurological disorder caused by tick-borne encephalitis virus (TBEV), a member of the Flavivirus genus. Currently, two vaccines are available in Europe against TBEV. However, TBE cases have been rising in Sweden for the past twenty years, and thousands of cases are reported in Europe, emphasizing the need for antiviral treatments against this virus. The NS2B-NS3 protease is essential for flaviviral life cycle and has been studied as a target for the design of inhibitors against several well-known flaviviruses, but not TBEV. In the present study, Compound 86, a known tripeptidic inhibitor of dengue (DENV), West Nile (WNV) and Zika (ZIKV) proteases, was predicted to be active against TBEV protease using a combination of in silico techniques. Further, Compound 86 was found to inhibit recombinant TBEV protease with an IC50 = 0.92 mu M in the in vitro enzymatic assay. Additionally, two more peptidic analogues were synthetized and they displayed inhibitory activities against both TBEV and ZIKV proteases. In particular, Compound 104 inhibited ZIKV protease with an IC50 = 0.25 mu M. These compounds represent the first reported inhibitors of TBEV protease to date and provides valuable information for the further development of TBEV as well as pan-flavivirus protease inhibitors.

  • 215.
    Akaberi, Dario
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Chinthakindi, Praveen K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Båhlström, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Palanisamy, Navaneethan
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Identification of a C2-symmetric diol based human immunodeficiency virus protease inhibitor targeting Zika virus NS2B-NS3 protease2020In: Journal of Biomolecular Structure and Dynamics, ISSN 0739-1102, E-ISSN 1538-0254, Vol. 38, no 18, p. 5526-5536Article in journal (Refereed)
    Abstract [en]

    Zika virus (ZIKV) is an emerging mosquito-borne flavivirus and infection by ZIKV Asian lineage is known to cause fetal brain anomalies and Guillain-Barrés syndrome. The WHO declared ZIKV a global public health emergency in 2016. However, currently neither vaccines nor antiviral prophylaxis/treatments are available. In this study, we report the identification of a C2-symmetric diol-based Human immunodeficiency virus type-1 (HIV) protease inhibitor active against ZIKV NS2B-NS3 protease. The compound, referred to as 9b, was identified by in silico screening of a library of 6265 protease inhibitors. Molecular dynamics (MD) simulation studies revealed that compound 9b formed a stable complex with ZIKV protease. Interaction analysis of compound 9b's binding pose from the cluster analysis of MD simulations trajectories predicted that 9b mostly interacted with ZIKV NS3. Although designed as an aspartyl protease inhibitor, compound 9b was found to inhibit ZIKV serine protease in vitro with IC50 = 143.25 ± 5.45 µM, in line with the in silico results. Additionally, linear interaction energy method (LIE) was used to estimate binding affinities of compounds 9b and 86 (a known panflavivirus peptide hybrid with IC50 = 1.64 ± 0.015 µM against ZIKV protease). The LIE method correctly predicted the binding affinity of compound 86 to be lower than that of 9b, proving to be superior to the molecular docking methods in scoring and ranking compounds. Since most of the reported ZIKV protease inhibitors are positively charged peptide-hybrids, with our without electrophilic warheads, compound 9b represents a less polar and more drug-like non-peptide hit compound useful for further optimization.Communicated by Ramaswamy Sarma.

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    fulltext
  • 216.
    Akaberi, Dario
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Krambrich, Janina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ling, Jiaxin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Chen, Luni
    Department of Microbiology and Tumour and Cell Biology (MTC), Karolinska Institute, Solna, Sweden.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mitigation of the replication of SARS-CoV-2 by nitric oxide in vitro2020In: Redox Biology, E-ISSN 2213-2317, Vol. 37, article id 101734Article in journal (Refereed)
    Abstract [en]

    The ongoing SARS-CoV-2 pandemic is a global public health emergency posing a high burden on nations' health care systems and economies. Despite the great effort put in the development of vaccines and specific treatments, no prophylaxis or effective therapeutics are currently available. Nitric oxide (NO) is a broad-spectrum antimicrobial and a potent vasodilator that has proved to be effective in reducing SARS-CoV replication and hypoxia in patients with severe acute respiratory syndrome. Given the potential of NO as treatment for SARS-CoV-2 infection, we have evaluated the in vitro antiviral effect of NO on SARS-CoV-2 replication. The NO-donor S-nitroso-N-acetylpenicillamine (SNAP) had a dose dependent inhibitory effect on SARS-CoV-2 replication, while the non S-nitrosated NAP was not active, as expected. Although the viral replication was not completely abolished (at 200 μM and 400 μM), SNAP delayed or completely prevented the development of viral cytopathic effect in treated cells, and the observed protective effect correlated with the level of inhibition of the viral replication. The capacity of the NO released from SNAP to covalently bind and inhibit SARS-CoV-2 3CL recombinant protease in vitro was also tested. The observed reduction in SARS-CoV-2 protease activity was consistent with S-nitrosation of the enzyme active site cysteine.

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  • 217.
    Akaberi, Dario
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pourghasemi Lati, Monireh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Krambrich, Janina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berger, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Turunen, Pauliina
    Science for Life Laboratory, Human Antibody Therapeutics, Drug Discovery and Development Platform, Solna, Sweden.
    Gullberg, Hjalmar
    Science for Life Laboratory, Biochemical and Cellular Assay Facility, Drug Discovery and Development Platform, Department of Biochemistry and Biophysics, Stockholm University, Solna, Stockholm, Sweden.
    Moche, Martin
    Department of Medical Biochemistry and Biophysics, Protein Science Facility, Karolinska Institutet, Stockholm, Sweden.
    Chinthakindi, Praveen Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Nyman, Tomas
    Department of Medical Biochemistry and Biophysics, Protein Science Facility, Karolinska Institutet, Stockholm, Sweden..
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Sandberg, Kristian
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Verho, Oscar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Identification of unique and potent inhibitors of SARS-CoV-2 main protease from DNA-encoded chemical librariesManuscript (preprint) (Other academic)
  • 218.
    Akbari, Camilla
    et al.
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden..
    Dodd, Maja
    Karolinska Univ Hosp, Dept Upper GI, Div Hepatol, Stockholm, Sweden..
    Stål, Per
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Upper GI, Div Hepatol, Stockholm, Sweden..
    Nasr, Patrik
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden.;Linköping Univ, Dept Gastroenterol & Hepatol, Div Internal Med, Linköping, Sweden.;Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden..
    Ekstedt, Mattias
    Kechagias, Stergios
    Linköping Univ, Dept Gastroenterol & Hepatol, Div Internal Med, Linköping, Sweden.;Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden..
    Vessby, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Zhang, Xiao
    Merck & Co Inc, Rahway, NJ USA..
    Wang, Tongtong
    Merck & Co Inc, Rahway, NJ USA..
    Jemielita, Thomas
    Merck & Co Inc, Rahway, NJ USA..
    Fernandes, Gail
    Merck & Co Inc, Rahway, NJ USA..
    Engel, Samuel S.
    Merck & Co Inc, Rahway, NJ USA..
    Hagström, Hannes
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Upper GI, Div Hepatol, Stockholm, Sweden.;Karolinska Univ Hosp, Div Hepatol, C1 77, S-14186 Stockholm, Sweden..
    Shang, Ying
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden..
    Long-term major adverse liver outcomes in 1,260 patients with non-cirrhotic NAFLD2024In: JHEP Reports, E-ISSN 2589-5559, Vol. 6, no 2, article id 100915Article in journal (Refereed)
    Abstract [en]

    Background & Aims

    Long-term studies of the prognosis of NAFLD are scarce. Here, we investigated the risk of major adverse liver outcomes (MALO) in a large cohort of patients with NAFLD.

    Methods

    We conducted a cohort study with data from Swedish university hospitals. Patients (n = 1,260) with NAFLD without cirrhosis were diagnosed through biopsy or radiology, and had fibrosis estimated through vibration-controlled transient elastography, biopsy, or FIB-4 score between 1974 and 2020 and followed up through 2020. Each patient was matched on age, sex, and municipality with up to 10 reference individuals from the general population (n = 12,529). MALO were ascertained from Swedish national registers. The rate of events was estimated by Cox regression.

    Results

    MALO occurred in 111 (8.8%, incidence rate = 5.9/1,000 person-years) patients with NAFLD and 197 (1.6%, incidence rate = 1.0/1,000 person-years) reference individuals during a median follow up of 13 years. The rate of MALO was higher in patients with NAFLD (hazard ratio = 6.6; 95% CI = 5.2–8.5). The risk of MALO was highly associated with the stage of fibrosis at diagnosis. In the biopsy subcohort (72% of total sample), there was no difference in risk between patients with and without non-alcoholic steatohepatitis. The 20-year cumulative incidences of MALO were 2% for the reference population, 3% for patients with F0, and 35% for F3. Prognostic information from biopsy was comparable to FIB-4 (C-indices around 0.73 vs. 0.72 at 10 years).

    Conclusions

    This study provides updated information on the natural history of NAFLD, showing a high rate of progression to cirrhosis in F3 and a similar prognostic capacity of non-invasive tests to liver biopsy.

    Impact and implications

    Several implications for clinical care and future research may be noted based on these results. First, the risk estimates for cirrhosis development are important when communicating risk to patients and deciding on clinical monitoring and treatment. Estimates can also be used in updated health-economic evaluations, and for regulatory agencies. Second, our results again highlight the low predictive information obtained from ascertaining NASHstatus by histology and call for more objective means by which to define NASH. Such methods may include artificial intelligence-supported digital pathology. We highlight that NASH is most likely the causal factor for fibrosis progression in NAFLD, but the subjective definition makes the prognostic value of a histological NASH diagnosis of limited value. Third, the finding that prognostic information from biopsy and the very simple Fibrosis-4 score were comparable is important as it may lead to fewer biopsies and further move the field towards non-invasive means by which to define fibrosis and, importantly, use non-invasive tests as outcomes in clinical trials. However, all modalities had modest discriminatory capacity and new risk stratification systems are needed in NAFLD. Repeated measures of non-invasive scores may be a potential solution.

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  • 219.
    Akca, Ozan
    et al.
    Univ Louisville, Dept Anesthesiol & Perioperat Med, Neurosci ICU, Louisville, KY 40292 USA..
    Ball, Lorenzo
    Univ Genoa, IRCCS AOU San Martino IST, Dept Surg Sci & Integrated Diagnost, Genoa, Italy..
    Belda, F. Javier
    Univ Valencia, Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Biro, Peter
    Univ Hosp Zurich, Inst Anesthesiol, Zurich, Switzerland..
    Cortegiani, Andrea
    Univ Palermo, Policlin Paolo Giaccone, Sect Anesthesia Analgesia Intens Care & Emergency, Dept Biopathol & Med Biotechnol DIBIMED, Palermo, Italy..
    Eden, Arieh
    Lady Davis Carmel Med Ctr, Dept Anesthesiol Crit Care & Pain Med, Haifa, Israel..
    Ferrando, Carlos
    Univ Valencia, Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Gattinoni, Luciano
    Gottingen Univ, Dept Anesthesiol Emergency & Intens Care Med, Gottingen, Germany..
    Goldik, Zeev
    Gregoretti, Cesare
    Univ Palermo, Policlin Paolo Giaccone, Sect Anesthesia Analgesia Intens Care & Emergency, Dept Biopathol & Med Biotechnol DIBIMED, Palermo, Italy..
    Hachenberg, Thomas
    Otto von Guericke Univ, Dept Anaesthesiol & Intens Care Med, Magdeburg, Germany..
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Hopf, Harriet W.
    Univ Utah, Dept Anesthesiol, Salt Lake City, UT USA..
    Hunt, Thomas K.
    Univ Calif San Francisco, Div Gen Surg, San Francisco, CA 94143 USA..
    Pelosi, Paolo
    Univ Genoa, IRCCS AOU San Martino IST, Dept Surg Sci & Integrated Diagnost, Genoa, Italy..
    Qadan, Motaz
    Harvard Univ, Dept Surg, Massachusetts Gen Hosp, Cambridge, MA 02138 USA..
    Sessler, Daniel I.
    Cleveland Clin, Inst Anesthesiol, Dept Outcomes Res, Cleveland, OH 44106 USA..
    Soro, Marina
    Univ Valencia, Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Sentürk, Mert
    Istanbul Univ, Istanbul Sch Med, Dept Anaesthesiol & Reanimat, Istanbul, Turkey..
    WHO Needs High FIO2?2017In: TURKISH JOURNAL OF ANAESTHESIOLOGY AND REANIMATION, ISSN 2149-0937, Vol. 45, no 4, p. 181-192Article in journal (Refereed)
    Abstract [en]

    World Health Organization and the United States Center for Disease Control have recently recommended the use of 0.8 FIO2 in all adult surgical patients undergoing general anaesthesia, to prevent surgical site infections. This recommendation has arisen several discussions: As a matter of fact, there are numerous studies with different results about the effect of FIO2 on surgical site infection. Moreover, the clinical effects of FIO2 are not limited to infection control. We asked some prominent authors about their comments regarding the recent recommendations

  • 220.
    Akerlund, Anna
    et al.
    Div Clin Microbiol, Lab Med, Jönköping, Region Jonkopin, Sweden.;Linköping Univ, Dept Clin & Expt Med, Linköping, Sweden.;Linköping Univ Hosp, Dept Clin & Expt Med, Div Clin Microbiol, Linköping, Sweden..
    Petropoulos, Alexandros
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden..
    Malmros, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Giske, Christian G.
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Microbiol, Stockholm, Sweden..
    Blood culture diagnostics: a Nordic multicentre survey comparison of practices in clinical microbiology laboratories2022In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 28, no 5Article in journal (Refereed)
    Abstract [en]

    Objectives: Accurate and rapid microbiological diagnostics are crucial to tailor treatment and improve outcomes in patients with severe infections. This study aimed to assess blood culture diagnostics in the Nordic countries and to compare them with those of a previous survey conducted in Sweden in 2013. Methods: An online questionnaire was designed and distributed to the Nordic clinical microbiology laboratories (CMLs) (n = 76) in January 2018. Results: The response rate was 64% (49/76). Around-the-clock incubation of blood cultures (BCs) was supported in 82% of the CMLs (40/49), although in six of these access to the incubators around the clock was not given to all of the cabinets in the catchment area, and 41% of the sites (20/49) did not assist with satellite incubators. Almost half (49%, 24/49) of the CMLs offered opening hours for >= 10 h during weekdays, more commonly in CMLs with an annual output >= 30 000 BCs. Still, positive BCs were left unprocessed for 60-70% of the day due to restrictive opening hours. Treatment advice was given by 23% of CMLs (11/48) in >= 75% of the phone contacts. Rapid analyses (species identification and susceptibility testing with short incubation), performed on aliquots from positive cultures, were implemented in 18% of CMLs (9/49). Compared to 2013, species identification from subcultured colonies (<6 h) had become more common. Conclusions: CMLs have taken action to improve aspects of BC diagnostics, implementing satellite incubators, rapid species identification and susceptibility testing. However, the limited opening hours and availability of clinical microbiologists are confining the advantages of these changes. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

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  • 221. Akerstedt, T.
    et al.
    Alfredsson, L.
    Westerholm, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Fischer, H.
    Nilsson, L. -G
    Nordin, M.
    Fatigue/sleepiness and important aspects of sleep restoration improve across aging2014In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 23, p. 241-241Article in journal (Other academic)
  • 222. Akerstedt, T.
    et al.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Gruber, G.
    Theorell-Haglöw, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Schwarz, J.
    What does good sleep mean in terms of macro and microstructure of sleep in women and how does age affect this relation?2014In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 23, p. 240-240Article in journal (Other academic)
  • 223.
    Akerstedt, T.
    et al.
    Karolinska Inst, Clin Neurosci, Stockholm, Sweden.;Stockholm Univ, Stress Res Inst, Stockholm, Sweden..
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Theorell-Haglöw, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Gruber, G.
    Siesta Grp, Vienna, Austria..
    Schwarz, J.
    Stockholm Univ, Stress Res Inst, Stockholm, Sweden..
    The polysomnographical characteristics of women who have sought medical help for sleep problems - a large study of sleep macro and micro architeture2016In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 25, p. 90-90Article in journal (Other academic)
  • 224.
    Akerstedt, T.
    et al.
    Karolinska Inst, Stockholm, Sweden.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Theorell-Haglöw, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Schwaz, J.
    Stockholm Univ, Stocholm, Sweden.
    What Characterizes the Combination of Seeking Medical Help for Insomnia and Snoring in Terms of PSG and Metabolic Parameters?2017In: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 40, p. A34-A34Article in journal (Other academic)
  • 225.
    Akerstedt, T.
    et al.
    Stockholm Univ, Stress Res Inst, Stockholm, Sweden.
    Theorell-Haglöw, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Schwarz, J.
    Stockholm Univ, Stress Res Inst, Stockholm, Sweden.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    The change in sleepiness across 10 years of aging and its relation to changes in polysomnographic variables2017In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 40, no Supplement 1, p. E8-E8Article in journal (Other academic)
  • 226.
    Akerstedt, Torbjorn
    et al.
    Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden;Stockholm Univ, Stress Res Inst, Stockholm, Sweden.
    Schwarz, Johanna
    Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden;Stockholm Univ, Stress Res Inst, Stockholm, Sweden.
    Gruber, Georg
    Siesta Grp, Vienna, Austria.
    Theorell-Haglöw, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Women with both sleep problems and snoring show objective impairment of sleep2018In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 51, p. 80-84Article in journal (Refereed)
    Abstract [en]

    Objective: Combined insomnia and obstructive sleep apnea has been the focus of considerable research with respect to its health effects. A related issue is whether sleep disturbances in combination with snoring might exert effects on objective sleep variables in the non-clinical general population. The purpose of the present study was to investigate the polysomnographical characteristics of individuals who had sought medical help for both disturbed sleep and for snoring. No previous work of this type has been carried out. Method: For this study we used a representative set of data of 384 women with one night of in-home PSG. We identified those individuals who had sought medical help for sleep problems (SL), individuals that had sought help for snoring (SN), as well as those that had sought help for either both (Combined), or for neither (Control). Results: Our results yielded an N of 46, 16, 21, and 301 individuals, respectively. A one-factor analysis of variance showed significant main effects on N1% (F = 10.2, p < 0.001), N3% (F = 2.7, p < 0.05), AHI/h (F = 5.5, p < 0.001), and a delta power measure (F = 3.8, p < 0.05). The combined group showed significantly higher levels than the other groups for N1% (29% vs < 21%), AHI/h (19/h vs < 10/h) and lower levels for N3%, and a measure of delta power. Reported sleep quality measures did not show the same pattern, since the highest/lowest value were found for either the group presenting snoring alone or sleep problems alone. Conclusion: We concluded that individuals who had sought help for both insomnia and snoring showed impaired sleep in terms of PSG and that this was not reflected in ratings of sleep or health. This suggests that simultaneous sleep disturbances and snoring may potentiate each other to cause impaired sleep, yet the mechanism still needs to be elucidated.

  • 227.
    Akerstedt, Torbjorn
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Stockholm Univ, Stress Res Inst, Dept Psychol, Stockholm, Sweden.;Karolinska Inst, Clin Neurosci, S-17177 Stockholm, Sweden..
    Schwarz, Johanna
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Stockholm Univ, Stress Res Inst, Dept Psychol, Stockholm, Sweden..
    Theorell-Haglöw, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    What do women mean by poor sleep?: A large population-based sample with polysomnographical indicators, inflammation, fatigue, depression, and anxiety2023In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 109, p. 219-225Article in journal (Refereed)
    Abstract [en]

    Survey studies indicate that reports of disturbed sleep are prevalent and may be prospectively linked to several major diseases. However, it is not clear what self-reported disturbed sleep represents, since the link with objective sleep measures (polysomnography; PSG) seems very weak. The purpose of the present study was to try to investigate what combination of variables (PSG, inflammation, fatigue, anxiety, depression) that would characterize those who complain of disturbed sleep. This has never been done before. Participants were 319 women in a population-based sample, who gave ratings of sleep quality, fatigue, depression, and anxiety, then had their sleep recorded at home, and had blood drawn the following morning for analysis of immune parameters. Correlations and hierarchical multivariable regression analyses were applied to the data. For ratings of difficulties initiating sleep, the associations in the final step were beta =.22, (p <.001) for fatigue, beta = 0.22 (p <.001) for anxiety, and beta = 0.17 (p <.01) for sleep latency, with R-2 = 0.14. The rating of repeated awakenings was associated with fatigue (beta = 0.35, p <.001) and C-reactive protein (CRP) (beta = 0.12, p <.05), with R-2 = 0.19. The rating of early morning awakenings was associated with fatigue (beta = 0.31, p <.001), total sleep time (TST) (beta = -0.20, p <.01), and CRP (beta = 0.15, p <.05), with R-2 = 0.17. Interleukin-6 and Tumour Necrosis Factor were not associated with ratings of sleep problems. The results indicate that subjective fatigue, rather than objective sleep variables, is central in the perception of poor sleep, together with CRP.

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  • 228.
    Akerud, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wiberg-Itzel, Eva
    Dept of Obstetrics and Gynecology, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
    Lactate distribution in culture medium of human myometrial biopsies incubated under different conditions2009In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 297, no 6, p. E1414-E1419Article in journal (Refereed)
    Abstract [en]

    It is generally believed that a relationship exists between muscle fatigue and intracellular accumulation of lactate. This reasoning is relevant to obstetrical issues. Myocytes in uterus work together during labor, and the contractions need to be strong and synchronized for a child to be delivered. At labor dystocia, the progress of labor becomes slow or arrested after a normal beginning. It has been described that, during labor dystocia, when the force of the contractions is low, the uterus is under hypoxia, and anaerobic conditions with high levels of lactate in amniotic fluid dominate. The purpose of this study was to examine whether myometrial cells are involved in the production of lactate in amniotic fluid and whether there are differences in production and distribution of lactate in cells incubated under aerobic and anaerobic conditions. We also wanted to elucidate the involvement of specific membrane-bound lactate carriers. Women undergoing elective caesarean section were included. Myometrial biopsies from uteri were collected and subjected to either immunohistochemistry to identify lactate carriers or in vitro experiments to analyze production of lactate. The presence of lactate carriers named monocarboxylate transporters 1 and 4 was verified. Myometrial cells produced lactate extracellularly, and the lactate carriers operated differently under anaerobic and aerobic conditions; while being mainly unidirectional under anaerobic conditions, they became bidirectional under aerobic conditions. Human myometrial cells produced and delivered lactate to the extracellular medium under both anaerobic and aerobic conditions. The delivery was mediated by lactate carriers.

  • 229. Akhoondi, Shahab
    et al.
    Sun, Dahui
    von der Lehr, Natalie
    Apostolidou, Sophia
    Klotz, Kathleen
    Maljukova, Alena
    Cepeda, Diana
    Fiegl, Heidi
    Dofou, Dimitra
    Marth, Christian
    Mueller-Holzner, Elisabeth
    Corcoran, Martin
    Dagnell, Markus
    Nejad, Sepideh Zabihi
    Nayer, Babak Noori
    Zali, Mohammad Reza
    Hansson, Johan
    Egyhazi, Susanne
    Petersson, Fredrik
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grander, Dan
    Reed, Steven I
    Widschwendter, Martin
    Sangfelt, Olle
    Spruck, Charles
    FBXW7/hCDC4 is a general tumor suppressor in human cancer2007In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 67, no 19, p. 9006-9012Article in journal (Refereed)
    Abstract [en]

    The ubiquitin-proteasome system is a major regulatory pathway of protein degradation and plays an important role in cellular division. Fbxw7 (or hCdc4), a member of the F-box family of proteins, which are substrate recognition components of the multisubunit ubiquitin ligase SCF (Skpl-Cdc53/ Cullin-F-box-protein), has been shown to mediate the ubiquitin-dependent proteolysis of several oncoproteins including cyclin El, c-Myc, c-Jun, and Notch. The oncogenic potential of Fbxw7 substrates, frequent allelic loss in human cancers, and demonstration that mutation of FBXW7 cooperates with p53 in mouse tumorigenesis have suggested that Fbxw7 could function as a tumor suppressor in human cancer. Here, we carry out an extensive genetic screen of primary tumors to evaluate the role of FBXW7 as a tumor suppressor in human tumorigenesis. Our results indicate that FBXW7 is inactivated by mutation in diverse human cancer types with an overall mutation frequency of ∼ 6%. The highest mutation frequencies were found in tumors of the bile duct (cholangio-carcinomas, 35%), blood (T-cell acute lymphocytic leukemia, 31%), endometrium (9%), colon (9%), and stomach (6%). Approximately 43% of all mutations occur at two mutational "hotspots," which alter Arg residues (Arg465 and Arg479) that are critical for substrate recognition. Furthermore, we show that Fbxw7Arg465 hotspot mutant can abrogate wild-type Fbxw7 function through a dominant negative mechanism. Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer.

  • 230.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Ubhayasekera, Kumari
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Kullinger, Merit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research.
    Plasma levels of arginines at term pregnancy in relation to mode of onset of labor and mode of childbirth2023In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 90, no 3, article id e13767Article in journal (Refereed)
    Abstract [en]

    PROBLEM: The exact biochemical mechanisms that initiate labor are not yet fully understood. Nitric oxide is a potent relaxant of uterine smooth muscles until labor starts, and its precursor is L-arginine. Asymmetric (ADMA) and symmetric (SDMA) dimethylarginines, are potent NO-inhibitors. However, arginines (dimethylarginines and L-arginine) are scarcely studied in relation to labor and childbirth. We aimed to investigate arginines in women with spontaneous (SLVB) and induced (ILVB) term labor with vaginal birth and in women undergoing elective caesarean section (ECS).

    METHOD OF STUDY: Women at gestational week 16-18 were recruited to the population-based prospective cohort study BASIC at the Uppsala University Hospital, Sweden. Plasma samples taken at start of labor were analyzed for arginines, from SLVB (n = 45), ILVB (n = 45), and ECS (n = 45), using Ultra-High Performance Liquid Chromatography. Between-group differences were assessed using Kruskal-Wallis and Mann-Whitney U-test.

    RESULTS: Women with SLVB and ILVB had higher levels of ADMA (p < .0001), SDMA (p < .05) and lower L-arginines (p < .01), L-arginine/ADMA (p < .0001), and L-arginine/SDMA (p < .01, respectively <.001) compared to ECS. However, ILVB had higher ADMA (p < .0001) and lower L-arginine (p < .01), L-arginine/ADMA (p < .0001), and L-arginine/SDMA (p < .01) compared to SLVB. Results are adjusted for gestational length at birth and cervical dilatation at sampling.

    CONCLUSION: Our novel findings of higher levels of dimethylarginines in term vaginal births compared to ECS give insights into the biochemical mechanisms of labor. These findings might also serve as a basis for further studies of arginines in complicated pregnancies and labor.

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  • 231.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Marita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive biology.
    Sub-clinical atherosclerosis in the common carotid artery in women with/without previous pre-eclampsia: A seven-year follow-up2019In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 290, p. 206-213Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Pre-eclampsia is associated with increased risk of cardiovascular disease and premature death. However, conventional common carotid artery intima-media thickness (CCA-IMT) measurement does not reflect this. In contrast, measurement of the individual CCA intima and media thicknesses clearly indicates increased vascular risk both at diagnosis and about one year after pre-eclampsia. This study examined whether individual CCA wall layers, risk factors for cardiovascular disease, and markers of endothelial dysfunction had normalized or remained unfavorable seven years after pre-eclampsia.

    METHODS: The individual CCA intima and media thicknesses were measured using 22 MHz ultrasound. Conventional cardiovascular risk factors were recorded. A thick intima, thin media and high intima/media thickness ratio (I/M) are signs of sub-clinical atherosclerosis.

    RESULTS: The median age of women with previous pre-eclampsia (cases = 23) or normal pregnancies (controls = 35) was 39/37 years. At follow-up (median about seven years), the intima remained thicker and the I/M was higher in cases than in controls [all p < 0.0001; p < 0.001 after adjustment for time to follow-up, body mass index (BMI), and mean arterial pressure (MAP)], whereas the CCA-IMT was illogically thinner. Further, BMI, MAP, hip circumference, abdominal height, serum endostatin and apolipoprotein B levels were higher in cases (all p < 0.05). Intima and I/M measurements were correlated with age, MAP, endostatin and apolipoprotein B, whereas no logical correlations were found for CCA-IMT.

    CONCLUSIONS: The arteries in cases but not controls were still adversely affected after seven years. Measuring intima thickness and I/M appears preferable to measuring CCA-IMT for demonstrating vascular risk after pre-eclampsia.

  • 232.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Marita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Artery Wall Layer Dimensions during Normal Pregnancy: A longitudinal study using non-invasive high-frequency ultrasound2013In: American Journal of Physiology. Heart and Circulatory Physiology, ISSN 0363-6135, E-ISSN 1522-1539, Vol. 304, no 2, p. H229-H234Article in journal (Refereed)
    Abstract [en]

    The vascular effects of normal pregnancy were investigated by estimating the intima and media thicknesses of the common carotid artery separately using 22MHz ultrasound (Collagenoson, Meudt, Germany) in 57 healthy women with normal pregnancies and pregnancy outcomes, in all three trimesters and at one year postpartum. A thick intima, thin media and high intima/media (I/M) ratio are signs of a less healthy artery wall. The mean artery wall layer dimensions remained fairly constant during pregnancy but the intima thickness and I/M thickness ratio appeared to improve (decrease) postpartum (p<0.001 for both). The cardiovascular risk parameters age, body mass index (BMI), and blood pressure in the first trimester were associated with higher I/M ratios, especially in the second trimester, whereas higher serum estradiol levels were significantly associated with a lower I/M ratio. Changes from the first to second trimesters in I/M ratio, taking into account differential changes in intima and media thickness, were significantly (p<0.05-0.001) associated with all risk parameters tested except age, which was associated with increased intima thickness (p=0.02). Associations with third trimester values and changes from first to third trimesters were similar but less apparent. Thus, fairly constant mean artery wall layer dimensions during pregnancy appeared to improve postpartum. However, higher age, BMI or blood pressure, and lower serum estradiol levels in the first trimester appeared to negatively affect the artery wall, strongly suggesting that pregnancy has negative vascular effects in some women. A less likely explanation involves possible adaptation to physiological changes during and after pregnancy.

  • 233.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Naessen, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Changes in the Artery Wall Layer Dimensions in Women with Preeclampsia: an investigation using non-invasive high frequency ultrasound2012In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 91, no S159, p. 28-28Article in journal (Other academic)
    Abstract [en]

    Background:

    Preeclampsia (PE) is associated with increased risk for cardiovascular disease later in life. Whether, the artery wall layer dimensions differ between PE and normal pregnancy is unclear. The aim of this study was to estimate if women with PE have different common carotid artery wall layer dimensions than women with normal pregnancy, both during pregnancy and about one year postpartum.

    Methods:

    By using high-frequency (22MHz) ultrasound (Collagenoson, Meudt, Germany) separate estimates of the common carotid artery intima and media layers were obtained and the I/M ratio was calculated in women with PE (n=55 during pregnancy and n=48 at postpartum) and with normal pregnancy (n=65 during pregnancy and n=59 at postpartum). Thick intima, thin media and a high intima/media ratio are signs of less healthy artery wall and vice versa.

    Results:

    In women with PE, the intima was thicker (0.18 } 0.03 vs. 0.11 } 0.02; p < .001), the media was thinner (0.47 } 0.12 vs. 0.55 } 0.14; p = .001) and the I/M ratio was higher (0.41 } 0.14 vs. 0.20 } 0.05; p < .001) compared to women with normal pregnancy. Further, for changes from pregnancy to postpartum, both for PE and normal pregnancy, the intima and the I/M ratio had improved but still significantly higher in women with PE than in women with normal pregnancy.

    Conclusion:

    In women with PE, we found a thicker intima, thinner media and a higher I/M ratio compared to women with normal pregnancy, indicating a more negatively affected artery wall layer dimensions. Persisting negative effects of PE on artery wall at postpartum, despite improvement of artery wall layers compared to values during pregnancy, indicates a permanent damage of the vascular system in this group of women.

  • 234.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Gynecological endocrinology.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics.
    Larsson, Marita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Gynecological endocrinology.
    Association between angiogenic factors and signs of arterial aging in women with pre-eclampsia2017In: Ultrasound in Obstetrics and Gynecology, ISSN 0960-7692, E-ISSN 1469-0705, Vol. 50, p. 93-99Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Pre-eclampsia (PE) is associated with an increased risk of cardiovascular disease (CVD) later in life. In PE there is a substantial increase in levels of the anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt1) and decreased levels of the pro-angiogenic factor placental growth factor (PlGF). Elevated levels of sFlt1 are also found in individuals with CVD. The aims of this study were to assess sFlt1, PlGF and the sFlt1/PlGF ratio and their correlation with signs of arterial aging by measuring common carotid artery (CCA) intima and media thicknesses and their ratio (I/M ratio) in women with and without PE.

    METHODS: Serum sFlt1 and PlGF levels were measured using commercially available enzyme-linked immunosorbent assay kits, and CCA intima and media thicknesses were estimated using high-frequency (22 MHz) ultrasonography in 55 women at PE diagnosis and 64 women with normal pregnancies at a similar gestational age, with reassessment one year postpartum. A thick intima, thin media and a high I/M ratio indicate a less healthy arterial wall.

    RESULTS: During pregnancy, higher levels of sFlt1, lower levels of PlGF and thicker intima, thinner media and higher I/M ratios were found in women with PE vs. controls (all p < 0.0001). Further, sFlt1 and the sFlt1/PlGF ratio were positively correlated with intima thickness and I/M ratio (all p < 0.0001), but negatively correlated with media thickness (p = 0.002 and 0.03, respectively). About one year postpartum, levels of sFlt1 and the sFlt1/PlGF ratio had decreased in both groups, but compared with controls women in the PE group still had higher levels (p = 0.001 and 0.02, respectively). Further, sFlt1 levels and the sFlt1/PlGF ratio were still positively correlated with intima thickness and I/M ratio.

    CONCLUSIONS: Higher sFlt1 levels and sFlt1/PlGF ratios in women with PE were positively associated with signs of arterial aging during pregnancy. About one year postpartum sFlt1 levels and the sFlt1/PlGF ratios were still higher in the PE group, and also associated with the degree of arterial aging.

  • 235.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Gynecological endocrinology.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics. Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Larsson, Marita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Gynecological endocrinology.
    Serum Pentraxin 3 is associated with signs of arterial alteration in women with preeclampsia.2017In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 241, p. 417-422Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Preeclampsia (PE) in pregnancy is a state of exaggerated inflammation and is associated with an increased risk of cardiovascular disease (CVD) later in life. Levels of pentraxin 3 (PTX3), a novel inflammation marker, are increased during PE and in individuals with CVD. The primary aim of this study was to assess whether serum PTX3 in women with PE is associated with adverse arterial effects; a thicker intima and higher intima/media (I/M) ratio in the common carotid artery (CCA).

    METHODS: Serum PTX3 levels were measured using commercially available enzyme-linked immunosorbent assay kits, and individual CCA intima and media thicknesses were estimated by 22MHz non-invasive ultrasound in 55 women at PE diagnosis and 64 women with normal pregnancies at a similar gestational age, and about one year postpartum. A thick intima, thin media and high I/M ratio indicate a less healthy artery wall.

    RESULTS: During pregnancy serum PTX3 correlated positively with intima thickness and I/M ratio but negatively with media thickness (all p<0.0001), indicating adverse arterial effects. About one year postpartum, PTX3 levels had decreased in both groups and there remained no significant group difference or significant correlation with CCA wall layers.

    CONCLUSIONS: Higher levels of serum PTX3 in women with PE were significantly associated with signs of adverse arterial effects during pregnancy, but not one year postpartum, supporting the rapid dynamics of PTX3.

  • 236.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Larsson, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Dimethylarginines correlate to common carotid artery wall layer dimensions and cardiovascular risk factors in pregnant women with and without preeclampsia2018In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 275, p. E69-E70Article in journal (Other academic)
  • 237.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR).
    Larsson, Marita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive biology.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, Uppsala, Sweden.;Uppsala Univ, Dept Med Chem, Analyt Pharmaceut Chem, Uppsala, Sweden..
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, Uppsala, Sweden.;Uppsala Univ, Dept Med Chem, Analyt Pharmaceut Chem, Uppsala, Sweden..
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive biology.
    Dimethylarginines correlate to common carotid artery wall layer dimensions and cardiovascular risk factors in pregnant women with/without preeclampsia: A group comparative study2021In: European Journal of Obstetrics, Gynecology, and Reproductive Biology, ISSN 0301-2115, E-ISSN 1872-7654, Vol. 258, p. 288-293Article in journal (Refereed)
    Abstract [en]

    Objectives: Asymmetric- and symmetric dimethylarginines (ADMA, SDMA) are elevated in cardiovascular disease (CVD). Preeclampsia is a pregnancy-specific syndrome and is an independent risk factor for subsequent CVD. Aims were to investigate whether ADMA, SDMA levels and L-arginine/ADMA and I.arginine/SDMA ratios during pregnancy and their changes from pregnancy to postpartum are associated to arterial wall layer dimensions and cardiovascular risk factors in women with and without preeclampsia. Study design: Dimethylarginines were analyzed by LC-MS, and the common-carotid-artery (CCA) intima and media thicknesses were estimated using 22-MHz non-invasive ultrasonography in women with preeclampsia (cases = 48) and normal pregnancies (controls = 58) in similar gestational age, with reassessment one-year postpartum. A thick intima, thin media and high intima/media ratio (I/M) indicates a less healthy arterial wall. Results: The median age of cases and controls was 30 years. During pregnancy, women with preeclampsia had higher plasma ADMA, SDMA and lower t-arginine/ADMA and L-arginine/SDMA (all p <0.01) than women with normal pregnancies. Further, ADMA, SDMA, L-arginine/ADMA and L-arginine/SDMA correlated to intima thickness (r(s) = 0.33/0.33/-0.33/-0.35 and p <0.01), UM (r(s) = 0.26/0.28/-0.22/-0.26 and p <0.05) and mean arterial pressure (MAP) (rs = 0.43/0.42/-0.39/-0.40 and p <0.0001). Changes in ADMA, SDMA and t-arginine/SDMA from pregnancy to postpartum correlated to changes in intima thickness (r(s) = 0.22/0.32/-0.21 and p < 0.05/<0.01/<0.05), I/M (r(s) = 0.22/0.31/0.08 and p < 0.05/<0.01/=0.43) and MAP (r(s) = 0.31/0.53/-0.25 and p < 0.01/<0.001/<0.05). No correlations were found for conventional CCA intima-media-thickness. Conclusions: Dimethylarginines were associated to signs of adverse effects on arterial wall layer dimensions and cardiovascular risk factors in women with and without preeclampsia, during pregnancy and to their changes from pregnancy up to one-year postpartum. (C) 2021 The Authors. Published by Elsevier B.V.

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  • 238. Akkoyunlu, Mustafa
    et al.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Capiau, Carine
    van Opstal, Omer
    Forsgren, Arne
    The acylated form of protein D of Haemophilus influenzae is more immunogenic than the nonacylated form and elicits an adjuvant effect when it is used as a carrier conjugated to polyribosyl ribitol phosphate1997In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 65, no 12, p. 5010-5016Article in journal (Refereed)
    Abstract [en]

    The nonacylated form of protein D (PDm) of Haemophilus influenzae has been shown to induce the production of antibodies that are bactericidal to homologous and heterologous nontypeable H. influenzae (NTHi) strains. In this study, immunization of rats with lipoprotein D (LPD) induced higher levels of anti-protein D immunoglobulin G and A serum antibodies than immunization with PDm, and the bactericidal activities of sera from LPD-immunized rats were greater than those of sera from PDm-immunized rats. Immunization with LPD or PDm did not prevent the development of acute otitis media (AOM) when rats were challenged with 10(4) CFU of an NTHi strain. However, on the eighth day of bacterial challenge, 50% (5 of 10) of LPD-immunized rats had recovered from otitis media and 30% (3 of 10) had negative middle ear cultures, whereas only 30% (3 of 10) of PDm-immunized rats had recovered, though none was culture positive. Immunization with an inactivated homologous bacterial strain elicited 70% protection (i.e., 7 of 10 rats) in the rat otitis media model. LPD and PDm were also conjugated to the H. influenzae type b (Hib) capsular polysaccharide, polyribosyl ribitol phosphate (PRP), to test protein D-conjugated PRP vaccine's potential for protection against Hib infection. When two LPD-conjugated and two PDm-conjugated PRP vaccines, each containing a different protein concentration, and a tetanus toxoid-conjugated vaccine (ACT-HIB) were tested in the experimental model of rat otitis induced with a Hib strain (Minn A), both of the LPD-conjugated and one of the PDm-conjugated vaccines induced significant protection from AOM, the level of protection being highest in animals given the vaccine with the highest LPD content. Sera from these rats also manifested the highest anti-PRP and anti-LPD antibody levels and the highest bactericidal activities against a Hib strain and an NTHi strain.

  • 239.
    Akre, K
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Signorello, LB
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Engstrand, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Bergstrom, R
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Larsson, S
    Department of Surgical Sciences.
    Eriksson, BI
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Nyren, O
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Risk for gastric cancer after antibiotic prophylaxis in patients undergoing hip replacement2000In: Cancer Res, Vol. 60, p. 6376-Article in journal (Refereed)
  • 240. Aktaa, Suleman
    et al.
    Abdin, Amr
    Arbelo, Elena
    Burri, Haran
    Vernooy, Kevin
    Blomström-Lundqvist, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology-Arrhythmia.
    Boriani, Giuseppe
    Defaye, Pascal
    Deharo, Jean-Claude
    Drossart, Inga
    Foldager, Dan
    Gold, Michael R
    Johansen, Jens Brock
    Leyva, Francisco
    Linde, Cecilia
    Michowitz, Yoav
    Kronborg, Mads Brix
    Slotwiner, David
    Steen, Torkel
    Tolosana, José Maria
    Tzeis, Stylianos
    Varma, Niraj
    Glikson, Michael
    Nielsen, Jens Cosedis
    Gale, Chris P
    European Society of Cardiology Quality Indicators for the care and outcomes of cardiac pacing: developed by the Working Group for Cardiac Pacing Quality Indicators in collaboration with the European Heart Rhythm Association of the European Society of Cardiology2022In: Europace, ISSN 1099-5129, E-ISSN 1532-2092, Vol. 24, no 1, p. 165-172Article in journal (Refereed)
    Abstract [en]

    AIMS: To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults undergoing cardiac pacing.

    METHODS AND RESULTS: Under the auspice of the Clinical Practice Guideline Quality Indicator Committee of the European Society of Cardiology (ESC), the Working Group for cardiac pacing QIs was formed. The Group comprised Task Force members of the 2021 ESC Clinical Practice Guidelines on Cardiac Pacing and Cardiac Resynchronization Therapy, members of the European Heart Rhythm Association, international cardiac device experts, and patient representatives. We followed the ESC methodology for QI development, which involved (i) the identification of the key domains of care by constructing a conceptual framework of the management of patients receiving cardiac pacing, (ii) the development of candidate QIs by conducting a systematic review of the literature, (iii) the selection of the final set of QIs using a modified-Delphi method, and (iv) the evaluation of the feasibility of the developed QIs. Four domains of care were identified: (i) structural framework, (ii) patient assessment, (iii) pacing strategy, and (iv) clinical outcomes. In total, seven main and four secondary QIs were selected across these domains and were embedded within the 2021 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronization therapy.

    CONCLUSION: By way of a standardized process, 11 QIs for cardiac pacing were developed. These indicators may be used to quantify adherence to guideline-recommended clinical practice and have the potential to improve the care and outcomes of patients receiving cardiac pacemakers.

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  • 241.
    Aktaa, Suleman
    et al.
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Leeds, W Yorkshire, England.;Univ Leeds, Leeds Inst Data Analyt, Leeds, W Yorkshire, England.;Leeds Teaching Hosp NHS Trust, Dept Cardiol, Leeds, W Yorkshire, England.
    Batra, Gorav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Cleland, John G. F.
    Univ Glasgow, Glasgow Royal Infirm, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.;Univ Glasgow, Glasgow Royal Infirm, Glasgow Clin Trials Unit, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland.;Imperial Coll London, Natl Heart & Lung Inst, London, England.
    Coats, Andrew
    Univ Warwick, Coventry, W Midlands, England.;European Soc Cardiol, Heart Failure Assoc, Brussels, Belgium.
    Lund, Lars H.
    Karolinska Inst, Dept Med, Unit Cardiol, Stockholm, Sweden.;Karolinska Univ Hosp, Heart & Vasc Theme, Stockholm, Sweden.
    McDonagh, Theresa
    Kings Coll Hosp London, Dept Cardiol, Denmark Hill, London, England.;Kings Coll London, British Heart Fdn, Ctr Excellence, Sch Cardiovasc Med & Sci, London, England.
    Rosano, Giuseppe
    St Georges Hosp NHS Trust Univ London, Cardiovasc Clin Acad Grp, London, England.;IRCCS San Raffaele Pisana, Rome, Italy.
    Seferovic, Petar
    Univ Belgrade, Serbian Acad Sci & Arts, Fac Med, Heart Failure Ctr,Med Ctr, Belgrade, Serbia.
    Vasko, Peter
    Univ Hosp, Dept Cardiol, Linköping, Sweden.;SWEDEHEART Swedish Web Syst Enhancement & Dev Evi, Växjö, Sweden.;SwedeHF Swedish Heart Failure Registry, Växjö, Sweden.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Maggioni, Aldo P.
    Natl Assoc Hosp Cardiologists Res Ctr ANMCO, Florence, Italy.
    Casadei, Barbara
    Univ Oxford, NIHR Oxford Biomed Res Ctr, Div Cardiovasc Med, Oxford, England.
    Gale, Chris P.
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Leeds, W Yorkshire, England.;Univ Leeds, Leeds Inst Data Analyt, Leeds, W Yorkshire, England.;Leeds Teaching Hosp NHS Trust, Dept Cardiol, Leeds, W Yorkshire, England.
    Data standards for heart failure: the European Unified Registries for Heart Care Evaluation and Randomized Trials (EuroHeart)2022In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 43, no 23, p. 2185-+Article in journal (Refereed)
    Abstract [en]

    Standardized data definitions are essential for assessing the quality of care and patient outcomes in observational studies and randomized controlled trials. The European Unified Registries for Heart Care Evaluation and Randomized Trials (EuroHeart) project of the European Society of Cardiology (ESC) aims to create contemporary pan-European data standards for cardiovascular diseases, including heart failure (HF). We followed the EuroHeart methodology for cardiovascular data standard development. A Working Group including experts in HF registries, representatives from the Heart Failure Association of the ESC, and the EuroHeart was formed. Using Embase and Medline (2016-21), we conducted a systematic review of the literature on data standards, registries, and trials to identify variables pertinent to HF. A modified Delphi method was used to reach a consensus on the final set of variables. For each variable, the Working Group developed data definitions and agreed on whether it was mandatory (Level 1) or additional (Level 2). In total, 84 Level 1 and 79 Level 2 variables were selected for nine domains of HF care. These variables were reviewed by an international Reference Group with the Level 1 variables providing the dataset for registration of patients with HF on the EuroHeart IT platform. By means of a structured process and interaction with international stakeholders, harmonized data standards for HF have been developed. In the context of the EuroHeart, this will facilitate quality improvement, international observational research, registry-based randomized trials, and post-marketing surveillance of devices and pharmacotherapies across Europe.

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  • 242. Aktaa, Suleman
    et al.
    Batra, Gorav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Blackman, Daniel J
    Ludman, Peter F
    Mamas, Mamas A
    Abdel-Wahab, Mohamed
    Angelini, Gianni D
    Czerny, Martin
    Delgado, Victoria
    De Luca, Giuseppe
    Eustachio, Agricola
    Foldager, Dan
    Hamm, Christian W
    Iung, Bernard
    Mangner, Norman
    Mehilli, Julinda
    Murphy, Gavin J
    Mylotte, Darren
    Parma, Radoslaw
    Petronio, Anna Sonia
    Popescu, Bodgan A
    Sondergaard, Lars
    Teles, Rui C
    Sabaté, Manel
    Terkelsen, Christian J
    Testa, Luca
    Wu, Jianhua
    Maggioni, Aldo P
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Casadei, Barbara
    Gale, Chris P
    Data standards for transcatheter aortic valve implantation: the European Unified Registries for Heart Care Evaluation and Randomised Trials (EuroHeart).2023In: European Heart Journal - Quality of Care and Clinical Outcomes, ISSN 2058-5225, E-ISSN 2058-1742, Vol. 9, no 5, p. 529-536, article id qcac063Article in journal (Refereed)
    Abstract [en]

    AIMS: Standardized data definitions are necessary for the quantification of quality of care and patient outcomes in observational studies and randomised controlled trials (RCTs). The European Unified Registries for Heart Care Evaluation and Randomised Trials (EuroHeart) project of the European Society of Cardiology (ESC) aims to create pan-European data standards for cardiovascular diseases and interventions, including transcatheter aortic valve implantation (TAVI).

    METHODS AND RESULTS: We followed the EuroHeart methodology for cardiovascular data standard development. A Working Group of 29 members representing 12 countries was established and included a patient representative, as well as experts in the management of valvular heart disease from the European Association of Percutaneous Cardiovascular Interventions (EAPCI), the European Association of Cardiovascular Imaging (EACVI) and the Working Group on Cardiovascular Surgery. We conducted a systematic review of the literature and used a modified Delphi method to reach consensus on a final set of variables. For each variable, the Working Group provided a definition, permissible values and categorized the variable as mandatory (Level 1) or additional (Level 2) based on its clinical importance and feasibility. In total, 93 Level 1 and 113 Level 2 variables were selected, with the level 1 variables providing the dataset for registration of patients undergoing TAVI on the EuroHeart IT platform.

    CONCLUSION: This document provides details of the EuroHeart data standards for TAVI processes of care and in-hospital outcomes. In the context of EuroHeart, this will facilitate quality improvement, observational research, registry-based RCTs and post-marketing surveillance of devices and pharmacotherapies.

  • 243. Aktaa, Suleman
    et al.
    Batra, Gorav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Baigent, Colin
    Erlinge, David
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Ludman, Peter
    Maggioni, Aldo P.
    Price, Susanna
    Weston, Clive
    Casadei, Barbara
    Gale, Chris P.
    European Society of Cardiology methodology for the development of quality indicators for the quantification of cardiovascular care and outcomes2022In: European Heart Journal - Quality of Care and Clinical Outcomes, ISSN 2058-5225, E-ISSN 2058-1742, Vol. 8, no 1, p. 4-13Article, review/survey (Refereed)
    Abstract [en]

    AIMS: It is increasingly recognised that tools are required for assessing and benchmarking quality of care in order to improve it. The European Society of Cardiology (ESC) is developing a suite of quality indicators (QIs) to evaluate cardiovascular care and support the delivery of evidence-based care. This paper describes the methodology used for their development.

    METHODS AND RESULTS: We propose a four-step process for the development of the ESC QIs. For a specific clinical area with a gap in care delivery, the QI development process includes: 1) the identification of key domains of care by constructing a conceptual framework of care; 2) the construction of candidate QIs by conducting a systematic review of the literature; 3) the selection of a final set of QIs by obtaining expert opinions using the modified Delphi method; and 4) the undertaking of a feasibility assessment by evaluating different ways of defining the QI specifications for the proposed data collection source. For each of the four steps, key methodological areas need to be addressed to inform the implementation process and avoid misinterpretation of the measurement results.

    CONCLUSION: Detailing the methodology for the ESC QIs construction enables healthcare providers to develop valid and feasible metrics to measure and improve the quality of cardiovascular care. As such, high-quality evidence may be translated into clinical practice and the 'evidence-practice' gap closed.

  • 244.
    Akula, Srinivas
    et al.
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, POB 7011, SE-75007 Uppsala, Sweden..
    Riihimaki, Miia
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    Waern, Ida
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, POB 7011, SE-75007 Uppsala, Sweden..
    Abrink, Magnus
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, SE-75007 Uppsala, Sweden..
    Raine, Amanda
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Wernersson, Sara
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, POB 7011, SE-75007 Uppsala, Sweden..
    Quantitative Transcriptome Analysis of Purified Equine Mast Cells Identifies a Dominant Mucosal Mast Cell Population with Possible Inflammatory Functions in Airways of Asthmatic Horses2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 22, article id 13976Article in journal (Refereed)
    Abstract [en]

    Asthma is a chronic inflammatory airway disease and a serious health problem in horses as well as in humans. In humans and mice, mast cells (MCs) are known to be directly involved in asthma pathology and subtypes of MCs accumulate in different lung and airway compartments. The role and phenotype of MCs in equine asthma has not been well documented, although an accumulation of MCs in bronchoalveolar lavage fluid (BALF) is frequently seen. To characterize the phenotype of airway MCs in equine asthma we here developed a protocol, based on MACS Tyto sorting, resulting in the isolation of 92.9% pure MCs from horse BALF. We then used quantitative transcriptome analyses to determine the gene expression profile of the purified MCs compared with total BALF cells. We found that the MCs exhibited a protease profile typical for the classical mucosal MC subtype, as demonstrated by the expression of tryptase (TPSB2) alone, with no expression of chymase (CMA1) or carboxypeptidase A3 (CPA3). Moreover, the expression of genes involved in antigen presentation and complement activation strongly implicates an inflammatory role for these MCs. This study provides a first insight into the phenotype of equine MCs in BALF and their potential role in the airways of asthmatic horses.

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  • 245.
    Akyurek, Levent M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Paul, Leendert C
    Funa, Keiko
    Larsson, Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Fellstrom, Bengt C
    Department of Medical Sciences.
    Smooth muscle cell migration into intima and adventitia during development of transplant vasculopathy.1996In: Transplantation, Vol. 62, p. 1526-Article in journal (Refereed)
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    Akyurek, LM
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Fellstrom, B
    Department of Medical Sciences.
    Yang, Z-Q
    Funa, K
    Hansson, G K
    Larsson, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Inducible and endothelial nitric oxide synthase expression during development of transplant arteriosclerosis in rat aortic grafts.1996In: Am J Pathol, Vol. 149, p. 1981-Article in journal (Refereed)
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    Akyurek, LM
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Funa, K
    Wanders, A
    Department of Medical Sciences.
    Larsson, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Fellstrom, BC
    Department of Medical Sciences.
    Inhibition of transplant arteriosclerosis in rat aortic grafts by lowmolecular weight heparin derivatives.1995In: Transplantation, Vol. 59, p. 1517-Article in journal (Refereed)
  • 248.
    Akyurek, LM
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Johnsson, C
    Department of Surgical Sciences.
    Lange, D
    Georgii-Hemming, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Larsson, Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Fellstrom, Bengt
    Department of Medical Sciences.
    Funa, Keiko
    Tufveson, Gunnar
    Department of Surgical Sciences.
    Tolerance induction ameliorates allograft vasculopathy in rat aortic transplants. Influence of Fas-mediated apoptosis.1998In: J Clin Invest, Vol. 101, p. 2889-Article in journal (Refereed)
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    Akyurek, LM
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Larsson, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Funa, K
    Wanders, A
    Department of Medical Sciences.
    Kaijser, M
    Department of Medical Sciences.
    Fellstrom, B
    Department of Medical Sciences.
    Inhibition by Angiopeptin and low molecular weight heparin derivatives.1995In: Transpl Proc, Vol. 27, p. 3555Other (Other scientific)
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    Akyurek, LM
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Larsson, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Zhong-qun, Yan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Hansson, GK
    Funa, K
    Fellstrom, B
    Department of Medical Sciences.
    Nitric oxide synthase isoforms in transplant vessels.1997In: Transpl Proc, Vol. 29, p. 2571Other (Other scientific)
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