| 1. |
- Holm, Anna, 1973-
(author)
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Acute coronary syndrome : bleeding, platelets and gender
- 2019
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Doctoral thesis (other academic/artistic)abstract
- BACKGROUNDBleeding complications increase mortality in patients with acute coronary syndrome (ACS). Potential gender difference in bleeding regarding prevalence, location, severity and prognostic impact is still controversial and not well investigated. In regard to this aspect the relevance of triple antithrombotic therapy (TAT) is questioned. There is an ongoing debate on the clinical implications of TAT and furthermore assumed that bleeding complications, except impact on outcome, also are associated with great influence on health economy.The main focus of this thesis was to further investigate the incidence and impact of bleeding complications in patients treated for ACS, with special reference to gender disparities, TAT and health economics. The thesis will highlight the importance of improved bleeding prevention strategies for both men and women.METHODPaper I, II and IIIObservational studies from the SWEDEHEART register.In paper I we investigated patients hospitalised with myocardial infarction (MI) during 2006–2008. Outcomes were in-hospital bleedings, in-hospital mortality and one-year mortality in hospital survivors.In paper II, all patients with MI, in the County of Östergötland, Sweden during 2010 were included and followed for one year. The patients' medical records were evaluated, in relation to short and long-term bleeding complications, bleeding location, withdrawal of platelet inhibiting drugs and nonfatal MI and death.Paper III included all patients discharged with (TAT) in the County of Östergötland 2009-2015. Information about bleeds and ischemic complications during one-year follow-up were retrieved from the medical records. Estimation of the health care costs associated with bleeding episodes were added to the evaluation.Paper IVPatients with MI, scheduled for coronary angiography were recruited. All patients received clopidogrel and aspirin. A subgroup of patients received GP IIb/IIIa-inhibitor. Outcomes were platelet aggregation assessed at several time points, using a Multiplate impedance aggregometer, measurement of P-selectin in plasma, evaluation of high residual platelet reactivity (HRPR) and low residual platelet reactivity (LRPR) respectively and incidence of bleeding complications. A comparison between women and men was performed.RESULTSPaper IA total number of 50.399 patients were included, 36.6% women. In-hospital bleedings were more common in women (1.9% vs. 3.1%, p<0.001) even after multivariable adjustment (OR 1.17, 95%, CI 1.01–1.37). The increased risk for women was found in STEMI (OR 1.46, 95% CI 1.10–1.94) and in those who underwent PCI (OR 1.80, 95% CI 1.45–2.24).In contrast the risk was lower in medically treated women (OR 0.79, 95% CI 0.62–1.00). After adjustment, in-hospital bleeding was associated with higher risk of oneyear mortality in men (OR 1.35, 95% CI 1.04–1.74), whereas this was not the case in women (OR 0.97, 95% CI 0.72–1.31).Paper IIIn total 850 consecutive patients were included. The total incidence of bleeding events was 24.4% (81 women and 126 men, p=ns). The incidence of all in hospital bleeding events was 13.2%, with no gender difference. Women had significantly more minor nonsurgery related bleeding events than men (5% vs 2.2%, p=0.02). During follow-up, 13.5% had a bleeding, with more non-surgery related bleeding events among women, 14.7% vs 9.7% (p=0.03). The most common bleeding localisation was the gastrointestinal tract, more in women than men (12.1% vs 7.6%, p=0.03). Women also had more access site bleeding complications (4% vs 1.7%, p=0.04), while men had more surgery related bleeding complications (6.4% vs 0.9%, p≤0.001). Increased mortality was found only in men with non-surgery related bleeding events (p=0.008).Paper IIIAmong 272 identified patients, 156 bleeds occurred post-discharge, of which 28.8% were of gastrointestinal origin. In total 54.4% had at least one bleed during or after the index event and 40.1% bled post-discharge of whom 28.7% experienced a TIMI major or minor bleeding. Women discontinued TAT prematurely more often than men (52.9 vs 36.1%, p=0.01) and bled more (48.6 vs. 37.1%, p=0.09). One-year mean health care costs were EUR 575 and EUR 5787 in non-bleeding and bleeding patients, respectively.Paper IVWe recruited 125 patients (37 women and 88 men). We observed significantly more inhospital bleeding events in women as compared to men (18.9% vs 6.8%, p=0.04). There were no differences in platelet aggregation using three different agonists, reflecting treatment of GPIIb/IIIa inhibitors, clopidogrel and aspirin, at four different time-points nor were there any differences in p-selectin in plasma 3 days after admission.CONCLUSIONThere is a remarkably high bleeding incidence among patients treated with DAPT and even more so if treated with TAT. Female gender is an independent risk factor of inhospital bleeding after myocardial infarction, this higher bleeding risk in women appears to be restricted to invasively treated patients and STEMI patients. Even if women had higher short- and long-term mortality, there was no difference between the genders among those who bled. After multivariable adjustment the prognostic impact of bleeding complications was higher in menWomen seem to experience more minor/minimal bleeding complications than men, predominantly GI bleeding events and access site bleeding events, with no apparent impact on outcome.In contrast men with non-surgery related bleeding complications had higher mortality. There is a lack of differences between the genders concerning platelet aggregation. Our results do not support gender disparities in platelet reactivity and excess dosing as a major explanation for increased bleeding risk in women. Improved bleeding prevention strategies are warranted for both men and women.
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| 2. |
- Holm, Anna, 1973-, et al.
(author)
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Sex differences in platelet reactivity in patients with myocardial infarction treated with triple antiplatelet therapy-results from assessing platelet activity in coronary heart disease (APACHE)
- 2021
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In: Platelets. - : Taylor & Francis. - 0953-7104 .- 1369-1635. ; 32:1, s. 524-532
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Journal article (peer-reviewed)abstract
- )Several earlier studies have reported increased risk of bleeding in women with myocardial infarction, (MI) compared to men. The reasons for the observed difference are incompletely understood, but one suggested explanation has been excess dosing of antithrombotic drugs in women. The aim of this prospective observational study was to assess sex differences in platelet activity in patients treated with three different platelet inhibitors. We recruited 125 patients (37 women and 88 men) with MI, scheduled for coronary angiography. All patients received clopidogrel and aspirin. A subgroup of patients received glycoprotein (GP) IIb/IIIa-inhibitor. Platelet aggregation in whole blood was assessed at several time points, using impedance aggregometry. SolubleP-selectin was measured 3 days after admission. There were no significant differences between women and men in baseline features or comorbidities except higher frequency of diabetes, lower hemoglobin value, and lower estimated glomerular filtration rate, in women on admission. We observed significantly more in-hospital bleeding events in women compared to men (18.9% vs. 6.8%,p= .04). There were no differences in platelet aggregation using three different agonists, reflecting treatment effect of GPIIb/IIIa-inhibitors, clopidogrel, and aspirin, 6-8 hours, 3 days, 7-9 days, or 6 months after loading dose. Moreover, there was no significant difference in solubleP-selectin. The main finding of this study was a consistent lack of difference between the sexes in platelet aggregation, using three different agonists at several time-points. Our results do not support excess dosing of anti-platelet drugs as a major explanation for increased bleeding risk in women.
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| 3. |
- Nilsson, Sigrid, 1997-
(author)
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Vasomotor Symptoms, Cardiovascular Risk and the Role of Physical Activity in Midlife Women
- 2023
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Doctoral thesis (other academic/artistic)abstract
- Background: The menopausal transition is, for most women, accompanied by hot flushes and night sweats (i.e., vasomotor symptoms, VMS). VMS has been associated with a worsened cardiovascular risk profile, but whether VMS constitutes an independent risk marker for developing subclinical atherosclerotic cardiovascular disease (ASCVD) is still uncertain. Visceral adipose tissue (VAT) contributes more to systemic low-grade inflammation than abdominal subcutaneous adipose tissue (ASAT), enhancing atherosclerosis development. Physical activity is an effective behavioral strategy to maintain and improve cardiovascular health. Whether a resistance training intervention (RTI) could reduce low-grade inflammation and VAT volume in postmenopausal women with VMS remains unclear, and whether the RTI-associated effects could be maintained over time requires further investigation.Material and Methods: This thesis is based on three studies. Study 1 was conducted on a subset of participants from the cross-sectional population-based Swedish CArdioPulmonary BioImage Study (SCAPIS), including women 50-64 years of age. The women underwent comprehensive cardiovascular assessments and completed an extensive female-specific questionnaire. VMS was assessed on a 4-point scale. Subclinical ASCVD was detected via coronary computed tomography angiography (CCTA), computed tomography (CT), and carotid ultrasound. Study 2 is a sub-study of 65 postmenopausal women with VMS and low physical activity, randomized to either three days/week of an RTI or unchanged physical activity for 15 weeks. Women underwent anthropometric measurements, magnetic resonance imaging (MRI), and blood sampling at baseline and after 15 weeks. During the last followup contact in Study 2 after two years, 35 women agreed to attend an additional clinic visit to reevaluate cardiovascular risk markers, marking the inception of Study 3.Results: Of 2995 women included in Study 1, 14.2% reported severe VMS (n = 425), 18.1% moderate VMS (n = 543), and 67.7% no or mild VMS (n = 2027). Current or previous severe VMS, but not moderate VMS, was significantly associated with CCTA-detected coronary atherosclerosis, with odds ratio (OR) before and after multivariable adjustment 1.36, 95% confidence interval (CI) 1.08 – 1.72 and 1.33, 95% CI 1.02 – 1.72, respectively. This association was only present for >5 years durations of severe VMS or when the onset of severe VMS occurred before menopause. Adjustment for menopausal hormone therapy strengthened the association for women with severe VMS >5 years (OR 1.67, 95% CI 1.16 – 2.40). Women compliant with an RTI had compared to a control group (CG), decreased adiponectin (p < 0.01), ASAT (p < 0.01), VAT (p < 0.01), total abdominal adipose tissue (TAAT) (p < 0.01) and fat ratio (p <0.001). Furthermore, an RTI reduced moderate to severe VMS frequency to six months post-intervention compared to a CG, but did neither contribute to preserved cardiovascular health markers nor improved health-related quality of life (HRQoL) after two years compared to a CG.Conclusions: There is a need for extra vigilance regarding cardiovascular risk factors in the group of women suffering from severe VMS. Implementing a 15-week RTI in these women could counteract the VAT redistribution and alter the frequency of moderate to severe VMS with maintained effects up to six months.
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| 4. |
- Amrutkar, Manoj, et al.
(author)
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Genetic Disruption of Protein Kinase STK25 Ameliorates Metabolic Defects in a Diet-Induced Type 2 Diabetes Model
- 2015
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 64:8, s. 2791-2804
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Journal article (peer-reviewed)abstract
- Understanding the molecular networks controlling ectopic lipid deposition, glucose tolerance, and insulin sensitivity is essential to identifying new pharmacological approaches to treat type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a negative regulator of glucose and insulin homeostasis based on observations in myoblasts with acute depletion of STK25 and in STK25-overexpressing transgenic mice. Here, we challenged Stk25 knockout mice and wild-type littermates with a high-fat diet and showed that STK25 deficiency suppressed development of hyperglycemia and hyperinsulinemia, improved systemic glucose tolerance, reduced hepatic gluconeogenesis, and increased insulin sensitivity. Stk25(-/-) mice were protected from diet-induced liver steatosis accompanied by decreased protein levels of acetyl-CoA carboxylase, a key regulator of both lipid oxidation and synthesis. Lipid accumulation in Stk25(-/-) skeletal muscle was reduced, and expression of enzymes controlling the muscle oxidative capacity (Cpt1, Acox1, Cs, Cycs, Ucp3) and glucose metabolism (Glut1, Glut4, Hk2) was increased. These data are consistent with our previous study of STK25 knockdown in myoblasts and reciprocal to the metabolic phenotype of Stk25 transgenic mice, reinforcing the validity of the results. The findings suggest that STK25 deficiency protects against the metabolic consequences of chronic exposure to dietary lipids and highlight the potential of STK25 antagonists for the treatment of type 2 diabetes.
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| 5. |
- Berin, Emilia, 1992-
(author)
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Resistance Training and Physical Activity in Postmenopausal Women : Effects on Vasomotor Symptoms, Quality of Life and Microcirculation
- 2023
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Doctoral thesis (other academic/artistic)abstract
- Background Menopause is a physiological event, but is associated with bothersome symptoms as well as physical changes that affect women’s health. About 75 % of women experience vasomotor symptoms (hot flushes and night sweats) related to menopause that often reduce quality of life. The vasomotor symptoms may be attributed to dysfunctional temperature regulation centrally in the hypothalamus and peripherally in the skin’s circulation. The most effective treatment for vasomotor symptoms is menopausal hormone therapy, but not all women are able to, or want to, use it. In addition to the impact on quality of life, studies have associated vasomotor symptoms and menopause with macrovascular endothelial dysfunction. Previous studies on the association of these factors with the skin’s microcirculatory function are small and few. Observational studies have associated physical activity and exercise with less vasomotor symptoms, but the evidence from intervention trials is of low quality and the results are ambiguous. Physical activity has established general health effects, and could potentially decrease vasomotor symptoms by effects on endogenous opioids centrally, and by more efficient thermoregulation peripherally. The aim of this thesis was to investigate the effect of resistance training on vasomotor symptoms and health-related quality of life in postmenopausal women, and to explore the women’s experiences of the training to find barriers and facilitators. We also aimed to investigate whether the skin’s microcirculatory function differed between women regarding menopausal status, vasomotor symptoms, menopausal hormone therapy, and physical activity. Material and methods The first study was an open randomized controlled trial including 65 postmenopausal women with moderate to severe vasomotor symptoms and low physical activity levels. We randomized the women to 15 weeks of resistance training (intervention) or unchanged physical activity (control). The participants registered vasomotor symptoms daily in a diary, and answered health-related quality of life questionnaires at baseline and at 15 weeks. The first 15 women to finish the intervention were recruited to a qualitative study. The women’s experiences of the resistance training intervention were explored in individual interviews after the intervention period, and all were followed-up with telephone interviews after one year. The third study was cross-sectional, including 1148 women from Linköping, 50-64 years old, who participated in the Swedish CArdioPulmonary bioImage Study (SCAPIS). These women answered a questionnaire about menopausal status, vasomotor symptoms and menopausal hormone therapy use, and wore accelerometers for seven days to assess physical activity. The skin’s microcirculation was assessed at rest and during post-occlusive reactive hyperemia. Results Moderate to severe vasomotor symptoms per 24 hours decreased significantly more in the group of women randomized to resistance training compared with the control group (mean difference -2.7, 95% CI -4.2 to -1.3). The resistance training group improved in domains of menopause-specific health-related quality of life compared with the control group but there was little impact on generic health-related quality of life. In the qualitative study we found that the vasomotor symptoms acted as a “trigger” for the women to become motivated to exercise. Their motivation then evolved from being driven by hopes of symptom relief into being driven by a wish for general well-being, which was still a driving force after one year. Microvascular function did not differ between postmenopausal and premenopausal women, or between women with or without vasomotor symptoms or menopausal hormone therapy. Women with higher levels of objectively measured and self-reported physical activity had a better reactivity of the skin’s microcirculation. The differences remained significant after adjusting for BMI, smoking, hypertension, diabetes, and education. Conclusions Resistance training could be effective for decreasing vasomotor symptoms and improving some aspects of health-related quality of life in motivated postmenopausal women. The vasomotor symptoms themselves spurred motivation to exercise, indicating they present an opportunity to increase physical activity. When a woman seeks medical advice for vasomotor symptoms, this could be a chance for health care professionals to help her initiate or increase exercise. Women who performed more physical activity and exercise had better skin microvascular function, but no association with VMS was found. Future studies are needed to investigate what type and dose of exercise is the most effective to reduce vasomotor symptoms and whether there is a way to predict for whom exercise will or will not be an effective intervention.
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| 6. |
- Heiss, Christina, et al.
(author)
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The gut microbiota regulates hypothalamic inflammation and leptin sensitivity in Western diet-fed mice via a GLP-1R-dependent mechanism
- 2021
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 35:8
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Journal article (peer-reviewed)abstract
- Mice lacking a microbiota are protected from diet-induced obesity. Previous studies have shown that feeding a Western diet causes hypothalamic inflammation, which in turn can lead to leptin resistance and weight gain. Here, we show that wild-type (WT) mice with depleted gut microbiota, i.e., germ-free (GF) and antibiotic-treated mice, have elevated levels of glucagon-like peptide-1 (GLP-1), are protected against diet-induced hypothalamic inflammation, and have enhanced leptin sensitivity when fed a Western diet. Using GLP-1 receptor (GLP-1R)-deficient mice and pharmacological inhibition of the GLP-1R in WT mice, we demonstrate that intact GLP-1R signaling is required for preventing hypothalamic inflammation and enhancing leptin sensitivity. Furthermore, we show that astrocytes express the GLP-1R, and deletion of the receptor in glial fibrillary acidic protein (GFAP)-expressing cells diminished the antibiotic-induced protection against diet-induced hypothalamic inflammation. Collectively, our results suggest that depletion of the gut microbiota attenuates diet-induced hypothalamic inflammation and enhances leptin sensitivity via GLP-1R-dependent mechanisms.
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| 7. |
- Henningsson, Susanne, 1977, et al.
(author)
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Interleukin-6 gene polymorphism -174G/C influences plasma lipid levels in women.
- 2006
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In: Obesity (Silver Spring, Md.). - 1930-7381. ; 14:11, s. 1868-73
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Journal article (peer-reviewed)abstract
- Elevated levels of the pro-inflammatory cytokine interleukin-6 (IL-6) have been associated with cardiovascular risk factors. The objective of this study was to investigate potential associations between the promoter polymorphism IL-6 -174G/C and the following indices of metabolism: BMI, waist-to-hip ratio, and plasma levels of IL-6, cholesterol, low-density lipoprotein, triglycerides, high-density lipoprotein, leptin, and C-reactive protein in 252 42-year-old women and 245 51-year-old men. Subgroups were also studied 5 years later. The CC genotype of the IL-6 polymorphism was associated with lower levels of cholesterol and low-density lipoprotein (p < 0.001) in women. This finding was replicated in the follow-up, when a significant association between the CC genotype and low triglycerides was also observed. The association between the C allele and lipid pattern found in women was not found in men, where on the contrary, C carriers tended to display elevated triglycerides. IL-6 genotype was not associated with IL-6 plasma levels in either sample. The results suggest different effects of the IL-6 polymorphism on metabolic indices in women and men. None of the associations between IL-6 genotype and lipid pattern seemed to result from an effect of the polymorphism on IL-6 plasma levels.
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| 8. |
- Holm, Anna, et al.
(author)
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Bleeding complications after myocardial infarction in a real world population - An observational retrospective study with a sex perspective
- 2018
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In: Thrombosis Research. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0049-3848 .- 1879-2472. ; 167, s. 156-163
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Journal article (peer-reviewed)abstract
- Introduction: The aim of the current study was to assess bleeding events, including severity, localisation and prognostic impact, in a real world population of men and women with myocardial infarction (MI). Methods and results: In total 850 consecutive patients were included during 2010 and followed for one year. Bleeding complications were identified by searching of each patients medical records and characterised according to the TIMI criteria. For this analysis, only the first event was calculated. The total incidence of bleeding events was 24.4% (81 women and 126 men, p=ns). The incidence of all inhospital bleeding events was 13.2%, with no sex difference. Women had significantly more minor non-surgery related bleeding events than men (5% vs 2.2%, p=0.02). During follow-up, 13.5% had a bleeding, with more non-surgery related bleeding events among women, 14.7% vs 9.7% (p=0.03). The most common bleeding localisation was the gastrointestinal tract, more in women than men (12.1% vs 7.6%, p=0.03). Women had also more access site bleeding complications (4% vs 1.7%, p=0.04), while men had more surgery related bleeding complications (6.4% vs 0.9%, p=0.001). Increased mortality was found only in men with non-surgery related bleeding events (p=0.008). Conclusions: Almost one in four patients experienced a bleeding complication through 12 months follow-up after a myocardial infarction. Women experienced more non-surgery related minor/minimal bleeding complications than men, predominantly GI bleeding events and access site bleeding events, with no apparent impact on outcome. In contrast men with non-surgery related bleeding complications had higher mortality. Improved bleeding prevention strategies are warranted for both men and women.
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| 9. |
- Holm, Anna, 1973-, et al.
(author)
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Long term risk and costs of bleeding in men and women treated with triple antithrombotic therapy : An observational study
- 2021
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In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 16:3
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Journal article (peer-reviewed)abstract
- Objectives Bleeding is the most common non-ischemic complication in patients with coronary revascularisation procedures, associated with prolonged hospitalisation and increased mortality. Many factors predispose for bleeds in these patients, among those sex. Anyhow, few studies have characterised the population receiving triple antithrombotic therapy (TAT) as well as long term bleeds from a sex perspective. We investigated the one year rate of bleeds in patients receiving TAT, potential sex disparities and premature discontinuation of TAT. We also assessed health care costs in bleeders vs non-bleeders. Setting Three hospitals in the County of ostergotland, Sweden during 2009-2015. Participants All patients discharged with TAT registered in the SWEDEHEART registry. Primary and secondary outcome measures All bleeds receiving medical attention during one-year follow-up were collected by retrieving relevant information about each patient from medical records. Resource use associated with bleeds was assigned unit cost to estimate the health care costs associated with bleeding episodes. Results Among 272 patients, 156 bleeds occurred post-discharge, of which 28.8% were gastrointestinal. In total 54.4% had at least one bleed during or after the index event and 40.1% bled post discharge of whom 28.7% experienced a TIMI major or minor bleeding. Women discontinued TAT prematurely more often than men (52.9 vs 36.1%, p = 0.01) and bled more (48.6 vs. 37.1%, p = 0.09). One-year mean health care costs were EUR 575 and EUR 5787 in non-bleeding and bleeding patients, respectively. Conclusion The high bleeding incidence in patients with TAT, especially in women, is a cause of concern. There is a need for an adequately sized randomised, controlled trial to determine a safe but still effective treatment for these patients.
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| 10. |
- Holm, Anna, et al.
(author)
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Mapping of Human Papilloma Virus, p16, and Epstein-Barr Virusin Non-Malignant Tonsillar Disease
- 2019
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In: Laryngoscope Investigative Otolaryngology (LIO). - : Wiley-Blackwell. - 2378-8038. ; 4:3, s. 285-291
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Journal article (peer-reviewed)abstract
- Objectives: Due to their location in the entrance of the aero‐digestive tract, tonsils are steadily exposed to viruses. Human papilloma virus (HPV) and Epstein‐Barr virus (EBV) are two potentially oncogenic viruses that tonsils encounter. The incidence of HPV positive tonsillar cancer is on the rise and it is unknown when infection with HPV occurs.Aim: To investigate if tonsils are infected with HPV and EBV, to study the co‐expression of HPV and its surrogate marker p16, and to evaluate the number of EBV positive cells in benign tonsillar disease.Materials and Methods: Tonsils from 40 patients in a university hospital were removed due to hypertrophy, chronic or recurrent infection. These were analyzed for presence of HPV, its surrogate marker p16, and EBV. HPV was studied using PapilloCheck (a PCR method), while p16 was identified in epithelial and lymphoid tissue with immunohistochemistry and EBV using EBER‐ISH (Epstein‐Barr encoding region–in situ hybridization).Results: HPV was not detected, and p16 was present at low numbers in all epithelial samples as well as in 92.5% of the lymphoid tonsillar samples. At least one EBER‐positive cell was seen in 65% of cases. Larger numbers of EBER‐expressing cells were only seen in two cases.Conclusion: These findings demonstrate that EBV and HPV infect tonsils independently, but further studies are warranted to confirm their infectious relationship.Level of Evidence: Cross‐sectional study
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