| 1. |
- Ekerstad, Niklas, et al.
(författare)
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Clinical Frailty Scale classes are independently associated with 6-month mortality for patients after acute myocardial infarction
- 2022
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Ingår i: European Heart Journal. - : Oxford University Press. - 2048-8726 .- 2048-8734. ; 11:2, s. 89-98
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Data on the prognostic value of frailty to guide clinical decision-making for patients with myocardial infarction (MI) are scarce. To analyse the association between frailty classification, treatment patterns, in-hospital outcomes, and 6-month mortality in a large population of patients with MI.Methods and results: An observational, multicentre study with a retrospective analysis of prospectively collected data using the SWEDEHEART registry. In total, 3381 MI patients with a level of frailty assessed using the Clinical Frailty Scale (CFS-9) were included. Of these patients, 2509 (74.2%) were classified as non-vulnerable non-frail (CFS 1–3), 446 (13.2%) were vulnerable non-frail (CFS 4), and 426 (12.6%) were frail (CFS 5–9). Frailty and non-frail vulnerability were associated with worse in-hospital outcomes compared with non-frailty, i.e. higher rates of mortality (13.4% vs. 4.0% vs. 1.8%), cardiogenic shock (4.7% vs. 2.5% vs. 1.9%), and major bleeding (4.5% vs. 2.7% vs. 1.1%) (allP < 0.001), and less frequent use of evidence-based therapies. In Cox regression analyses, frailty was strongly and independently associated with 6-month mortality compared with non-frailty, after adjustment for age, sex, the GRACE risk score components, and other potential risk factors [hazard ratio (HR) 3.32, 95% confidence interval (CI) 2.30–4.79]. A similar pattern was seen for vulnerable non-frail patients (fully adjusted HR 2.07, 95% CI1.41–3.02).Conclusion: Frailty assessed with the CFS was independently and strongly associated with all-cause 6-month mortality, also after comprehensive adjustment for baseline differences in other risk factors. Similarly, non-frail vulnerability was independently associated with higher mortality compared with those with preserved functional ability.
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| 2. |
- Frodlund, Martina, et al.
(författare)
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The serological immunogenicity of the third and fourth doses of COVID-19 vaccine in patients with inflammatory rheumatic diseases on different biologic or targeted DMARDs: a Swedish nationwide study (COVID-19-REUMA)
- 2024
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Ingår i: MICROBIOLOGY SPECTRUM. - : AMER SOC MICROBIOLOGY. - 2165-0497. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Studies investigating the immunogenicity of additional COVID-19 vaccine doses in immunosuppressed patients with inflammatory rheumatic diseases (IRD) are still limited. The objective was to explore the antibody response including response to omicron virus subvariants (sBA.1 and sBS.2) after third and fourth COVID-19 vaccine doses in Swedish IRD patients treated with immunomodulating drugs compared to controls. Antibody levels to spike wild-type antigens (full-length protein and S1) and the omicron variants sBA.1 and sBA.2 (full-length proteins) were measured. A positive response was defined as having antibody levels over cut-off or >= fourfold increase in post-vaccination levels for both antigens. Patients with arthritis, vasculitis, and other autoimmune diseases (n = 414), and controls (n = 61) receiving biologic/targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs) with or without conventional synthetic DMARDs participated. Of these, blood samples were available for 370 patients and 52 controls after three doses, and 65 patients and 15 controls after four doses. Treatment groups after three vaccine doses were rituximab (n = 133), abatacept (n = 22), IL6r inhibitors (n = 71), JAnus Kinase inhibitors (JAK-inhibitors) (n = 56), tumor necrosis factor inhibitor (TNF-inhibitors) (n = 61), IL12/23/17 inhibitors (n = 27), and controls (n = 52). The percentage of responders after three and four vaccine doses was lower in rituximab-treated patients (59% and 57%) compared to controls (100%) (P < 0.001). After three doses, the percentage of responders in all other groups was 100%, including response to omicron sBA.1 and sBA.2. In rituximab-treated patients, higher baseline immunoglobulin G (IgG) and longer time-period between rituximab and vaccination predicted better response. In this Swedish nationwide study including IRD patients three and four COVID-19 vaccine doses were immunogenic in patients treated with IL6r inhibitors, TNF-inhibitors, JAK-inhibitors, and IL12/23/17-inhibitors but not in rituximab. As >50% of rituximab patients responded to vaccines including omicron subvariants, these patients should be prioritized for additional vaccine doses. IMPORTANCE Results from this study provide further evidence that additional doses of COVID-19 vaccines are immunogenic and result in satisfactory antibody response in a majority of patients with inflammatory rheumatic diseases (IRD) receiving potent immunomodulating treatments such as biological or targeted disease-modifying anti-rheumatic drugs (DMARDs) given as monotherapy or combined with traditional DMARDs. We observed that rituximab treatment, both as monotherapy and combined with csDMARDs, impaired antibody response, and only roughly 50% of patients developed a satisfactory antibody response including response to omicron subvariants after the third vaccine. In addition, higher IgG levels at the last rituximab course before the third vaccine dose and a longer time after the last rituximab treatment increased the chance of a satisfactory antibody response. These results indicate that rituximab-treated patients should be prioritized for additional vaccine doses. CLINICAL TRIALS EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) with number 2021-000880-63.
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| 3. |
- Jakszyn, Paula, et al.
(författare)
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Hepcidin levels and gastric cancer risk in the EPIC-EurGast study
- 2017
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 141:5, s. 945-951
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Tidskriftsartikel (refereegranskat)abstract
- Hepcidin is the main regulator of iron homeostasis and dysregulation of proteins involved in iron metabolism has been associated with tumorogenesis. However, to date, no epidemiological study has researched the association between hepcidin levels and gastric cancer risk. To further investigate the relationship between hepcidin levels and gastric cancer risk, we conducted a nested case-control study (EURGAST) within the multicentric European Prospective Investigation into Cancer and Nutrition study. The study included 456 primary incident gastric adenocarcinoma cases and 900 matched controls that occurred during an average of 11 years of follow-up. We measured serum levels of hepcidin-25, iron, ferritin, transferrin and C-reactive protein. Odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of gastric cancer by hepcidin levels were estimated from multivariable conditional logistic regression models. Mediation effect of the ferritin levels on the hepcidin-gastric cancer pathway was also evaluated. After adjusting for relevant confounders, we observed a statistically significant inverse association between gastric cancer and hepcidin levels (OR 5 ng/l = 0.96, 95% CI = 0.93–0.99). No differences were found by tumor localization or histological type. In mediation analysis, we found that the direct effect of hepcidin only represents a nonsignificant 38% (95% CI: −69%, 91%). In summary, these data suggest that the inverse association of hepcidin levels and gastric cancer risk was mostly accounted by ferritin levels. Further investigation including repeated measures of hepcidin is needed to clarify their role in gastric carcinogenesis.
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| 4. |
- Johansson, Monica
(författare)
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Organizing Policy : A Policy Analysis starting from SMEs in Tuscany and the County of Jönköping
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The importance of small and medium size enterprises (SMEs) for economicdevelopment is frequently debated. SMEs have been called “the backbone of the European economy and the best potential source of jobs and growth”. Political intentions are expressed in numerous programmes, strategies, and organizations, all claiming that their objective is to assist SMEs. The purpose of the thesis is to explore the interaction between politicalaspirations and adequate solutions to SMEs’ challenges. The thesis adopts a comparative perspective, using two completely differentcultural, institutional and historical contexts, the Italian region Tuscany and theCounty of Jönköping. The study follows bottom-up logic, starting off withinterviewed businesspersons’ and other actors’ narratives on how they organizeto face and deal with challenges and opportunities. The challenges andpossibilities and the problem solving processes described by SMEs are outlinedthrough the identification and description of four case studies. Narratives by businesspersons and other actors indicate that only a few of theaspirations and strategies expressed by politicians and decision makers, whoelaborate the objectives of SME policy, actually reach enterprises. A gap seemsto exist between aspirations and realization. The study suggests that animportant part of the explanation to the missing link is found in the differentlifeworlds of SMEs, politicians and other decision makers. How can the gap be bridged? The study concludes that policy is not statementsonly; it is organizing. For organizing to ensue, individuals with a commondefinition of challenges need to get together. The concept of lifeworlds cannotbe ignored.
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| 5. |
- Jones, Geraint H., et al.
(författare)
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The Comet Interceptor Mission
- 2024
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Ingår i: Space Science Reviews. - : Springer Nature. - 0038-6308 .- 1572-9672. ; 220:1
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Tidskriftsartikel (refereegranskat)abstract
- Here we describe the novel, multi-point Comet Interceptor mission. It is dedicated to the exploration of a little-processed long-period comet, possibly entering the inner Solar System for the first time, or to encounter an interstellar object originating at another star. The objectives of the mission are to address the following questions: What are the surface composition, shape, morphology, and structure of the target object? What is the composition of the gas and dust in the coma, its connection to the nucleus, and the nature of its interaction with the solar wind? The mission was proposed to the European Space Agency in 2018, and formally adopted by the agency in June 2022, for launch in 2029 together with the Ariel mission. Comet Interceptor will take advantage of the opportunity presented by ESA’s F-Class call for fast, flexible, low-cost missions to which it was proposed. The call required a launch to a halo orbit around the Sun-Earth L2 point. The mission can take advantage of this placement to wait for the discovery of a suitable comet reachable with its minimum Δ V capability of 600 ms − 1 . Comet Interceptor will be unique in encountering and studying, at a nominal closest approach distance of 1000 km, a comet that represents a near-pristine sample of material from the formation of the Solar System. It will also add a capability that no previous cometary mission has had, which is to deploy two sub-probes – B1, provided by the Japanese space agency, JAXA, and B2 – that will follow different trajectories through the coma. While the main probe passes at a nominal 1000 km distance, probes B1 and B2 will follow different chords through the coma at distances of 850 km and 400 km, respectively. The result will be unique, simultaneous, spatially resolved information of the 3-dimensional properties of the target comet and its interaction with the space environment. We present the mission’s science background leading to these objectives, as well as an overview of the scientific instruments, mission design, and schedule.
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| 6. |
- Ny, Tor, 1949-, et al.
(författare)
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The gene for t-PA
- 1988
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Ingår i: Tissue-type plasminogen activator (t-PA). - : CRC Press. - 0849346088 ; , s. 83-100
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Bokkapitel (refereegranskat)
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| 7. |
- Ochala, Julien, et al.
(författare)
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Defective regulation of contractile function in muscle fibres carrying an E41K beta-tropomyosin mutation.
- 2008
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Ingår i: The Journal of physiology. - : Wiley. - 1469-7793 .- 0022-3751. ; 586:Pt 12, s. 2993-3004
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Tidskriftsartikel (refereegranskat)abstract
- A novel E41K beta-tropomyosin (beta-Tm) mutation, associated with congenital myopathy and muscle weakness, was recently identified in a woman and her daughter. In both patients, muscle weakness was coupled with muscle fibre atrophy. It remains unknown, however, whether the E41K beta-Tm mutation directly affects regulation of muscle contraction, contributing to the muscle weakness. To address this question, we studied a broad range of contractile characteristics in skinned muscle fibres from the two patients and eight healthy controls. Results showed decreases (i) in speed of contraction at saturated Ca(2+) concentration (apparent rate constant of force redevelopment (k(tr)) and unloaded shortening speed (V(0))); and (ii) in contraction sensitivity to Ca(2+) concentration, in fibres from patients compared with controls, suggesting that the mutation has a negative effect on contractile function, contributing to the muscle weakness. To investigate whether these negative impacts are reversible, we exposed skinned muscle fibres to the Ca(2+) sensitizer EMD 57033. In fibres from patients, 30 mum of EMD 57033 (i) had no effect on speed of contraction (k(tr) and V(0)) at saturated Ca(2+) concentration but (ii) increased Ca(2+) sensitivity of contraction, suggesting a potential therapeutic approach in patients carrying the E41K beta-Tm mutation.
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| 8. |
- Ohlsson, Bodil, et al.
(författare)
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Chronic Intestinal Pseudo-Obstruction due to Buserelin-Induced Formation of Anti-GnRH Antibodies.
- 2007
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Ingår i: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 132:1, s. 45-51
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: A 30-year-old woman, treated with buserelin, an analogue of gonadotropin-releasing hormone (GnRH) (also called luteinizing hormone-releasing hormone, LH-RH), developed chronic intestinal pseudo-obstruction (CIPO). The sudden onset of this disease in a previously healthy woman perplexed us. CIPO refers to a gastrointestinal disorder that can have a variety of causes, such as drugs, among others. Thus, we wanted to examine whether in this patient the development of CIPO is related to the treatment with buserelin. Methods: The patient was examined using esophagogastroduodenoscopy, esophageal, and antroduodenojejunal manometry, gastric emptying tests, and histologic analyses and immunohistochemistry on full-thickness biopsies including staining with anti-GnRH antibody. Plasma samples were examined by the standard serologic analyses and specifically for the occurrence of anti-GnRH antibodies by enzyme-linked immunosorbent assay methods. Results: CIPO was diagnosed based on symptoms (abdominal pain, vomiting, and constipation), and the results of the clinical examinations, such as signs of esophageal aperistalsis, delayed gastric emptying, and small intestinal bursts. Histologic examination revealed a decreased number of myenteric neurons as well as increased neuronal degeneration and an abnormal immune profile. There was a loss of GnRH-containing neurons. The patient had high plasma titers of anti-GnRH antibodies, which occurred on the occasions of the treatment with buserelin. Conclusions: Our findings suggest that the patient has developed CIPO due to buserelin-induced formation of anti-GnRH antibodies destroying GnRH-producing neurons of the myenteric plexus.
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| 9. |
- Ohlsson, Monica, et al.
(författare)
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Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin
- 2012
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 135:6, s. 1682-1694
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T > C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.
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| 10. |
- Ohlsson, Monica
(författare)
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Muscle diseases with damaged sarcomeres - causes and consequences
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Muscle diseases, also called myopathies, are usually defined as diseases where the pathology is confined to the muscle itself. This excludes diseases caused by structural abnormalities in the peripheral nerve, from the anterior horn cell to the neuromuscular junction. Much effort has been made to elucidate the pathogenesis of skeletal muscle diseases that result from mutations in sarcomeric and associated proteins, highlighting their importance in normal muscle structure and function. The short-term goals in this field are to determine the remaining causative genes behind the skeletal muscle diseases and to learn more about the pathogenesis behind these diseases. The long-term goals are to develop more specific therapy in the future. In paper I we investigated two children with nemaline myopathy and identified two de novo heterozygous mutations not previously described in the skeletal α-actin gene (ACTA1). The marked variability in clinical features in spite of similar muscle pathology in early childhood was demonstrated. The severe muscle atrophy with replacement of fat and connective tissue found in one of the patients demonstrated that nemaline myopathy might be progressive in some cases. In paper II we investigated a mother and daughter with similar clinical but different morphological features, nemaline myopathy and cap disease. We identified a heterozygous missense mutation in the β-tropomyosin gene, TPM2, the first mutation to be found in cap disease. We concluded that candidate genes in cap disease ought to be found within the genes encoding for sarcomeric proteins, especially those previously associated with nemaline myopathy and that mutations in TPM2 might be a common cause of cap disease. In paper III we investigated three unrelated patients and identified three de novo heterozygous mutations in TPM2: a three–base pair deletion in-frame, a three-base pair duplication in-frame, and a missense mutation. The hypothesis that mutations in TPM2 are a common cause of cap disease was confirmed. In muscle biopsy specimens, a coarse-meshed and irregular intermyofibrillar network was found. These specific pathological findings may be clues towards a correct diagnosis and indicate that the pathogenesis involves defective assembly of myofilaments. In paper IV we had the opportunity to investigate one of the original cases of cap disease. In this patient we found a de novo heterozygous missense mutation in TPM3. The observation that cap disease, like nemaline myopathy, is associated with mutations in TPM2 as well as in TPM3 and shows similar clinical presentation supports our concept that cap disease is related to nemaline myopathy and all genes encoding components of the sarcomeric thin filament should be considered as candidate genes in patients with cap disease. In paper V we investigated seven individuals from two apparently unrelated families with a dominantly inherited adult-onset myopathy with early respiratory failure. All patients had muscle weakness in the pelvic girdle, neck flexors and trunk muscles together with prominent calf hypertrophy. Muscle histopathological features included eosinophilic deposits and extensive myofibrillar lesions with marked Z-disk alterations. Genetic analysis with array data using SNP markers demonstrated that the affected individuals shared a large haplotype on chromosome 2q31, including the giant titin gene (TTN). Further studies include the investigation of the TTN gene and other genes of interest in this region. This study has deepened the understanding of inherited myopathies associated with damaged sarcomeres by describing new mutations in causative genes, which in the end could lead to new therapy strategies.
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