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- Ranebo, Mats, 1970-
(författare)
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Rotator Cuff Tears : Short- and long-term aspects on treatment outcome
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rotator cuff tear is a common disorder and there is a lack of knowledge of appropriate treatment and consequences of different treatment modalities. The overall aim of this thesis was to examine short- and long-term results of rotator cuff tear treatment.In Paper I we did a retrospective 21 to 25-year follow-up of a consecutive series of patients with partial and full-thickness rotator cuff tears, treated with acromioplasty without cuff repair. The cuff status had been documented in a specific perioperative protocol in all patients at the index operation. We did x-ray, ultrasonography and clinical scores with Constant score and Western Ontario Rotator Cuff index (WORC) at follow-up. We identified 111 patients with either a partial or a full-thickness tear, but at follow-up 21 were deceased and 11 were too ill from medical conditions unrelated to their shoulder. Out of the remaining 78 eligible patients, 69 were examined (follow-up rate 88 %) and they had a mean age at the index operation of 49 years (range 19-69 years). Forty-five had a partial tear and 24 a full-thickness tear at the index operation. At follow-up, 74% of patients with full-thickness tear had cuff tear arthropathy grade 2 or more according to the arthropathy classification of Hamada (grade 1 to 5) and 87% had developed tear progression (i.e. a larger tear). Corresponding numbers in those with a partial tear was 7 % arthropathy and 42 % tear progression, and the differences between the full-thickness group and the partial tear group was significant for both outcome measures (P<0.001 for both analyses). In those with arthropathy, the mean Constant score was 47 (standard deviation [SD], 23), the mean age and gender-adjusted Constant score 62 (SD, 27) and the mean WORC 58 % (SD, 26). Patients with a partial tear at follow-up had mean Constant score and WORC within the normal range. In multivariable analysis with logistic regression, having a full-thickness tear at the index operation was a risk factor for arthropathy (odds ratio [OR] 37.8; 95% confidence interval [CI], 8.2-175.0) and for tear progression (OR 6.09; 95% CI, 1.41-26.29).In Paper II we examined the contralateral shoulder in the same patients as in paper I and with the same methodology. Sixty-one patients were examined and 38 had had a partial tear at the index operation 21-25 years ago and 23 a full-thickness tear. The overall rate of contralateral full-thickness tears was 50.8 %, which is higher than the 16-35 % rate found in previous studies of newly diagnosed cuff patients. The rate of contralateral full-thickness tear ranged from 13.6 % in patients with a partial tear in the index shoulder at follow-up, to 90 % in patients with a full-thickness tear and arthropathy in the index shoulder. There was a significant correlation regarding conditions between shoulders in the same patient, with a Spearman coefficient of 0.72 for the number of ten-dons with a full-thickness tear, 0.31 for Hamada grade of arthropathy and 0.65 for Constant score. The number of tendons with a full-thickness tear in the index shoulder at follow-up was a risk factor for a contralateral full-thickness tear (OR 3.28; 95% CI, 1.67-6.44) in a multi-variable logistic regression model. We also found that cuff tear arthropathy was significantly more common in patients who had undergone an acromioplasty (P<0.001), a finding which is not confirmatory but may generate a hypothesis.Paper III addressed 17 to 20-year results after operation with a synthetic interposition graft for irreparable cuff tears. We used X-ray, ultrasonography and clinical scores at follow-up. We identified a consecutive series of 13 patients, one of whom was deceased at follow-up. Ten of the remaining 12 participated in a complete follow-up and 2 did only x-ray examination. Nine out of 12 (75 %; 95% CI, 43-95 %) had cuff tear arthropathy Hamada grade 2 or more in the index shoulder at follow-up. The mean Constant score was 46 (SD, 26) and the mean WORC 59 % (SD, 20). Seven out of 12 had contralateral cuff tear arthropathy, and the difference in frequency of arthropathy between shoulders was not statistically significant (P=0.667).In Paper IV we tested whether early repair of small cuff tears, involving mainly supraspinatus, would give a superior clinical result com-pared to physiotherapy without repair in a prospective randomised trial with 12 months follow-up. We used Constant score as the primary out-come, and WORC, EQ-VAS and Numerical Rating Scale for pain (NRS) as secondary outcomes. We also aimed at assessing the rate of tear progression in unrepaired shoulders and the healing rate in repaired shoulders by Magnetic Resonance Imaging (MRI) performed at 12 months. With a high grade of follow-up (100 % for 12 months Constant score and 95 % for 12 months MRI), the repair group had a 12 months median Constant score of 83 (Quartile range [QR], 25) and the conservative group 78 (QR, 22). This between-group difference in medians of 4.5 (95% CI,-5 to 9; P=0.68) was not statistically significant and we did not detect any significant differences in the secondary outcomes at 12 months. The retear rate was 6.5 % in repaired patients and 29 % of unrepaired patients had a tear enlargement >5 mm.The results in this thesis indicate that patients with small, traumatic, full-thickness tears of mainly supraspinatus have no clinical benefit of early surgical repair compared to physiotherapy alone, but in the long-term, patients with full-thickness tears have an increased risk of tear progression, cuff tear arthropathy and low clinical scores. These results are especially important in the treatment decision of repair or not in younger patients. Having a full-thickness tear is also a risk factor for having a contralateral cuff tear, a phenomenon that underlines the importance of endogenous factors in the development of rotator cuff tears. If a cuff tear is not repairable to bone, the addition of a synthetic inter-position graft does not seem to prevent cuff tear arthropathy.
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| 2. |
- Byenfeldt, Marie, 1967-
(författare)
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Ultrasound based shear wave elastography of the liver : a non-invasive method for evaluation of liver disease
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Detecting liver disease at an early stage is important, given that early intervention decreases the risk of developing cirrhosis and subsequently hepatocellular cancer (HCC). The non-invasive ultrasound-based shear wave elastography (SWE) has been used clinically for a decade to assess liver stiffness. This method is reliable, rapid and can be performed in an outpatient setting without known risks for the patient. However, increased variance in SWE results has been detected, without clear explanation. Factors that affect SWE results needs to be identified. Data are insufficient regarding the reliability of SWE with different body positions and probe pressures. Men have higher SWE results than women, also for unclear reasons. Increasing the reliability of SWE is crucial for understanding how factors such as overweight and obesity, cardiovascular and antiviral medication, age, sex, smoking habits, hepatic steatosis and cirrhosis affect SWE results.Aims: The overall aim of the studies included in this thesis was to increase the reliability of SWE liver. The specific aims were to investigate patient-related factors associated with increased uncertainty in SWE results. Another aim was to investigate the influence of increased intercostal probe pressure on liver stiffness assessment with SWE liver. The final aims were to investigate the influence of postural changes, sagittal abdominal diameter (SAD) and skin-to-liver capsule distance (SCD) on SWE results, along with sex-based differences for SWE results and cardiovascular medication.Methods: All enrolled participants in these studies were consecutive patients with various liver diseases presenting at the radiology department Östersunds Hospital. The patients were examined using SWE liver method at the ultrasound unit between April 2014 and May 2018. Inclusion criteria were that participants be adults (age ≥18 years) who had provided written consent for participating in the study. The exclusion criterion was an inability to communicate. Current guidelines for SWE of the liver were used in the thesis with the following exceptions: In study II, increased intercostal probe pressure was used, and in study III, postural change was used. Study I included 188 patients; study II included 112 patients, and studies III and IV involved 200 patients. The four studies were conducted as cross-sectional and clinical trial, using quantitative methods.Results: Factors associated with low variance for SWE results were age, sex, and presence of cirrhosis, the use of antiviral and/or cardiovascular medication, smoking habits, and body mass index. Factors associated with increased uncertainty in SWE results were increased SCD and the presence of steatosis. With increased probe pressure SCD decreased and the quality of shear wave increased. The results showed that the number of required measurements can be reduced. A postural change to left decubitus decreased SCD. For patients with increased SAD and increased SWE result in the supine position, SWE result decreased with a postural change to left decubitus. The SWE results, SCD and SAD significantly differed between women and men. SWE results was higher in the presence of increased SAD (≥23 cm) among men, but not among women.Conclusions: SWE of the liver is a reliable, non-invasive method for diagnosing liver disease. Results in this thesis suggest that for patients with SCD ≥2.5 cm, shear wave measures could be of poor quality and the SWE exam less reliable. In these cases, increased probe pressure may facilitate a reliable SWE exam. With such adjustments in probe pressure, the ultrasound-based SWE method can be superior for examination in patients with overweight or obesity. An effect of SAD ≥23 cm was seen for men with liver fibrosis only, which may explain the higher SWE result for men compared to women. Depending on the severity of liver disease and SAD, a postural change to left decubitus can produce a different outcome. As SAD increased, liver stiffness did, as well. Increased SAD thus is linked to increased liver stiffness, indicating that SAD should be taken into account when performing SWE of the liver.
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| 5. |
- Norlin, Anna-Karin, 1977-
(författare)
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Exploring the Biopsychosocial Model in Irritable Bowel Syndrome : with emphasis on stress, comorbidities and fatigue
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundIrritable bowel syndrome (IBS) is a common, chronic, relapsing, and sometimes disabling, symptombased disorder of gut brain interactions. It has got a female predominance and occurs in all ages, with a slight decrease among elderly. The IBS symptoms can affect everyday work and social life in addition to an increased use of health care resources. Most IBS patients are diagnosed and helped in primary health care (PHC). For many patients, available treatment is insufficient. It is known that both extraintestinal symptoms such as fatigue, as well as comorbidities such as mood disorders, chronic pain syndromes, and insomnia contribute to the illness burden, often to a larger extent than the gastrointestinal symptoms as such.Even though the pathophysiology of IBS is not completely known, it is now conceptualized as a disorder of altered brain-gut interactions, where a biopsychosocial model helps in understanding the symptoms. Exposure to stress is thought to play an important role overall in the pathology of IBS, as well as immune activation at least in a subgroup of patients.This thesis aimed to gain deeper understanding of the biopsychosocial mechanisms of IBS and its associations with stress, comorbidities, and fatigue.Methods Study I and II are based on the Twin cities IBS study population, which included IBS patients and a control group of other patients without gastrointestinal complaints from ten PHC centres in the county of Östergötland. Alongside demographics, psychosocial questionnaires and a GI symptom diary, it included analyses of hair cortisol concentrations (HCC) evaluated in study I, and data on self-rated health as well as diagnoses of comorbidities, and number of health care contacts from a regional registry, evaluated for study II.Study III of this thesis is based on the Brain-Gut study with a population of secondary care IBS patients, and healthy controls (HC). It included self-rated measures of fatigue impact on the daily life and early adverse life events, as well as measures of circulating TNF-α, and analyses of resting-state functional magnetic resonance imaging of brain areas within a mesocorticolimbic circuitry of known relevance for fatigue.Results Study I: Perceived stress was higher in the IBS group while a considerable portion of IBS patients had low levels of HCC. No association between perceived stress and HCC was seen in either group.Study II: IBS patients had lower self-rated health and more PHC utilization than the non-IBS patients. Good self-rated health was independently associated with younger age, higher sense of coherence and less gastrointestinal pain in both groups. In IBS, PHC utilization was associated with comorbidities in general, and sleep disorders in particular.Study III: Fatigue impact on daily life, and TNF- α were higher in IBS patients than in HC. In IBS, further an association was seen between fatigue impact on the one hand, and TNF- α, emotional abuse in childhood, as well as altered mesocorticolimbic connectivity on the other.Conclusion In conclusion this thesis firstly emphasizes that IBS patients in many ways, including health outcomes, consists a vulnerable group of PHC patients. We add evidence for a possible suppression of the stress response system in a substantial portion of IBS patients.Further, comorbid sleep disorders seem to be particularly associated with excess PHC utilization in IBS and could possibly be a target for treatment interventions. Moreover, alongside treating gastrointestinal pain, efforts to improve the individuals’ sense of coherence could be one way to achieve better self-rated health in both IBS and non-IBS patients.Finally, we suggest that fatigue in IBS is associated with immune activation, central alterations and to some extend also previous childhood trauma.
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- Alshiekh, Shehab Abdulaziz
(författare)
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Immunogenetics of Type 1 diabetes and Celiac disease
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- AbstractThe primary purpose of understanding disease etiology is to explain how a specific phenotype is determined by genotype. In pursue of this aim, exploring the diversity in DNA sequence variants that affect biomedical traits, especially those related to the onset and progression of genetically determined human disease. The human leukocyte antigens (HLA) are highly polymorphic cell surface proteins encoded in the major histocompatibility complex (MHC) region on chromosome 6. The HLA molecules are integral regulators for susceptibility to several autoimmune and inflammatory diseases, including type 1 diabetes (T1D) and celiac disease (CD), which share high-risk HLA haplotypes. Through next-generation sequencing (NGS), an integrated genotyping system of HLA loci was developed to genotype alleles of the MHC region. The full depth of allele association was used to target the novel mechanisms of HLA-associated risk alleles in T1D and CD. The research presented in this thesis aimed to use high-resolution genotyping with NGS of HLA loci and study extended associations in patients with T1D and CD as well as in a group of patients affected by both diseases (T1D w/CD). The main findings of importance were: -• HLA-DRB3, DRB4, and DRB5 affect the risk of islet autoimmunity and progression to the clinical onset of T1D and should be considered when examining the role of HLA-DR genetic risk. • Two distinct CD risk DR3-DQA1*05:01-DQB*02:01 haplotypes distinguished by either HLA-DRB3*01:01:02 and DRB3*02:02:01 alleles in the DRB3*01:01:02- DQA1*05:01-DQB1*02:01 extended haplotype distinguished the risk of CD, indicating that different DRB1*03:01-DQB1*02:01 haplotypes confer different risks for CD among patients of Scandinavian background. • HLA-DRB4*01:03:01, DRB3*01:01:02, and DRB3*02:02:01 are associated with T1D and CD of which DRB4*01:03:01 confers the strongest risk allele for T1D w/CD.• HLA-A*68:01:02 was identified as an additional allele positively associated between T1D w/CD and T1D. In conclusion, by utilizing high-resolution sequencing technologies for extended genotyping of HLA class I and II genetic determinants, the full spectrum of alleles and haplotypes variation associated with T1D and CD were explored. This basic knowledge should prove helpful contribution in building comprehensive inventories of genotype-phenotype relationships and resolving some of the HLA roles in the heritability risk for either T1D or CD, as well as in genetic models for the risk of developing both diseases.
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| 8. |
- Al-Dury, Samer
(författare)
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Understanding the molecular mechanisms of bile acid receptor activation for the treatment of human liver disease
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Farnesoid X receptor (FXR) is a nuclear transcription factor that is activated by bile acids and regulates bile acid homeostasis, glucose and lipid metabolism. FXR activation by a ligand has been identified as a therapeutic modality for a range of liver and metabolic diseases. Although bile acids and FXR are known to be key players in the interplay between the liver, gastrointestinal tract, lipid and glucose metabolism, the interactions are complex and not well understood. To date, FXR activation studies to decipher the underlying molecular mechanisms of its action have almost exclusively been conducted in mouse models, which are of limited human relevance due to interspecies differences between mice and humans in bile acid composition, metabolism and FXR activation patterns. Looking at bile acid homeostasis from another angle; the apical sodium-dependent bile acid transporter (ASBT; also known as ileal bile acid transporter (IBAT)) is an important FXR target gene and it is pivotal for the physiological reabsorption of conjugated bile acids from the ileum back to the liver. IBAT inhibition results in an increased bile acid load in the colon and subsequently a lower bile acid pool. To date, IBAT inhibitors have been used in animal models for the treatment of non-alcoholic steatohepatitis (NASH), and in humans they have been sparsely tested in clinical trials for the treatment of chronic constipation and severe itch that is associated with cholestatic liver diseases, such as primary biliary cholangitis (PBC) and pediatric liver disease. Paper I presents a prospective open-label phase IIa pilot study with IBAT inhibitor A4250 to assess the safety and efficacy of this compound in alleviating itch in patients with PBC. In this study, 10 patients with PBC were treated with A4250 for four weeks. Despite some subjective improvements in pruritus severity, the study needed to be stopped prematurely because of abdominal side effects. Paper II examines how the FXR agonist obeticholic acid (OCA) may increase the risk of gallstone formation in susceptible patients. In this randomized, double-blinded placebo control trial Obeticholic Acid in Gallstone Surgery (OCAGS), 20 patients were randomised to either OCA 25 mg/day or a matching placebo for 3 weeks prior to undergoing a laparoscopic cholecystectomy. Bile acids, fibroblast growth factor 19 (FGF19) and lipids were measured both in serum and gallbladder bile before and after treatment. The index of cholesterol saturation and bile acid pool hydrophobicity were calculated and both were higher in the OCA treated group, implying a higher risk of cholelithiasis. Gene analysis suggested a biliary origin of FGF19. We concluded that treatment with OCA leads to a higher risk of gallstone formation. Paper III investigates how bile acids and FXR interactions modulate metabolic phenotypes in humans. In this double-blinded randomized control trial Obeticholic Acid in Bariatric Surgery & Gallstone Surgery OCABSGS, we explored the effects of FXR activation on bile acid turnover. We found by performing ChIP-Seq that the expression of FXR-DNA binding sites was not related to OCA-treatment; rather, it seems to be predetermined by the phenotype (obese vs non-obese). In contrast, RNA-Seq indicated induction of FXR target genes by OCA as compared to placebo. In conclusion, our experiments explore a novel treatment modality for pruritus patients with cholestatic liver disease. However, given the side effects, the clinical applicability of this compound is doubtful. Our studies also offer a unique insight into gallbladder pathophysiology and the mechanisms leading to the formation of gallstones in susceptible populations during treatment with FXR agonists. We have also shown that FXR transcriptional signalling in human DNA is altered in the obese phenotype, which may underlie aberrant metabolism and liver function in obesity.
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