| 1. |
- 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. |
- Kampmann, Christian, 1975-
(författare)
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Go with your gut : The human intestinal microbiota, international travel, Campylobacter and ESBL-producing Enterobacteriaceae
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Up to 100 million people travel annually from industrialized countries to resource-limited ones. Each traveller contains an internal ecosystem composed of tens of trillions of microbes, known as the intestinal microbiota, which has a large effect on health. The microbiota seems to be highly individual and mostly stable but can be significantly affected by several factors. Many international travellers are at high risk of getting infected by Campylobacter, the most common cause of bacterial enteritis worldwide. Campylobacter infection can cause a wide range of symptoms, with varying severity, for reasons largely unknown. Travel also radically increases the risk of colonization by antibiotic-resistant intestinal bacteria, notably Extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (EPE). To date, there are no therapies available for EPE-decolonization. In this thesis, it was investigated whether the bacterial intestinal microbiota affected susceptibility to Campylobacter and if international travel as such had an impact on the microbiota. In a prospective, observational study, 67 healthy Swedes, travelling in groups to countries with a high risk of Campylobacter infection, were followed. The travellers answered questionnaires and delivered two faecal samples before and three samples after the trip. These samples were cultured for enteropathogens and analysed for the microbiota composition. Low diversity of microbiota seemed to increase the risk of Campylobacter jejuni infection, whereas a high relative abundance of Lachnospiraceae might decrease the risk (Paper I). Furthermore, the overall bacterial diversity did not seem to change in connection with travelling. However, the bacterial family Enterobacteriaceae (otherwise connected with inflammation, infection and antibiotic-resistance) was shown to be dramatically increased in abundance immediately after travel, and the family Christensenellaceae (otherwise connected with beneficial health conditions) simultaneously decreased (Paper II). Eight travellers, from two different destinations, were infected with closely related C. jejuni isolates (ST353CC). The bacterial analysis of genomic and phenotypic characteristics revealed that the C. jejuni isolates of the travellers returning from one of the destinations and with more severe symptoms actually showed less pathogenic potential, compared to the isolates of travellers from the other destination and with milder symptoms. However, the travellers with more severe symptoms had much higher relative abundances of Bacteroidetes in their intestinal microbiota and, in contrast to the other travellers, excluded meat from their diet. (Paper III) Finally, we investigated in a randomized, placebo-controlled clinical trial of 80 established intestinal carriers of EPE, whether the oral probiotic product Vivomixx® could eradicate EPE. Vivomixx® was not superior to placebo (Paper IV).
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| 3. |
- 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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| 4. |
- Arroyo Vázquez, Jorge Alberto, 1979
(författare)
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Stent treatment of perforated duodenal ulcer - physiology and clinical aspects
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background The incidence of perforated duodenal ulcer is decreasing but still constitutes a life-threatening complication to peptic ulcer disease. Abdominal contamination from gastric or duodenal content occurs during perforations. Gastric content is normally sterile due to its low pH, but the wide-spread use of PPI might affect gastric bacterial flora. Gold standard treatment is sutured surgical closure, open or laparoscopic. Treatment with a covered stent has proven useful in cases of esophageal perforations. The same treatment strategy might be an option in selected cases with duodenal perforation. Stents placed over the pylorus might influence pyloric motility leading to stent migration. The aim of this thesis was to investigate the use of a covered stent to treat perforated duodenal ulcers including aspects on pyloric physiology and gastric bacterial colonization. Methods Paper I & II: Gastric and duodenal bacterial colonization was investigated taking swab samples from the mucosa for culturing during, clinical outpatient gastroscopies. PPI consumption was recorded. In paper II gastric pH was measured from gastric aspirate and bacterial growth was quantified. Paper III: Pyloric physiology was studied in an animal model using the EndoFLIP™ probe, mimicking a stent placed in the pylorus. Pyloric cross sectional area and pressure was recorded. Paper IV: Randomized clinical trial, patients presenting with signs of upper gastrointestinal perforation and free air on a CT scan were included and randomized to surgical closure or stent treatment. Laparoscopy was performed in all patients to verify the diagnosis. Results Paper I: 103 patients were analyzed. Gastric and duodenal bacterial colonization was more common in patients on continuous PPI treatment (p<0,0001). Dominating bacterial species were of oropharyngeal origin, most common were Streptococcus salivarius & mitis. Paper II: 107 patients were analyzed. Abundant bacterial growth (>104 CFU/ml) occurred in 16% in the stomach and 12% in the duodenum, significantly more in patients with PPI treatment (p<0,0001). Patients with abundant growth showed high gastric pH and old age. Paper III: When pylorus is stepwise dilated, it changes activity from acting as an opening and closing sphincter to a propulsion pump. At full distention, pyloric motility disappears. Pyloric opening and emptying is stimulated by food. Paper IV: 43 patients were included, 28 had a verified perforated duodenal ulcer, 15 randomized to surgical closure and 13 to stent treatment. Morbidity was 42% overall, 6 patients in each group had a complication of Clavien-Dindo grade 2-4 (n.s.). Mortality was 4% (n=1). For all patients, time from onset to intervention >12h correlated with complications Clavien-Dindo grade 3-5. Conclusion Bacterial flora found in the stomach and/or duodenum is mainly of oropharyngeal origin, more frequently occurring in patients with ongoing PPI treatment. Individuals with high gastric pH are more at risk for abundant gastric and/or duodenal bacterial colonization. Stent design influences pyloric motility, through pyloric distention, and seems to be of importance to avoid stent related complications. Stent treatment of perforated duodenal ulcer seems to be as safe and effective as surgical closure.
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| 5. |
- Linge, Jennifer, 1990-
(författare)
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Adverse Muscle Composition : Revisiting Sarcopenia in General Population and Liver Disease using Magnetic Resonance Imaging
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sarcopenia - from the Greek words 'sarx' (flesh) and 'penia' (loss) - was, when coined in 1989, a term denoting the decline in muscle mass and strength that occurs with aging. Such definition implies everyone suffers from sarcopenia to varying degrees, which naturally makes studying sarcopenia challenging. Early (practical) definitions of sarcopenia focused on identification of low muscle mass, while later definitions also include criteria of low muscle strength. Use of such definitions to study sarcopenia has shown that wasting is intensified in those suffering from metabolic diseases, and even more rapid in end-stage diseases. Although it is unknown whether sarcopenia accelerate disease or the other way around, detection of sarcopenia concurrent with other diseases clearly identifies a vulnerable subgroup of patients who may need more extensive care.In severe stages of liver disease, poor muscle health has been linked to higher morbidity and mortality, and may affect the outcome of liver transplantation. Sarcopenia is therefore recognized as an important factor that should affect both clinical decision-making and intervention in patients being evaluated for liver transplantation. However, sarcopenia is poorly understood (and commonly overlooked) in earlier stages of disease, where the potential of preventative care is greater. One challenge has been the prevalence of obesity in diseases that may precede more advanced disease, such as non-alcoholic fatty liver disease (NAFLD). Due to their larger body size, individuals with obesity need more muscle mass to maintain mobility function. Therefore, the threshold for what is considered ‘low muscle mass’ needs to be higher, or somehow adjusted for body size.This thesis started by applying the European definition of sarcopenia in 10,000 individuals aged 44-78 years volunteering for the UK Biobank imaging study. It was identified that current body size adjustments used to detect 'low muscle mass' were ineffective. The consequence of this was underdiagnosis of sarcopenia in individuals with overweight and obesity.Therefore, a more personalized muscle volume assessment, that was independent of body size, was developed with the aim to describe how much an individual is deviating from what is expected and address whether they have an 'adequate' amount of muscle volume - muscle volume z-score.Muscle volume was measured using magnetic resonance imaging and from the same images, muscle fat infiltration (indicating muscle quality) was also quantified. The first results indicated that muscle volume z-score and muscle fat infiltration were independently associated with mobility function and hospitalization, and that a combination of the two may identify the most vulnerable individuals. Therefore, thresholds were suggested to identify an adverse muscle composition (low muscle volume z-score combined with high muscle fat infiltration).Following studies investigated associations of adverse muscle composition with metabolic diseases, mobility function, and mortality in general population and NAFLD. Overall, the studies showed that adverse muscle composition was associated with increased morbidity and mortality independent of mobility function, and indicated that muscle composition assessment could provide clinically relevant information that may be useful in risk-stratification of heterogeneous disease populations like NAFLD.Today, the relevance of adverse muscle composition and potential clinical use cases are evaluated in the liver transplant setting through both European and American clinical studies.
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| 6. |
- 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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| 7. |
- 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. |
- Marques, Filipe
(författare)
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Overcoming the Barriers of Fine-Needle Aspiration
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cysts, closed sac-like structures filled with fluid or air, can form anywhere in the body. In the majority of cases, cysts are benign (not cancerous). However, these structures can also be precursors of cancer, pointing to the location where cancer can originate. This makes cysts a prime location for examination, especially when they occur in the pancreas. Pancreatic cancer has the lowest survival rate after five years in 2023 (12%) due to the late diagnosis, limiting treatment options. Fine-Needle Aspiration (FNA) is a diagnostic technique used to aspirate the liquid content of cysts. The liquid may possess cells used to determine cyst malignancy, yet up to 66% of samples have little to no cells.Firstly, we introduce a new concept of brush: the loop brush. Unlike traditional brushes with a handle and a block of bristles, the loop brush consists of a handle and a loop-shaped wire. The loop of loop brushes can be compressed within the inner diameter of an FNA needle and autonomously expanded to the size of cysts. Loops can be made of nitinol or commercially available absorbable sutures such as Monocryl, PDS II, and Catgut. Loop brushes increase the cell yield of modeled cysts by an order of magnitude and are, apparently, as safe as standard FNA (FNA without a loop brush). Such brushes could present a promising solution to the lack of cells in liquid samples of cysts, increasing treatment options and producing better, cost-effective care for patients.Secondly, we present a hand-sized microfluidic device to prepare rapid on-site evaluation(ROSE) of FNA samples. During ROSE, FNA samples are prepared by cytopathologists in the operating room for further inspection with a microscope. However, cytopathologists are often time-limited, preventing the dissemination of ROSE. Our device allows sample preparation with minimum chemical quantities and the potential to be implemented by all healthcare providers. This microfluidic device would allow the dissemination of ROSE, preventing the need for patients to return to the OR and accelerating diagnosis.
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| 9. |
- 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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| 10. |
- Blomdahl, Julia, 1991-
(författare)
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Non-Alcoholic Fatty Liver Disease : Insights into Alcohol Consumption, Genetics, and Proteomics
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- NAFLD (Non-Alcoholic Fatty Liver Disease) affects approximately a quarter of the global population and is closely linked to type 2 diabetes mellitus and obesity. The disease spectrum ranges from steatosis and steatohepatitis to fibrosis, cirrhosis, and hepatocellular cancer. However, accurately predicting which patients will experience a progressive disease course remains a significant challenge. The variant gene of PNPLA3 is known to be associated with NAFLD and a more progressive disease, although its precise function remains unclear. Patients with NAFLD typically consume small to moderate amounts of alcohol, with recommended thresholds set at a maximum of 210 gram per week for males and 140 grams per week in females. However, the impact of alcohol consumption on liver disease in NAFLD remains disputed, with conflicting research findings. Liver biopsy is considered the gold standard for diagnosing NAFLD. However, due to its impracticality for such a large population with the condition, various non-invasive methods have been explored for diagnosing and evaluating NAFLD. This thesis aimed to investigate the potential effects of moderate alcohol consumption on NAFLD histology, explore the potential role of variant PNPLA3 in NAFLD, and assess the use of proteomics in classifying fibrosis. In Papers I and II, moderate alcohol consumption was assessed through questionnaires, clinical interviews, and measurement of the direct alcohol biomarker phosphatidylethanol (PEth). Paper I, a cross-sectional study including 86 participants, showed an association between moderate consumption and advanced fibrosis. Moderate consumption was defined as consuming more than 66 grams of ethanol per week or a PEth-value over 50 ng/mL. Notably, individuals with both moderate alcohol consumption and a diagnosis of type 2 diabetes exhibited significantly more advanced fibrosis. Paper II was a cohort study where 82 participants were followed over 17.2 years. Similarly, participants with moderate alcohol consumption displayed significant fibrosis progression. The strongest association was observed in participants with PEth-value of 48 ng/mL or higher, or those with binge drinking. In Paper III, the potential role of variant PNPLA3 was explored, exhibiting impaired autophagic flux and reduced lipophagy in variant PNPLA3 cells. Liver biopsies of NAFLD individuals with variant PNPLA3 displayed an accumulation of lipid droplets positive for both PNPLA3 and LC3 (a common marker of the autophagosome). This suggests that PNPLA3 is part of the lipophagy process, which is impaired in the variant gene and contributes to steatosis. Paper IV examined two independent NAFLD cohorts. In the discovery cohort, 60 participants with biopsy-proven NAFLD were included, while 59 participants were included in the validation cohort. The study evaluated 266 proteins and found that a biomarker model combining ACE2, HGF, and IGFBP-7 distinguished between different fibrosis stages (F0–1 and F2–4) in both cohorts. In summary, measuring phosphatidylethanol is advisable in NAFLD patient evaluations. Elevated PEth-levels (≥48 ng/mL) or alcohol consumption exceeding 66 grams per week should warrant advice to abstain from alcohol. PNPLA3 is implicated in NAFLD pathophysiology, potentially through impaired lipophagy. While its clinical application remains uncertain, genetic profiling for NAFLD risk assessment may become part of future non-invasive approaches. Additionally, proteomics holds promise for non-invasive NAFLD assessment, with the combination of ACE2, HGF, and IGFBP-7 identifying significant fibrosis in two separate cohorts.
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