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- Holmbom, Martin, 1984-
(författare)
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Clinical Impact of Bloodstream Infections – Characterization, Risk factors and Outcome
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bloodstream infection (blood poisoning) and antibiotic resistance are increasing worldwide, and already cause the loss of millions of human lives each year. According to the World Health Organisation (WHO), bloodstream infections (BSIs) represent 20% of global mortality on a par with cardiac infarct, stroke, and major trauma. BSI may occur when bacteria from a focus of infection gain access to the circulation (bacteraemia). BSIs are usually divided into two subclasses: community- and hospital-onset infections, since disease this involves different patient groups, types of bacteria, and reasons for infection. Compared to other countries, Sweden has been fortunate in having a relatively low death rate from BSI and low antibiotic resistance. However, as our lifestyle changes, the age of the population increases with more disease as a result, and as the healthcare system responds, death from infection and antibiotic resistance are on the increase. It is important that we recognise ”warning symptoms” if we are to manage BSIs correctly and initiate effective treatment. It is difficult to design individualised empirical treatment, so it is very important to be aware of risk factors for BSI and local resistance patterns, and to have an effective management programme. Bacterial resistance to antibiotics is an increasing problem, especially in bowel organisms that can cause infections that are very difficult to treat. In short, antibiotic resistance arises as a result of evolutionary processes where bacteria protect themselves by developing resistance genes. These genes can be exchanged between similar organisms or transmitted to others that in turn cause resistant infection. The use of antibiotics leads to an evolutionary/selection process leading to resistance in bacteria, both normal and pathogenic, enabling resistant organisms to survive, thrive, and go on to cause infection. Antibiotic resistance is a threat to global health. This thesis aims to increase our awareness of a large group of patients who suffer bloodstream infection. BSIs are increasing globally, and the death toll is high. Antibiotic resistance is an increasing threat to the health of the population, and we are inundated by alarming reports of resistance getting out of control. What is the situation in Sweden, and can we identify risk factors for BSI and mortality? In Study I, our aim was to study the incidence and mortality of BSI in Östergötland. To be able to do this, a large patient population stretching over several years was required. The study design was thus population-based in the form of an observational cohort study where all blood culture results from 2000 to 2013 were analysed, and evaluated from clinical data. A total of 109,938 results were analysed resulting in 11,480 BSIs. We saw that the incidence of BSI increased by 64% (mostly community-onset BSIs). We also saw that mortality increased by 45%. These results illustrate the importance of nationwide cooperation to combat the increasing problem of BSI and its mortality, and the establishment of a nationwide BSI register. The aim of Study II was to assess resistance development in Östergötland and its relationship to mortality. A total of 9,587 microorganisms were analysed between 2008 and 2016. We observed an increase in quinolone resistance (3.7-7.7%) and cephalosporin resistance (2.5-5.2%) amongst Enterobacteriaceae. We then looked at BSIs caused by multiresistant bacteria showing a total of 245 cases (2.6%); an increase of 300%. Despite this, we did not see an increased mortality in this group. There are several possible explanations for the increase in BSI mortality of which antibiotic resistance is a predominant factor globally. We were unable to show this in our study, even so mortality is increasing and is currently at a high level. In Study III we therefore analysed risk factors associated with death during a community-acquired BSI, focusing on preliminary prehospital and hospital management. In a retrospective case-control study on 195 deaths matched 1:1 regarding age, gender, and microorganism, with 195 survivors (controls). Results showed that many patients had contacted the primary healthcare system because of infection before they became severely ill, and that the strongest affectable risk factor for death was delay (>24h) between primary healthcare visit and admission to hospital. This shows the need for increased awareness in society and amongst the medical profession of those patients at risk and symptoms that should raise the alarm, leading to more rapid treatment. In Studies I and II we found an increase in both BSIs and mortality, we also saw an increase in antibiotic resistance and multiresistant bacteria, mainly ESBL-producing E. coli. On the other hand, we did not see any coupling between multiresistance and mortality in this Swedish population. E. coli is a gram-negative bacteria that causes most BSIs. Since E. coli is predominantly a urine tract pathogen, Study IV aimed to study BSIs caused by ESBL-producing E. coli originating from the urinary tract. We studied the prevalence of E. coli clones, resistance genes and risk factors, as well as any signs of increased mortality from ESBL-producing E. coli compared to sensitive E. coli. Our main finding was a surprisingly low mortality from ESBL-producing E. coli (3%). Most patients in the ESBL-producing E. coli group received inadequate antibiotic treatment for at least 48h, but we did not see any sign of increased mortality or risk for serious sepsis with circulatory failure in this group. This finding is interesting and opens up for new studies on virulence factors and immunological factors that govern the immune response to BSI. The implementation of cost-effective monitoring systems including clinical microbiological epidemiology and early identification of BSI, together with information campaigns aimed at the public as well as healthcare personnel regarding patients at risk and symptoms giving cause for alarm, should lead to a radical reduction in morbidity and mortality from BSI. This requires new diagnostic tools to individualise both antibiotic treatment and targeted management based on microorganism virulence factors. Modernisation of the medical journal system with algorithms aimed at early identification of risk patients and automated suggestions for empirical antibiotic treatment based on antibiotic resistance seen in previous cultures and local resistance patterns, would certainly improve management. Furthermore, new immunological tests showing the type of immunological reaction to a serious BSI will lead to individualised immunotherapy that, together with antibiotic treatment, will further improve patient care in this important group.
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| 2. |
- Sundell, Micaela, 1989-
(författare)
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Epidemiological and Clinical Aspects of Hormonal Contraception and Menopausal Hormone Therapy in Women
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The main indications for therapy with female sex hormones are contraception and menopausal hormone therapy (MHT). The aim of this thesis was to investigate the use of hormonal contraception and MHT in different populations of women in Sweden, 2000–2021. The use of contraception in women with obesity was studied. The use of MHT in Sweden over time was studied and different run-in periods were validated to define an incident MHT user. We also investigated the risk of pulmonary embolism (PE) in women using MHT, including considerations regarding administration form, treatment duration and type of progestin used. Women with premature or early menopause after bilateral oophorectomy were studied with regard to dispensed MHT.Material and Methods: The studies were based on different data sources including electronical medical records, national mandatory health registers, and a national quality register (GynOp). The use of MHT over time was studied using defined daily doses (DDD) per 1,000 women per day, one-year prevalence and incidence proportion. The definition of an incident drug user was validated by calculating the predictive value of different run-in periods.Results: The most prescribed contraceptive method in women with obesity was progestin-only pills (44%), but 21% were prescribed combined hormonal contraceptives contrary to Swedish and European guidelines. Incident users with obesity were significantly more likely to discontinue their contraceptive method within one year, compared with normal weight women. The use of MHT decreased significantly after the turn of the century. In the 50–54 years age interval, the dispensed amount decreased from 282 DDD/1,000 women per day in 2000, to 77 in 2006. It then stabilised around 50 DDD/1,000 women per day during 2010 to 2017. The one-year prevalence followed the same pattern, with a plateau 2010–2016. From 2017, an increase in MHT dispensations was observed. A run-in period of 18 months had a PV of 88% in the 50 to 54 years age group and was found to be suitable and reliable for defining incident users of MHT at the ages close to menopause. The risk of PE was significantly increased in users of oral MHT, but not transdermal. The risk was highest in first-ever users (OR 2.32; 95% CI, 1.34–4.00) and was considerably lower in women who may have used MHT previously (OR 1.38; 95% CI, 1.01–1.89). 69% of all women with a bilateral oophorectomy had at least one dispensation of MHT within one year after surgery. Within this treated group the estimated treatment time constituted 63% of the remaining time to natural menopause.Conclusions: Progestin-only pills was the most prescribed contraceptive method in women with obesity, but many women with obesity were prescribed combined hormonal contraceptives contrary to clinical guidelines. The use of MHT decreased significantly after the turn of the century, but has increased since 2017 in the age groups close to menopause. The classifications used for prevalent and incident drug use are of importance to the results. The risk of pulmonary embolism is increased in users of oral but not transdermal MHT. There seems to be a significant undertreatment with hormone therapy in women with premature, surgical menopause.
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| 3. |
- Parenmark, Fredric, 1974-
(författare)
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Premature Discharge from Intensive Care with Special Reference to Night-Time Discharge and Capacity Transfers
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Objectives Intensive care is an expensive and limited resource, and when a demand supply mismatch between available beds and influx of patients occurs, one temporary measure is to discharge a patient to make room for the new admission. Sometimes the patient is discharged sooner from its original ICU than ideal; i.e., a so-called ‘premature discharge’. This could be either to a different ward within the same hospital if the patient is deemed well enough to cope with a lower level of care, or to another intensive care unit if critical care is still to be provided. Data from the Swedish intensive care register (SIR) showed that there was a high incidence and increased mortality of patients discharged at night. There were also differences in mortalities between patients that were transferred from one ICU to another. I have analysed the mortality associated with different types of ICU-to-ICU transfers and control groups and examined a national quality improvement project regarding discharges at night to see if mortality, incidence, or discharge culture could change. Methods All three studies are conducted with data from the Swedish intensive care register and vital status was ascertained by linking SIR to the Swedish population register. Study I consisted of two parts: mortality, and incidence of night-time discharge. The quality improvement project in Study I was analysed in a before and after approach with local improvement projects at different ICUs. In Studies II and III, transfers were grouped by the attending intensivist according to SIR guidelines into one of three defined categories: capacity transfer, clinical transfer, or repatriation. The groups were compared to each other in Study II, and capacity transfers were matched to a control group that remained in the ICU in Study III. Multilevel logistic regression was used, and all studies contained some statistics using individual ICUs as a random factor. Life sustaining treatment limitations were included in Studies II and III. Results In Study I, there was a decrease in night-time discharges during the study period. The incidence fell from 7.0% in 2006 to 4.9% in 2015. Alongside this, the mortality associated with night-time discharge was reduced, the odds ratio fell from 1.20 to 1.06 with a loss of significance. All this coincided in time with the national improvement project. Study II showed that 14.8% of all discharges from a Swedish ICU ended with transfer to another ICU, and that an increased mortality rate was associated with ICU-to-ICU transfers during periods of demand–supply mismatch. Capacity transfers were 15.8% of all transfers accounting for roughly 2.0% of ICU survivors. One in four capacity transferred patient died within 30 days of discharge, compared to one in seven for transfers due to clinical reasons. The third study showed that capacity transfer was associated with an average risk increase in 30-day mortality of 4.7%, and a 180-day mortality of 4.9% compared to non-transferred patients when analysed using a potential outcomes framework. Conclusion The studies concludes that patients experiencing a capacity transfer are exposed to increased mortality risk, both when compared to other types of inter hospital ICU-to-ICU transfers as well as when compared to patients that were not transferred. The increased risk appeared to be unrelated to patient characteristics and illness severity as well as many additional factors measured in the referring ICU. The studies also suggest that a suboptimal outcome after premature discharge at night can be changed and that a national project to adjust outcome and incidence can be undertaken with positive results.
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| 4. |
- Helmfrid, Ingela, 1964-
(författare)
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Exposure and body burden of environmental pollution and risk of cancer in a historically contaminated areas
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There are many villages where environmental contamination is substantial due to historical industrial activities. According to the European Environment Agency, there are about 2.5 million potentially contaminated sites in the European member states. In Sweden, there are about 80 000 more or less contaminated areas. About 1000 of them are classified into the highest risk category, Hazard Class 1, and should be remediated. Population exposure due to these industrially contaminated sites may contribute to adverse health effects and is a global environmental problem.The general aim of this thesis was to evaluate the occurrence of cancer in populations residing in contaminated areas in relation to indirect exposure via the long-term consumption of locally produced food, taking into account residential, occupational and lifestyle factors. Associations between reported local food consumption frequencies, biomarker concentrations and environmental and lifestyle factors were explored. The Swedish national cancer registers and questionnaire information was used to identify cancer risk groups in the study population. The questionnaire was evaluated regarding how well it reflected measured levels of biomarkers in human biological samples, and how the consumption of local food from contaminated areas contributed to the total body burden of contaminants.Despite historically high environmental levels of contaminants in the soil and sediments, current contaminant exposure in the studied population living in the contaminated areas was similar to or only moderately higher than that of the general population.No significant associations with increased cancer risk were detected in the highest tertile of metals concentrations in blood or PAH in urine.Reported long-term high consumption of certain local foods was associated with higher cadmium (vegetarian food) and lead (fish, meat) concentrations in blood and urine. Long-term high consumption of non-local food from places outside the study areas was not associated with increased concentrations of metals compared with consumers of local food. It was concluded that the questionnaire information on consumption of locally produced food describes differences in food consumption in the study population reasonably well.An increased risk of cancer was associated with smoking, family history of cancer and obesity. Residing in a contaminated area during the first five years of life was associated with an increased risk of cancer, which may indicate exposure to contaminants in early life. Also, long-term high consumption of particular local foods (fish, chicken, lamb, game meat) was associated with an increased risk of various forms of cancer, while reported high consumption of these foods from non-local sources was not associated with increased risk of cancer. The associations between habitual consumption of local food and different types of cancer may reflect a higher exposure in the past, and thus, if consumption of local food contributes to the risk of acquiring cancer, that contribution is probably lower today than previously. Furthermore, it cannot be ruled out that other contaminants in the food contribute to the increased cancer risks observed.In conclusion, the questionnaire that was developed for the present thesis can identify risk groups within populations and can be used as a tool in a health-risk assessment.
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