<p>The purposes of the thesis were to study associations between size at birth, short adult stature and risks of subnormal intellectual performance, high blood pressure, and overweight among males, and to study associations between size at birth, short adult stature and risk of overweight and giving birth to small for gestational age (SGA) infants among females.</p><p>The effect of short adult stature on intellectual performance among males was analyzed in two population-based cohort studies. Data were obtained from the Swedish Birth Register which was individually linked to the Swedish Conscript Register. Being born SGA was associated with increased risks of subnormal intellectual performance in all four dimensions included in the test, and lack of catch-up growth leading to short adult stature further increased this risk. If anything, logical performance was found to be most affected.</p><p>To estimate the risk of high blood pressure in males born SGA we used the Birth Register linked to the Conscript Register. Being born SGA was associated with a slightly increased risk of high systolic blood pressure, and being born light and ending up with short adult stature further increased this risk.</p><p>Association between short adult stature and overweight was analyzed in both males and females born SGA, in two different studies. In the male cohort data from the Birth Register was linked to the Conscript Register. In females the Birth Register was used twice, when the females were born and when they gave birth to their first child. In both the male and female cohort, there was an increased risk of becoming overweight among those born SGA who also ended up with short adult stature.</p><p>Finally, an intergeneration study was performed using the Birth Register to analyze associations between being born short for gestational age and giving birth to short infants. Catch-up growth to normal adult stature among women born short-for-gestational age was associated with reduced risk of giving birth to a short-for-gestational age infant.</p><p>Conclusions. Among males born SGA, short adult stature is associated with increased risk of subnormal intellectual performance, high blood pressure and overweight compared to those with normal adult stature. Similarly, among females born SGA, there is an increased risk of becoming overweight in those with short adult stature, compared with those not short as adult. Females born short for gestational age, with short adult stature are at increased risk of giving birth to a short infant.</p>

The purposes of the thesis were to study associations between size at birth, short adult stature and risks of subnormal intellectual performance, high blood pressure, and overweight among males, and to study associations between size at birth, short adult stature and risk of overweight and giving birth to small for gestational age (SGA) infants among females. The effect of short adult stature on intellectual performance among males was analyzed in two population-based cohort studies. Data were obtained from the Swedish Birth Register which was individually linked to the Swedish Conscript Register. Being born SGA was associated with increased risks of subnormal intellectual performance in all four dimensions included in the test, and lack of catch-up growth leading to short adult stature further increased this risk. If anything, logical performance was found to be most affected. To estimate the risk of high blood pressure in males born SGA we used the Birth Register linked to the Conscript Register. Being born SGA was associated with a slightly increased risk of high systolic blood pressure, and being born light and ending up with short adult stature further increased this risk. Association between short adult stature and overweight was analyzed in both males and females born SGA, in two different studies. In the male cohort data from the Birth Register was linked to the Conscript Register. In females the Birth Register was used twice, when the females were born and when they gave birth to their first child. In both the male and female cohort, there was an increased risk of becoming overweight among those born SGA who also ended up with short adult stature. Finally, an intergeneration study was performed using the Birth Register to analyze associations between being born short for gestational age and giving birth to short infants. Catch-up growth to normal adult stature among women born short-for-gestational age was associated with reduced risk of giving birth to a short-for-gestational age infant. Conclusions. Among males born SGA, short adult stature is associated with increased risk of subnormal intellectual performance, high blood pressure and overweight compared to those with normal adult stature. Similarly, among females born SGA, there is an increased risk of becoming overweight in those with short adult stature, compared with those not short as adult. Females born short for gestational age, with short adult stature are at increased risk of giving birth to a short infant.

Background: Immune responses are often divided into T helper 1 (Th1), Th2 and Treg like immunity. Allergy is associated with Th2 like responses to allergens and possibly to reduced regulatory functions. Activation via the CD2 receptor increases the production of the Th1 associated cytokine IFN-g and enhances the responses of activated T cells to IL-12. This may be due to an up-regulation of the signal-transducing β2-chain of the IL-12 receptor. CD2 function may be impaired in allergic children. As IL-12 is a strong promoter of Th1 like responses, this may be one contributing factor to the Th2-skewed immune responses found in allergic children. IL-27 and its receptor component WSX-1 may also play a role in Th1 like responses. The transcription factors T-bet, GATA-3 and Foxp3 are associated with Th1, Th2 and Treg type of immune responses, respectively. Aim: To investigate possible mechanisms behind the reduced Th1 and/or Treg associated immunity in relation to allergy by studying the CD2 induced regulation of IL-12Rβ2, WSX-1, T-bet, GATA-3 and Foxp3, as well as the production of different cytokines in children and adults. The aim was also to study the development of these factors during the first two years of life in relation to development of allergy in children from a country with high (Sweden) and low (Estonia) prevalence of allergy. Material and methods: Four different study groups were included; 32 12-year-old children, 38 7-year-old children, 61 children followed from birth to two years of age and 20 adults. Peripheral blood mononuclear cells were cultured with PHA (which partly signals via CD2), IL-2 and IL-12 alone and in combination or with anti-CD2 alone or combined with anti-CD28 antibodies. mRNA expression of cytokine receptors and transcription factors was analysed with real-time PCR and production of Th1, Th2 and Treg associated cytokines with ELISA. Results: We found lower PHA-induced IL-12Rβ2 and IFN-γ production in 12-year-old children with positive skin prick tests (SPT), compared with SPT negative children. We also found lower IL-2 induced IL-12Rβ2 in children with allergic airway symptoms and high IgE levels compared to children without a history of allergy and low IgE levels. This was accompanied with lower IL-2 and IL-12 induced IFN-γ. The spontaneous mRNA expression of IL-12Rβ2, WSX-1, T-bet, GATA-3 and Foxp3 was similar at birth and at 24 months. PHA induced up-regulation of all markers at all ages except for GATA-3, which was up-regulated in allergic children only at 6 and 12 months. PHA-induced T-bet and WSX-1 increased from birth to 24 months in non-allergic children. At a specific age, similar levels of all markers were found in allergic and non-allergic children, except for higher spontaneous IL-12Rβ2 at 24 months and higher PHA-induced WSX-1 at birth in allergic children. All cytokines increased with age. No clear differences were found between Swedish and Estonian children. CD2 stimulation induced Foxp3 and IL-10, while CD2 together with CD28 stimulation induced both Th1 and Th2 related transcription factors and cytokines. The combination also hampered the CD2 induced expression of Foxp3. Conclusions: The CD2 pathway and the response to IL-2 may be impaired in allergic children as lower IL-12Rβ2 and IFN-g were found in allergic, compared to non-allergic children. This difference was not found in adults. CD2 may be involved in induction of regulatory T cell responses as stimulation via CD2 in the absence of other co-stimulatory molecules induced Foxp3 and IL-10. Different developmental patterns of Th1 and Th2 associated factors may influence the development of allergic diseases in childhood.

Background: Chemotherapy has side effects that may interfere with food intake. Children suffering from a malignant disease are subjected to treatment with chemotherapy. They may therefore become at risk of undernutrition during the period of treatment. This in turn may increase the risk of infections, delayed therapy and influence the outcome of treatment. Few studies have investigated how children undergoing chemotherapy for cancer perceive food and eating. Attempts to improve food intake and the nutritional status require an understand-ing of how eating patterns are altered during chemotherapy in children. Study design: Dietary information and anthropometric data were collected after the initiation of chemotherapy in 14 children, consecutively admitted to the Paediatric Haematology and Oncology Unit at Umeå University Hospital. This initial study resulted in the establishment of more flexible mealtime routines on the ward. A follow-up study was conducted with another group of 11 children. Interviews were performed with a third group of 21 consecutively ad-mitted children, their parents and attending nurses. The focus was on the children’s own per-ception of and their parents’ and nurses’ attitudes to their food intake during hospitalisation. Recognition thresholds for the basic tastes were determined with 10 of the oldest of these children and 10 healthy controls. Results: Before introduction of new mealtime routines, the average daily oral energy intake during hospitalisation was 58% of the Swedish Nutrition Recommendations, SNR. The chil-dren had a significant weight loss up to three months after onset of chemotherapy. After the introduction of new mealtime routines, the average daily oral intake on hospital days was 61% of SNR and thus still lower than recommended despite efforts to serve palatable food on the ward. When enteral and parenteral nutrition was included, the energy intake came close to that recommended for healthy children, 91% of SNR. Both children and parents perceived that altered taste was an important cause of the children’s eating problems. The children also viewed food aversions, nausea and vomiting and pain as important causes, while the parents perceived nausea, food aversions and altered smell as significant factors. The nurses on the other hand, viewed nausea, the ward environment, and food rejection as a way of gaining some influence over the situation as important factors. The patients had significantly higher thresholds for bitter taste and significantly more patients made mistakes in taste recognition compared with controls. Conclusion and clinical implication: There seem to be changes both in the sense of taste as well as in the perception of food in children undergoing chemotherapy for malignant disease. Thus, single solutions such as providing a variety of “tasty food” in the hospital setting in order to improve food intake does not suffice for many paediatric cancer patients. The indi-vidual’s food preferences and aversions should be considered and combinations of oral, en-teral and parenteral nutrition support should be provided.

There is an increasing need for a local comprehensive cancer treatment centre that caters primarily to children. This design proposes a paediatric facility that will be located in Waterloo Region to meet the needs of the area’s rapidly increasing population. It will serve children under the age of eighteen, their families, and the surrounding community. The proposed site will be in Floradale, a small rural community in Waterloo Region, approximately 15 km from Kitchener/Waterloo. This site is located directly adjacent to the Woolwich Reservoir and was chosen because of its close proximity to this natural environment. Although it is located in a rural area, the proposed facility is still close to the urban core and the two existing general hospitals in the region. Based on the rapid population growth of the region, the city boundaries are quickly expanding outwards, closing the gap between Floradale and Kitchener/Waterloo. The thesis offers a series of design principles that have been applied to the proposed facility. The design principals were established by completing a historical review, researching a variety of architectural precedent studies, and through various site visits to healthcare facilities. In order for the proposed paediatric facility to be a successful, functioning component of the community, it will recognize and incorporate the existing services present in Floradale and Waterloo Region and build upon them. The design explores the existing community groups, organizations, services, and community needs in order to propose a holistic approach connecting services to the healthcare facility, which will in turn enhance community vitality. The purpose of a healthcare facility is to access, treat, and heal the patients and families that visit. This design creates a facility where the natural and the built environment will aid in the healing process.

There is an increasing need for a local comprehensive cancer treatment centre that caters primarily to children. This design proposes a paediatric facility that will be located in Waterloo Region to meet the needs of the area’s rapidly increasing population. It will serve children under the age of eighteen, their families, and the surrounding community. The proposed site will be in Floradale, a small rural community in Waterloo Region, approximately 15 km from Kitchener/Waterloo. This site is located directly adjacent to the Woolwich Reservoir and was chosen because of its close proximity to this natural environment. Although it is located in a rural area, the proposed facility is still close to the urban core and the two existing general hospitals in the region. Based on the rapid population growth of the region, the city boundaries are quickly expanding outwards, closing the gap between Floradale and Kitchener/Waterloo. The thesis offers a series of design principles that have been applied to the proposed facility. The design principals were established by completing a historical review, researching a variety of architectural precedent studies, and through various site visits to healthcare facilities. In order for the proposed paediatric facility to be a successful, functioning component of the community, it will recognize and incorporate the existing services present in Floradale and Waterloo Region and build upon them. The design explores the existing community groups, organizations, services, and community needs in order to propose a holistic approach connecting services to the healthcare facility, which will in turn enhance community vitality. The purpose of a healthcare facility is to access, treat, and heal the patients and families that visit. This design creates a facility where the natural and the built environment will aid in the healing process.

This thesis presents four studies, all designed to improve the problematic diagnostic situation concerning infants with suspected sepsis. Study I included 401 neonates with suspected sepsis. Nine signs of sepsis and C-reactive protein were prospectively recorded and logistic regression was used to assess associations between these signs and a subsequently confirmed diagnosis of sepsis. C-reactive protein and five of the clinical signs were statistically significantly associated with a positive bloodculture. When the material was stratified by gestational age, differences between premature and full term infants were detected.Studies II and III were prospective studies that used samples collected from neonates with suspected sepsis to evaluate a novel real-timepolymerase chain reaction (PCR) method. The results where compared with simultaneously collected blood cultures. Study II used plasma samples and resulted in a sensitivity of 42% and specificity of 95%. In study III, the protocol was improved and adapted to whole blood samples which resulted in a sensitivity of 79% and specificity of 90%. Both protocols included species-specific probes and study III indicated that PCR has the potential to detect bacteria in culture-negative sepsis.Staphylococcus epidermidis is the most common pathogen in neonatal sepsis, but there is still a lack of typing methods suitable for large materials of S. epidermidis. In Study IV we therefore evaluated a new S. epidermidisgenotyping method based on PCR for the repeat regions of four genes thatencode for cell wall anchoring proteins. The method was applied to 49well-defined neonatal blood isolates of S. epidermidis. The combination ofsdrF and aap seemed to be optimal, resulting in a diversity index of 0.92.Conclusions • Bradycardia, apnoea, low blood pressure, feeding intolerance and distended abdomen are obvious early signs of neonatal sepsis. Premature and full-term infants differ in terms of the signs they display in neonatal sepsis. • Blood is superior to plasma for developing PCR methods for bacterial DNA detection. The PCR method described in study III can detect neonatal bacteraemia, but it can be further improved before it is used in routine care. • There has been a lack of useful typing methods for S. epidermidis.We can now present PCR of the genes for the cell wall anchoring proteins sdrF and aap as a novel and feasible approach when there is a need to type a large number of S. epidermidis isolates.

Improved success of paediatric cardiac transplantation has resulted in increased survival of recipients into young adulthood (19 to 29 years of age). Young adults who received a heart transplant during childhood have experienced multiple life sustaining procedures. As survival and longevity increase, it is clear that transplant recipients experience negative physiological, psychological and social sequelae. With heart transplant offering individuals a chance to extend life into young adulthood, recipients need lifelong care and at age 18 they will transition from paediatric to adult healthcare facilities. The study addressed young adults circumstances of existence and their competing interests within various social environments. This research project applied Pierre Bourdieu’s theoretical concepts of habitus, field and capital, to conceptualize and engage with empirical knowledge production about young adults who have received a heart transplant during childhood. Using visual methodology, focused open-ended interviews were conducted with 12 young adults who had a heart transplant during childhood. Bourdieu’s work provided a theoretical framework to investigate transplant recipients’ identities and social repositioning in relation to dominant discourses of organ transplant and shifting relationships with health services providers. This study involved an iterative process to identify recipients’ encounters and new compositions in relation with others, in order to answer the research objective. These findings highlight that young adult transplant recipients struggle with relational dispositions that excludes them from various fields of social engagement; their struggle and exclusion from various fields is symbolic and is embedded in the structure of the dominant social order of the field from where they become excluded; the social order is taken up and embodied, leading young transplant recipients to practices of accommodation and “normalization”. Changes in healthcare practices, attuned to person implications and peer relationships can begin to address young transplant recipients’ contradictory social positions. Such an approach can potentially lead to improvement in ongoing care and services for young adults who require a lifetime of care. At the same time, it will allow nurses to better prepare and counsel young individuals who are preparing for a heart transplant.

Improved success of paediatric cardiac transplantation has resulted in increased survival of recipients into young adulthood (19 to 29 years of age). Young adults who received a heart transplant during childhood have experienced multiple life sustaining procedures. As survival and longevity increase, it is clear that transplant recipients experience negative physiological, psychological and social sequelae. With heart transplant offering individuals a chance to extend life into young adulthood, recipients need lifelong care and at age 18 they will transition from paediatric to adult healthcare facilities. The study addressed young adults circumstances of existence and their competing interests within various social environments. This research project applied Pierre Bourdieu’s theoretical concepts of habitus, field and capital, to conceptualize and engage with empirical knowledge production about young adults who have received a heart transplant during childhood. Using visual methodology, focused open-ended interviews were conducted with 12 young adults who had a heart transplant during childhood. Bourdieu’s work provided a theoretical framework to investigate transplant recipients’ identities and social repositioning in relation to dominant discourses of organ transplant and shifting relationships with health services providers. This study involved an iterative process to identify recipients’ encounters and new compositions in relation with others, in order to answer the research objective. These findings highlight that young adult transplant recipients struggle with relational dispositions that excludes them from various fields of social engagement; their struggle and exclusion from various fields is symbolic and is embedded in the structure of the dominant social order of the field from where they become excluded; the social order is taken up and embodied, leading young transplant recipients to practices of accommodation and “normalization”. Changes in healthcare practices, attuned to person implications and peer relationships can begin to address young transplant recipients’ contradictory social positions. Such an approach can potentially lead to improvement in ongoing care and services for young adults who require a lifetime of care. At the same time, it will allow nurses to better prepare and counsel young individuals who are preparing for a heart transplant.

This thesis explores aspects pertinent to the phenotypic classification of paediatric patients with inflammatory bowel disease (IBD). In the current era it has never been more important to have rigourous phenotypic classification to facilitate genotype-phenotype correlation studies as well as to optimize design of clinical trials of emerging therapies, where frequently response may differ according to phenotype of disease. The first study examined the reliability of the Montreal Classification for classifying paediatric IBD patients. This is the first study exploring the reliability of phenotypic classification in a paediatric population. The reliability of assigning an overall diagnosis of type of IBD was good, but not excellent. Amongst Crohn’s disease patients, reliability of assigning disease behaviour was excellent, while the reliability of assigning disease location categories varied from fair to good. The percentage agreement when describing disease extent for ulcerative colitis was high. The second study described the evolution of disease phenotype in a cohort of paediatric IBD patients. Similar to observations in adult-onset IBD, disease location was found to be relatively stable, while Crohn’s disease behaviour evolves from an inflammatory to a stricturing and/or penetrating phenotype in 20% of patients by 5 years of follow-up. The final study explored the association between 2 polymorphisms in the NOD2 gene with the requirement for intestinal resection (a surrogate marker of complicated disease) in models that included and excluded disease duration. Although no difference was found, this may have been influenced by data quality, which was suboptimal. In conclusion, this thesis has demonstrated that imprecision exists in the phenotyping of paediatric IBD patients, in whom phenotypic characteristics evolve over time. It is pertinent that disease duration be considered in any study attempting to make phenotypic correlations.