The development of palliative care in Indonesia has been slow due to the absence of palliative care guide lines and standards. This results in the limited provision of palliative care where it can only be found available in 14 hospitals in the whole country with a population over 260 million, and the palliative care is basically directed to adult patients. In the paediatric medicine field, the palliative care services in Indonesia is still in its infancy and currently palliative care is served by only one non-profit organization in Jakarta. With around 1,5 million people in Jakarta associated with living in poverty, this organization is focusing on providing free palliative care to children from marginalized communities. The questions that are raised out of these circumstances are how paediatric palliative care is practiced in Jakarta and what the rewarding and challenging parts of the job are. The aim of the study is to describe nurses' perspectives and experiences in giving home-based palliative care to children living with cancer and HIV from marginalized communities in Jakarta. A qualitative study design with content analysis was considered to be the method that fitted the goal of the study best. Semi structured interview was used as data collection method and there were seven nurses who participated in the interviews. The result is described by two main categories; the first category contains different topics that functioned as encouragements to the nurses, and the second category consists of various subjects that contribute to challenges that nurses encounter in their work. Lack of palliative education that lead to certain attitudes in the referral process, misperceptions about pain management and nurses’ stress management are discussed as some challenges encountered in the implementation of palliative care.

Numerical modelling and simulation are powerful tools for analysis and design, and with the improvement of computational power and numerical methods they are being applied on complex phenomena and systems. This work shows examples of the application of a very sophisticated numerical method, namely the Spectral/hp element method, in the study of the flow inside bioinspired complex geometries. The two topics investigated are fluid dynamic instabilities in a constricted channel and flow inside a paediatric ventricular assist device were studied by means of computational fluid mechanics. The constricted channel is an idealized model of a nasal cavity, which is characterized by complex airway channels, and also bears some resemblance to a human artery in the presence of an atherosclerotic plaques. The paediatric ventricular assist device is an actual device, designed by the Bioengineering research group of the Heart Institute of the Medicine School of the University of São Paulo, which works as a pump that assists the left ventricle of patients waiting for transplantation. Therefore, the aim of this thesis is to contribute in the understanding of biological and bio-inspired geometries flows, using computational tools. Linear and nonlinear stability were carried out for the constricted channel. Three different flow regimes were investigated: symmetric steady flow, which is stable for low Reynolds number, asymmetric steady flow, which rises as a result of the primary bifurcation of the symmetric flow and pulsatile flow. Direct stability analysis was carried out to determine the unstable regions and the critical values for each flow regime. The physical mechanisms behind the transition processes were studied by means of direct numerical simulations to characterize the bifurcations. Since the bifurcations had subcritical behaviour, the relevance of non-normal growth in these flows was assessed. Dependence on phase, Reynolds number and spanwise wavenumber of optimal modes were extensively investigated in stable regions of the three flow regimes. Convective instabilities were also studied in order to comprehend the physical mechanisms which led the optimal modes to their maxima growth, and different convective mechanisms were found. The flow inside the paediatric ventricular assist device was analyzed by means of threedimensional numerical simulations. A computational model based on special boundaries conditions was developed to model the pulsatile flow. In this model, the opening and closure of the mitral valve and diaphragm were represented with the use of specially devised boundary conditions. The driving force and the flow direction of the diaphragm were defined by velocity distribution on the diaphragm wall, and the opening and closure of the mitral valve were performed by a velocity waveform which goes to zero in the systolic period. Flow patterns, velocity fields and time-average wall shear rate were analyzed to evaluate the performance of the device. / Modelagem e simulação numéricas são ferramentas poderosas para análise e design, e com a melhoria do poder computacional e dos métodos numéricos, eles estão sendo aplicados em fenômenos e sistemas complexos. Este trabalho mostra exemplos de aplicações de um método numérico sofisticado, o método dos elementos espectrais/hp, no estudo do escoamento dentro de geometrias complexas bio-inspiradas. Os dois tópicos investigados são: instabilidades em dinâmica de fluido em um canal constrito e o escoamento dentro de um dispositivo de assistência ventricular pediátrica. O canal constrito é um modelo idealizado de uma cavidade nasal, que é caracterizada por canais complexos da via aérea, e também tem semelhança com uma artéria humana na presença de placas ateroscleróticas. O dispositivo de assistência ventricular pediátrica é um dispositivo real, projetado pelo grupo de pesquisa de Bioengenharia do Instituto do Coração da Faculdade de Medicina da Universidade de São Paulo, que funciona como uma bomba que auxilia o ventrículo esquerdo dos pacientes à espera de transplante. Portanto, o objetivo desta tese é contribuir na compreensão de escoamentos em geometrias biológicas e bio-inspiradas, usando ferramentas computacionais. Análises de estabilidade linear e não linear foram feitas para um canal constrito. Três diferentes regimes de escoamento foram empregados: escoamento estacionário simétrico, que é estável para baixo número de Reynolds, escoamento assimétrico, o qual é resultado da primeira bifurcação do escoamento simétrico e escoamento pulsátil. Análise de estabilidade direta foi executada para determinar as regiões instáveis em cada regime de escoamento. Os mecanismos físicos por trás do processo de transição foram estudados por meio de simulação numérica direta para caracterizar as bifurcações. Uma vez que, as bifurcações tiveram um comportamento subcrítico, a relevância do crescimento não normal nestes escoamentos foi avaliado. Assim, dependência com a fase, número de Reynolds e número de onda do modo tridimensional foram extensivamente investigados em regiões estáveis para os três regimes de escoamento. Instabilidades convectivas foram também estudadas a fim de compreender os mecanismos físicos que conduzem os modos ótimos para seus crescimentos máximos, e diferentes mecanismos convectivos foram encontrados. O escoamento dentro do dispositivo de assistência ventricular pediátrico foi analisado por meios de simulações numéricas tridimensionais. Um modelo computacional baseado em condições de contorno especiais foi desenvolvido para modelar o escoamento pulsátil. Neste modelo, a abertura e fechamento da válvula mitral e diafragma foram representados com o uso de condições de contorno especialmente elaboradas. A força motora e o direcionamento do fluxo do diafragma foram definidos por uma distribuição de velocidades na parede do diafragma, e a abertura e fechamento da válvula mitral foram executadas por uma função de onda de velocidade que vai a zero no período sistólico. Padrões do escoamento, campos de velocidade e tensão de cisalhamento no tempo foram analisadas para avaliar o desempenho do dispositivo.

<p><i>Chlamydia pneumoniae</i> is a human respiratory tract pathogen. Seroepidemiological studies indicate that <i>C. pneumoniae</i> infection is most common in school-aged children and infrequently detected in younger children.</p><p>The aims of this study were to further elucidate the prevalence of <i>C. pneumoniae</i> in paediatric populations and to describe the clinical implications of these infections.</p><p>The study population consisted of 367 children with respiratory tract diseases, 453 presumed healthy children at day-care, 69 children undergoing adenoidectomy and 1585 children from a population based cohort. Family members to infected day-care children were investigated. The laboratory methods used were polymerase chain reaction (PCR) on specimen from upper respiratory tract, serology by microimmunofluorescence (MIF), and immunohistochemistry (IHC) on adenoid tissue specimen. Personal data and medical history were obtained by the means of questionnaires and by the study of patient records.</p><p>In children younger than five years, the prevalence of <i>C. pneumoniae</i> was 17% as detected by PCR. This prevalence started to increase with increasing age from two years of age. The corresponding increase in serology as detected by MIF started at the age of four years. The prevalence at day-care centres varied from 4 to 39%. Both PCR and MIF underestimated the prevalence of <i>C. pneumoniae</i> detected by IHC. Families to infected children were investigated: mothers were more often infected than fathers were.</p><p>Most <i>C. pneumoniae</i> infections in small children were confined to the upper respiratory tract. These infections were usually mild or asymptomatic. Symptomatic disease may be of prolonged nature. No subsequent illness after <i>C. pneumoniae</i> infection was detected at follow-up after four years. In general, no association between <i>C. pneumoniae</i> and asthma was found, but <i>C. pneumoniae</i> may be of importance for asthma in some susceptible individuals. Previous <i>C. pneumoniae</i> infection reduced the risk for later atopy.</p><p>In conclusion, <i>C. pneumoniae</i> is a common finding in small children and most often causes relatively mild disease. If the acquisition of this infection early in life will have any implications for future health remains to be investigated.</p>

<p>Excessive weight gain has frequently been reported in adolescents with type 1 diabetes, especially in girls. In general, puberty is associated with reduced insulin sensitivity that is further diminished by overweight. The causes and consequences of excessive weight gain in adolescents with type 1 diabetes are not fully understood. The studies described in this thesis addressed body composition in adolescents with type 1 diabetes and the relationships between physical activity, energy intake and changes in body composition. Furthermore, the effect of metformin as additional therapy on glycaemic control and insulin sensitivity was examined in a randomised placebo-controlled study. Body mass index (BMI) and percentage body fat (%BF) were significantly higher in girls with type 1 diabetes compared to healthy control girls. Mean HbA1c during puberty, but not mean insulin dose, was positively related to BMI at the age of 18 in girls with diabetes. A centralised fat distribution was associated with poor glycaemic control, increased daily dosage of insulin and elevated cholesterol and triglyceride levels. Neither total physical activity nor total energy intake differed between adolescent girls with type 1 diabetes and healthy age-matched control girls. A high dietary fat intake was positively related to gain in %BF in girls with type 1 diabetes. Additional therapy with metformin for three months improved glycaemic control and peripheral insulin sensitivity in adolescents with poorly controlled type 1 diabetes. The improvement in glycaemic control was related to insulin sensitivity at baseline, implying that the most insulin resistant subjects benefited most from the metformin therapy. It is concluded that the excessive weight gain observed in girls with type 1 diabetes is mainly attributable to an increased fat mass and that dietary fat intake is of importance for this gain in body fat. Additional treatment with metformin improves glycaemic control in adolescents with poorly controlled type 1 diabetes.</p>

<p>The process of β-cell destruction that leads to type 1 diabetes (T1D) is incompletely understood and it is believed to be a result of both genetic and environmental factors. Enterovirus (EV) infections of the β-cells have been proposed to be involved, however, the effects of EV infections on human β-cells have been little investigated. This thesis summarises studies of three different Coxsackie B4 virus strains that have previously been shown to infect human islets. The effects of infections with these EV were studied <i>in vitro</i> in human islets and in a rat insulin-producing cell line. In addition, a pilot study was performed on isolated human islets to investigate the ability to treat such infections with an antiviral compound.</p><p>It was found that one of the virus strains replicated in human β-cells without affecting their main function for at least seven days, which <i>in vivo</i> may increase a virus’s ability to persist in islets.</p><p>Nitric oxide was induced by synthetic dsRNA, poly(IC), but not by viral dsRNA in rat insulinoma cells in the presence of IFN-γ, suggesting that this mediator is not induced by EV infection in β-cells and that poly(IC) does not mimic an EV infection in this respect.</p><p>All three virus strains were able to induce production of the T-cell chemoattractant interferon-γ-inducible protein 10 (IP-10) during infection of human islets, suggesting that an EV infection of the islets might trigger insulitis <i>in vivo</i>.</p><p>Antiviral treatment was feasible in human islets, but one strain was resistant to the antiviral compound used in this study.</p><p>To conclude, a potential mechanism is suggested for the involvement of EV infections in T1D. If EV infections induce IP-10 production in human islet cells <i>in vivo</i>, they might recruit immune cells to the islets. Together with viral persistence and/or virus-induced β-cell damage, this might trigger further immune-mediated β-cell destruction <i>in vivo</i>.</p>

Chlamydia pneumoniae is a human respiratory tract pathogen. Seroepidemiological studies indicate that C. pneumoniae infection is most common in school-aged children and infrequently detected in younger children. The aims of this study were to further elucidate the prevalence of C. pneumoniae in paediatric populations and to describe the clinical implications of these infections. The study population consisted of 367 children with respiratory tract diseases, 453 presumed healthy children at day-care, 69 children undergoing adenoidectomy and 1585 children from a population based cohort. Family members to infected day-care children were investigated. The laboratory methods used were polymerase chain reaction (PCR) on specimen from upper respiratory tract, serology by microimmunofluorescence (MIF), and immunohistochemistry (IHC) on adenoid tissue specimen. Personal data and medical history were obtained by the means of questionnaires and by the study of patient records. In children younger than five years, the prevalence of C. pneumoniae was 17% as detected by PCR. This prevalence started to increase with increasing age from two years of age. The corresponding increase in serology as detected by MIF started at the age of four years. The prevalence at day-care centres varied from 4 to 39%. Both PCR and MIF underestimated the prevalence of C. pneumoniae detected by IHC. Families to infected children were investigated: mothers were more often infected than fathers were. Most C. pneumoniae infections in small children were confined to the upper respiratory tract. These infections were usually mild or asymptomatic. Symptomatic disease may be of prolonged nature. No subsequent illness after C. pneumoniae infection was detected at follow-up after four years. In general, no association between C. pneumoniae and asthma was found, but C. pneumoniae may be of importance for asthma in some susceptible individuals. Previous C. pneumoniae infection reduced the risk for later atopy. In conclusion, C. pneumoniae is a common finding in small children and most often causes relatively mild disease. If the acquisition of this infection early in life will have any implications for future health remains to be investigated.

Excessive weight gain has frequently been reported in adolescents with type 1 diabetes, especially in girls. In general, puberty is associated with reduced insulin sensitivity that is further diminished by overweight. The causes and consequences of excessive weight gain in adolescents with type 1 diabetes are not fully understood. The studies described in this thesis addressed body composition in adolescents with type 1 diabetes and the relationships between physical activity, energy intake and changes in body composition. Furthermore, the effect of metformin as additional therapy on glycaemic control and insulin sensitivity was examined in a randomised placebo-controlled study. Body mass index (BMI) and percentage body fat (%BF) were significantly higher in girls with type 1 diabetes compared to healthy control girls. Mean HbA1c during puberty, but not mean insulin dose, was positively related to BMI at the age of 18 in girls with diabetes. A centralised fat distribution was associated with poor glycaemic control, increased daily dosage of insulin and elevated cholesterol and triglyceride levels. Neither total physical activity nor total energy intake differed between adolescent girls with type 1 diabetes and healthy age-matched control girls. A high dietary fat intake was positively related to gain in %BF in girls with type 1 diabetes. Additional therapy with metformin for three months improved glycaemic control and peripheral insulin sensitivity in adolescents with poorly controlled type 1 diabetes. The improvement in glycaemic control was related to insulin sensitivity at baseline, implying that the most insulin resistant subjects benefited most from the metformin therapy. It is concluded that the excessive weight gain observed in girls with type 1 diabetes is mainly attributable to an increased fat mass and that dietary fat intake is of importance for this gain in body fat. Additional treatment with metformin improves glycaemic control in adolescents with poorly controlled type 1 diabetes.

The process of β-cell destruction that leads to type 1 diabetes (T1D) is incompletely understood and it is believed to be a result of both genetic and environmental factors. Enterovirus (EV) infections of the β-cells have been proposed to be involved, however, the effects of EV infections on human β-cells have been little investigated. This thesis summarises studies of three different Coxsackie B4 virus strains that have previously been shown to infect human islets. The effects of infections with these EV were studied in vitro in human islets and in a rat insulin-producing cell line. In addition, a pilot study was performed on isolated human islets to investigate the ability to treat such infections with an antiviral compound. It was found that one of the virus strains replicated in human β-cells without affecting their main function for at least seven days, which in vivo may increase a virus’s ability to persist in islets. Nitric oxide was induced by synthetic dsRNA, poly(IC), but not by viral dsRNA in rat insulinoma cells in the presence of IFN-γ, suggesting that this mediator is not induced by EV infection in β-cells and that poly(IC) does not mimic an EV infection in this respect. All three virus strains were able to induce production of the T-cell chemoattractant interferon-γ-inducible protein 10 (IP-10) during infection of human islets, suggesting that an EV infection of the islets might trigger insulitis in vivo. Antiviral treatment was feasible in human islets, but one strain was resistant to the antiviral compound used in this study. To conclude, a potential mechanism is suggested for the involvement of EV infections in T1D. If EV infections induce IP-10 production in human islet cells in vivo, they might recruit immune cells to the islets. Together with viral persistence and/or virus-induced β-cell damage, this might trigger further immune-mediated β-cell destruction in vivo.

Type 1 diabetes (T1D) is a chronic disease caused by destruction of the insulin producing beta-cells in the pancreas. The incidence of T1D has increased rapidly, especially in the Western world and among young children. The pathogenesis of T1D is not fully understood, but the beta-cells are believed to be destroyed by an autoimmune process initiated years before the onset of T1D. During this pre-clinical period, autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and the tyrosine phosphatase-like protein IA-2 (IA-2A) can be detected and are used to identify individuals at risk of T1D. The major genetic determinant for T1D is the HLA class II genes, but also polymorphism in the insulin gene and CTLA-4 gene are associated with T1D. The risk genes cannot explain the rapid increase in incidence of T1D, therefore a role for different environmental factors has been suggested. The aim was to study the prevalence of beta-cell autoantibodies in children from the general population in relation to known genetic and environmental risk factors, and in young patients with T1D in high and low incidence areas. Short duration of breast-feeding was associated with an increased risk of developing beta-cell autoantibodies in children from the general population at 5-6 years of age. We found an association between positivity for GADA and/or IAA at the age of 5-6 years and a short duration of total breastfeeding, and also between positivity for GADA, IA-2A and/or IAA and a short duration of exclusive breast-feeding. Our findings suggest that breast-feeding has a long term protective effect on the risk of beta-cell autoimmunity in children from the general population. The T1D related risk genes were not associated with beta-cell autoantibodies other than GADA in children from the general population at 5-6 years of age. Children with the DR4-DQ8 haplotype were more often positive for GADA than children without this haplotype. We found no association of GADA with DR3-DQ2 haplotype or between these two haplotypes and any of the other autoantibodies. Our results suggest that beta-cell autoimmunity in children from the general population is not strongly associated with any risk genes of T1D other than DR4-DQ8. In the non-diabetic children with allergic heredity GADA was detectable in almost all children, IA-2A in about half and IAA in 10% of the children. The levels low of these autoantibodies fluctuated with age and different patterns of fluctuations were seen for GADA and IA-2A, which may reflect differences in the immune response to the autoantigens. In patients with newly diagnosed T1D, we found some differences between patients from a high incidence country (Sweden) and a country with a lower incidence (Lithuania). Among the Swedish patients, the prevalence of IAA and GADA or multiple autoantibodies was higher than in Lithuanian patients. The risk genes DR4-DQ8 and the heterozygous high risk combination DR4-DQ8/DR3-DQ2 was more common among the Swedish patients than Lithuanian patients. Patients with low levels of IAA had higher levels of HbA1c and ketones, indicating that patients without IAA or with low levels of IAA have a more severe onset of T1D. Our findings indicate that beta-cell autoimmunity is more pronounced in a high incidence area compared to an area with a lower incidence. In conclusion, short duration of breast-feeding is a risk factor for beta-cell autoantibodies in children from the general population, and the beta-cell autoantibodies in these children are not associated with specific risk genes. Children with newly diagnosed T1D in a high incidence area carry risk genes and have autoantibodies more often than newly diagnosed children from an area with a lower incidence, perhaps indicating different disease phenotypes.

Globally, neonatal mortality has remained basically unchanged for the last three to four decades and every year almost four million newborns die before reaching one month of age. This persistent mortality is related to an invisibility of the newborn child in policies and statistics and a neglect of health care decision-makers, planners and practitioners to deliver a perinatal continuum of care. In recent years attention has however been brought to the unchanged neonatal mortality in an effort to improve survival. The present thesis seeks to increase understanding of obstacles for better neonatal survival. The studies performed are undertaken as sub-studies to the NeoKIP project in Quang Ninh province in northern Vietnam, a randomized controlled trial of knowledge implementation for improved neonatal survival (Neonatal Health – Knowledge Into Practice, ISRCTN 44599712). In the first paper we investigated and discussed the scope of invisibility of neonatal mortality through measuring the accuracy of official statistics on neonatal deaths. The second paper reports an inquiry of determinants of neonatal mortality by use of a population-based case-referent design. Paper III and IV analyse delivery care utilization and care seeking patterns prior to and at delivery using narratives and GIS technique. There was a substantial under-reporting of neonatal mortality in the official statistics, with study results showing a four times higher neonatal mortality rate in Quang Ninh province than reported to the Ministry of Health. This neonatal mortality rate of 16/1000 live births (as compared to 4.2/1000 in official reports) was unevenly distributed in the province, showing large geographical discrepancies. In the rural and remote areas of Vietnam education level is lower and the concentrations of ethnic minorities and poor households are higher. Ethnic minority belonging was associated with a more than doubled risk of neonatal death compared to the hegemonic group of Kinh (OR 2.08 CI 95 % 1.39 – 3.10). This increased risk was independent of household economic status or maternal education level. Neonatal mortality was also associated with home deliveries, non-attendance to antenatal care and distance to the health care facilities. However, ethnic minority mothers still had an increased risk of experiencing a neonatal death even if they attended antenatal care, delivered at or lived close to a health facility. The invisibility of the neonatal period in health information systems hides the true width of the neonatal mortality challenge. By not acknowledging the problem, the marginalization of already disadvantaged groups continues, leaving ethnic minority babies with an elevated risk of dying during the first month in life. This example of ethnic inequity highlights the importance to target those most in need. The studies of the present thesis should therefore be looked upon as a contribution to the struggle to illuminate the global burden of neonatal mortality.