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The transporters primarily responsible for transporting important nutrients involved in energy metabolism have a wide substrate specificity setting up the potential for drug-nutrient transporter interactions. Pharmacological inhibition of nutrient transport across the lactating mammary and neonatal intestinal epithelial barrier can directly and indirectly affect growth and maturation of the developing neonate by either reducing the uptake of important nutrients by the neonate or by disrupting epithelial barrier integrity. My thesis focused on two transporters, OCTN2 and MCT1, expressed in immortalized intestinal and mammary epithelial cell cultures to assess the effects of their pharmacological inhibition on L-carnitine and butyrate flux, respectively, and polarized epithelial barrier integrity. Human colorectal adenocarcinoma (Caco-2) and bovine mammary (BME-UV) cell lines were grown into monolayers on 12-well tissue culture plates and subsequently exposed to the presence or absence of OCTN2 and MCT1 inhibitors for 6, 12, and 24 hours as well as 7 days. Failure to obtain a polarized mammary monolayer prevented the analysis of the direct effects of nutrient transport inhibition on nutrient flux forcing the focus on the indirect effects. To assess polarized epithelial barrier integrity, transepithelial electrical resistance and Lucifer yellow rejection rates were measured at each time point. No trend was noted between control and treated groups. To assess the acute and chronic effects of pharmacological exposure on polarized epithelial function, a limited appraisal of nutrient transporter expression and cellular homeostasis parameters was conducted. Following exposure at each time point, mRNA expression of OCTN1, OCTN2, MCT1, MCT2 and GADPH were measured using qPCR. Low mRNA yields resulted in an inability to assess transporter expression levels in the epithelial systems. Cellular homeostasis parameters were analyzed using the CellTiter-Glo Luminescent Cell Viability Assay, pH-Xtra Glycolysis Assay and MitoXpress Xtra Oxygen Consumption Assay. These assays measured ATP synthesis, glycolytic flux and cellular respiration, respectively. No significant trend was noted in ATP synthesis between control and treated groups. An upward trend in both glycolytic flux and cellular respiration was noted in treatment with both inhibitors in both cell lines. Complications in obtaining polarized monolayer forced the focus on the indirect affects, therefore, obtaining and utilizing a more accurate portrayal of the lactating mammary and neonatal intestinal epithelium is critical in answering this research question as both of these systems are highly synthetic and complex. By doing so, a more accurate representation of the effects of pharmacological inhibition of nutrient transporters essential for energy metabolism can be identified.

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Congenital diaphragmatic hernia (CDH) is a potentially fatal condition found in neonates where embryological defects in the diaphragm negatively impact fetal maturation and growth. The defect allows contents below the diaphragm to potentially migrate into the thoracic cavity during development, which could lead to secondary complication including pulmonary hypertension and left ventricular hypoplasia. CDH tends to have a high neonate mortality rate in congruence with the severity of the condition. Several risk factors for CDH include accompanying chromosomal abnormalities and the anatomical positions of organs in the fetus. Diagnosis is typically found with an ultrasound (US) in utero. There have been several studies in order to better understand the pathology of the disease and new techniques to try and alleviate the cases prenatally, however the risks involved with these procedures may outweigh the benefits. The standard practice for neonates that qualify for postnatal treatment is the use of extracorporeal membrane oxygenation (ECMO) postnatally, to facilitate oxygenated blood to the fetus via a bio-mechanical device. Recent treatment techniques that have revolutionized care for CDH include a delayed surgical intervention in order to reduce the risk of developing a pulmonary ailment such as pulmonary hypertension and/or lung hypoplasia. Interventions with inhaled nitric oxide have also been shown to relegate a similar outcome to those with ECMO intervention. Despite the advancements in knowledge, treatment, and technology, the mortality rate for CDH still hovers around 50% on average, yet that percentage can increase or decrease depending on the severity of the condition and any genetic abnormalities associated with it. Overall, while there have been great strides in treatment and understanding of CDH, additional research is necessary in order to provide the utmost care for future generations of CDH patients.

Orientador: Lígia Maria Suppo de Souza Rugolo / Coorientador: Paulo Roberto Margotto / Banca: Élson Roberto Ribeiro Faria / Banca: Maria Cristina Ferreira Sena / Resumo: Avaliar a sobrevida de recém-nascidos (RN) prematuros de acordo com a idade gestacional e peso ao nascer, e identificar as complicações da prematuridade associadas à maior mortalidade. Estudo prospectivo do tipo coorte. Foram incluídos RN entre 25 e 31 semanas e 6 dias nascidos vivos sem anomalias congênitas, e admitidos na UTI neonatal do Hospital Regional da Asa Sul, Brasília, entre 1º de agosto de 2009 e 31 de outubro de 2010. Os óbitos em sala de parto, não foram incluídos. Os RN foram estratificados em três faixas de idade gestacional: 25 a 27 semanas e 6 dias; 28 a 29 semanas e 6 dias; 30 a 31 semanas e 6 dias e acompanhados até 28 dias de vida. Variáveis independentes: dados gestacionais, de nascimento e evolução neonatal. Desfechos: sobrevida aos 28 dias e alterações no ultrassom de crânio. Para análise dos resultados utilizou-se o teste do Qui-quadrado, análise de variância, teste de Kruskal-Wallis, razão de risco com intervalo de confiança e regressão logística múltipla, com significância em 5%. A coorte compreendeu 198 prematuros < 32 semanas, estratificados em três grupos: G1=59 (25 a 27semanas e 6 dias), G2=43 (28 a 29 semanas e 6 dias) e G3=96 (30-31 semanas e 6 dias). Corioamnionite e reanimação ao nascimento foram mais frequentes em G1 e G2. Parto vaginal e RN PIG foram mais frequentes em G1. A morbidade neonatal foi inversamente proporcional à idade gestacional, exceto a enterocolite necrosante e a leucomalácia periventricular, que não diferiram entre os grupos. O risco de óbito foi significativamente maior em G1 e G2 em relação ao G3 (RR:4,14; IC:2,23-7.68 e RR=2,84; IC:1,41-5.74), respectivamente. A sobrevida em G1 foi de 52,5%, em G2 foi 67,4% e em G3 88,5%. A partir de 27 semanas e do peso de 700g a sobrevida foi maior que 50%. A regressão logística mostrou... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: To assess the survival rates of premature infants according to gestational age and birth weight, and to identify complications of prematurity associated with higher mortality. Prospective cohort study. Preterm infants with gestational age between 25 and 31 weeks and 6 days, born alive without congenital anomalies, and admitted in the NICU of Hospital Regional da Asa Sul, Brasília, between August 1st 2009 and October 31, 2010 were included. Neonates who died in the delivery room were excluded. Neonate were stratified into three gestational age groups: 25- 27 weeks and 6 days; 28- 29 weeks and 6 days; 30-31 weeks and 6 days, and followed until 28 days of life. Gestational data, delivery data and neonatal course were analyzed. Outcome: survival at 28 days and cranial ultrasound abnormalities. Data analysis was performed using the chi-square test, analysis of variance and the Kruskal-Wallis test, hazard ratio with confidence interval and multiple logistic regression. The level of significance was 5%. The cohort comprised 198 preterm infants less than 32 weeks, stratified into three groups: G1=59 (25-27weeks and 6 days), G2=43 (28- 29 weeks and 6 days) and G3=96 (30-31 weeks and 6 days). Chorioamnionitis and resuscitation in the delivery room were more frequent in G1 and G2. Vaginal delivery and newborns small for gestational age occurred significantly more in G1. Neonatal morbidity was inversely proportional to gestational age, except for necrotizing enterocolitis and leukomalacia that did not differ between the groups. The risk of death was significantly higher in groups 1 and 2 compared to 3 (RR: 4.14, CI: 2,23-7 .68 and RR = 2.84, CI:1,41 5-.74), respectively. The logistic regression analysis showed that pulmonary hemorrhage (OR: 3.33, 95% CI 1.41 to 7.90) and hyaline membrane disease... (Complete abstract click electronic access below) / Mestre

Philosophiae Doctor - PhD / The unacceptable high rate of maternal and neonatal deaths in Nigeria has been persistently unabated. Therefore, the present quality of maternal care evident by the magnitude of severe maternal/neonatal morbidity and mortality in this region makes designing of a model that will serve as a framework for provision of quality maternity care to women and their new-born a worthwhile study. The global report of deaths related to pregnancy and childbirth documented 600,000 maternal deaths annually. Developing countries, including Nigeria, have the highest burden of maternal and neonatal deaths resulting from complications related to pregnancy and childbirth. There has been no improvement in Nigeria as far as maternal and neonatal deaths are concerned. In Nigeria, the maternal mortality ratio in 2008 was recorded as 545/100,000 live births, and 576/100,000 live births in 2013. Women and children from low socioeconomic background are the vulnerable groups. The peculiarity of their vulnerability predisposes them to finding quicker and cheaper avenues to seek health care. The Primary Health Care (PHC) maternity facilities are to serve this large population of women and their babies at grassroots level. Few studies have been done to measure quality of antenatal and delivery care separately at higher level of care with resultant subjective findings and conclusions. Each of these aspects of maternity is a part of the whole and not the whole. Currently, there is gross dearth of literature regarding quality of maternity services at the disposal of the vulnerable women, who are likely to utilize the PHC facilities. The measurement of the quality of the existing maternity services at primary level is imperative for designing a more effective model capable of improving quality of services at this level. This study sought to develop a quality service improvement model for primary level-based maternity following rigorous analysis of the quality of its structure, the process and the outcome as proposed by Donabedian. The specific objectives of the study were to describe the status of infrastructures, equipment, instruments, medications; investigate the degree to which the services rendered are timely, appropriate, satisfactory and consistent with current professional knowledge; investigate the degree to which services rendered in the facilities are satisfactory to the women and uphold their basic reproductive rights; measure clients’ return rates for maternity-related services in the facilities; and to develop a validated model to guide provision of quality maternity care in PHC facilities. Using a theory-generating approach, the study was conducted in two distinct phases. The first phase focused on analysis of the existing maternity services at PHC level, while the second phase concentrate on model development. The first phase, which is an embedded mixed-methods approach, utilized validated clients’ questionnaire, health workers’ questionnaire, observation checklist, focused group discussions, and in-depth interviews for data collection. A multistage sampling method was used for sample size selection. Five local government areas (LGAs) in Ibadan were selected purposively. Similarly, all the facilities that offer maternity care in each LGA were purposively selected. Postnatal women, health workers in each facility, medical officers of health (MOHs) and heads of facilities were the participants in the study. A total of 755 postnatal women who participated in the surveys were recruited from the sample frames (attendance registers) using systematic random sampling. A validated structured questionnaire was utilized to elicit information on their experiences with their chosen places of antenatal and childbirth care from pregnancy to puerperium. Similarly, the 130 health workers who participated in the surveys were recruited from the sample frames (duty rosters) using systematic random sampling. A validated structured questionnaire was utilized to elicit information on their competences, attitudes and the midwifery practice in their respective facilities. In addition to the quantitative surveys, focus group discussions (FGDs) and in-depth interviews (IDIs) were conducted for some postnatal women and four MOHs/heads of group of facilities. The participants for the FGDs and the IDIs were conveniently and purposively selected, respectively. FGD guide and IDI guide were used to guide the interviewers. The study was approved by the Faculty Board Research and Ethics Committees, the Senate Research Committee of University of the Western Cape and Oyo State Research Ethical Review Committee in Nigeria. Informed consent was obtained from each study participant. Autonomy, anonymity, and confidentiality of information provided by the participants were ensured. Nobody was coerced to participate in the study. The data collected with the aid of observation checklist and questionnaire from the selected PHC, health workers and client (postnatal women) were analyzed using descriptive statistics (frequency/percentage distributions); while association between variables of interest and difference in mean values were done using chi-square and t-test statistics, respectively. The second phase of the study focused on model development, and was done in line with a theory- generating research process in the literature supported by McKenna & Slevin, (2008) and Chinn& Kramer (2014). The developed model was tested for its appropriateness, adequacy, accuracy and whether it represents reality, for it to be assumed effective in achieving the goal if applied in midwifery practice at primary level.Client-participants were between 15 and 44 years; their mean age ± standard deviation was 28 ±5.3. The health workers were between 20 and 58 years; mean age ± standard deviation being 41 ±10. Out of the 730 client-participants, 92.1 % were married. None of the women had access to preconception counselling in any health facility. A total of 92.6 % of the women received prenatal care under the existing traditional model of antenatal care (ANC), out of which 22.6 %registered for ANC in two different facilities for various reasons. Although there was gross shortage of manpower in all the facilities, the percentage of nurses/midwives was fewer than that of the community health extension workers (CHEWs) and health assistants (HAs), while only one medical doctor was employed to cover all the different types of facilities in each local government area . There was a questionable staff level of competence reported in the study. Evidence of training in life-saving skill (LSS), post-abortion care (PAC) and safe motherhood was rare among the health worker participants. Among health workers who had witnessed vaginal laceration and those who claimed to have performed episiotomy on women, 30.2% and 32.6 % would depend on other health workers for repair of the vaginal traumas, respectively. Partograph was not in use for management of progress of labour by any health worker in any of the facilities. Both quantitative and qualitative data analysis showed evidences of abuse of women’s rights to timely, quality and respectful maternity care and risky practices by the health workers. The conditions of the buildings used for PHC centres and the beds were not satisfactory. There was gross inadequacy of essential and basic items needed to provide standard and quality care across all the facilities, while significant proportion of the available equipment/instruments were obsolete, dirty, rusty and faulty. The infection prevention and control practices were sub- standard. Inadequate funding by respective local government authorities was implicated for the poor conditions of infrastructures, equipment/instruments, staff recruitments and consequent shortage of manpower. Low level of patients’ satisfaction, evidenced by verbal expression, percentage difference between antenatal registration and childbirth record, immunization clinic visits and childbirth record in each facility, was reported. Therefore, fixing the deplorable and/or non-commodious building infrastructures to meet the required standard, provision of facilities and items needed for quality care and infection prevention, recruitment of skilled qualified health professionals, establishing a new Primary Health Board in the state to provide efficient funding and effective monitoring systems were recommended, based on the findings of the study. Lastly, the implementation of the newly developed model is strongly recommended in order to improve women’s and new-born’s health. / Centre for Teaching and Learning Scholarship, School of Nursing, University of the Western Cape

Made available in DSpace on 2014-06-11T19:29:52Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-08-18Bitstream added on 2014-06-13T19:39:23Z : No. of bitstreams: 1 castro_mp_me_botfm.pdf: 325846 bytes, checksum: 488dfaca4c5d75ee2ad1616d30bc5819 (MD5) / Fundação de Ensino e Pesquisa em Ciências da Saúde (FEPECS) / Avaliar a sobrevida de recém-nascidos (RN) prematuros de acordo com a idade gestacional e peso ao nascer, e identificar as complicações da prematuridade associadas à maior mortalidade. Estudo prospectivo do tipo coorte. Foram incluídos RN entre 25 e 31 semanas e 6 dias nascidos vivos sem anomalias congênitas, e admitidos na UTI neonatal do Hospital Regional da Asa Sul, Brasília, entre 1º de agosto de 2009 e 31 de outubro de 2010. Os óbitos em sala de parto, não foram incluídos. Os RN foram estratificados em três faixas de idade gestacional: 25 a 27 semanas e 6 dias; 28 a 29 semanas e 6 dias; 30 a 31 semanas e 6 dias e acompanhados até 28 dias de vida. Variáveis independentes: dados gestacionais, de nascimento e evolução neonatal. Desfechos: sobrevida aos 28 dias e alterações no ultrassom de crânio. Para análise dos resultados utilizou-se o teste do Qui-quadrado, análise de variância, teste de Kruskal-Wallis, razão de risco com intervalo de confiança e regressão logística múltipla, com significância em 5%. A coorte compreendeu 198 prematuros < 32 semanas, estratificados em três grupos: G1=59 (25 a 27semanas e 6 dias), G2=43 (28 a 29 semanas e 6 dias) e G3=96 (30-31 semanas e 6 dias). Corioamnionite e reanimação ao nascimento foram mais frequentes em G1 e G2. Parto vaginal e RN PIG foram mais frequentes em G1. A morbidade neonatal foi inversamente proporcional à idade gestacional, exceto a enterocolite necrosante e a leucomalácia periventricular, que não diferiram entre os grupos. O risco de óbito foi significativamente maior em G1 e G2 em relação ao G3 (RR:4,14; IC:2,23-7.68 e RR=2,84; IC:1,41-5.74), respectivamente. A sobrevida em G1 foi de 52,5%, em G2 foi 67,4% e em G3 88,5%. A partir de 27 semanas e do peso de 700g a sobrevida foi maior que 50%. A regressão logística mostrou... / To assess the survival rates of premature infants according to gestational age and birth weight, and to identify complications of prematurity associated with higher mortality. Prospective cohort study. Preterm infants with gestational age between 25 and 31 weeks and 6 days, born alive without congenital anomalies, and admitted in the NICU of Hospital Regional da Asa Sul, Brasília, between August 1st 2009 and October 31, 2010 were included. Neonates who died in the delivery room were excluded. Neonate were stratified into three gestational age groups: 25- 27 weeks and 6 days; 28- 29 weeks and 6 days; 30-31 weeks and 6 days, and followed until 28 days of life. Gestational data, delivery data and neonatal course were analyzed. Outcome: survival at 28 days and cranial ultrasound abnormalities. Data analysis was performed using the chi-square test, analysis of variance and the Kruskal-Wallis test, hazard ratio with confidence interval and multiple logistic regression. The level of significance was 5%. The cohort comprised 198 preterm infants less than 32 weeks, stratified into three groups: G1=59 (25-27weeks and 6 days), G2=43 (28- 29 weeks and 6 days) and G3=96 (30-31 weeks and 6 days). Chorioamnionitis and resuscitation in the delivery room were more frequent in G1 and G2. Vaginal delivery and newborns small for gestational age occurred significantly more in G1. Neonatal morbidity was inversely proportional to gestational age, except for necrotizing enterocolitis and leukomalacia that did not differ between the groups. The risk of death was significantly higher in groups 1 and 2 compared to 3 (RR: 4.14, CI: 2,23-7 .68 and RR = 2.84, CI:1,41 5-.74), respectively. The logistic regression analysis showed that pulmonary hemorrhage (OR: 3.33, 95% CI 1.41 to 7.90) and hyaline membrane disease... (Complete abstract click electronic access below)

The purpose of this study was to determine the safety and pharmacokinetic profile of firocoxib in healthy neonatal foals. Foals are more sensitive to the side effects of nonsteroidal anti-inflammatory drugs, (NSAIDs), particularly due to immature renal clearance mechanisms and ulcerogenic effects on gastric mucosa. Firocoxib, a novel second generation NSAID, is reported to have reduced side effects due to its COX-2 selectivity. The pharmacokinetic profile of firocoxib in neonates has not been established, making reliable dosing difficult. We hypothesized that firocoxib given per os at the labeled dose to neonatal foals would be absorbed and not be associated with clinically significant adverse events. Seven healthy American Quarter Horse foals of mixed gender were administered 0.1mg/kg firocoxib orally q24h for nine consecutive days, commencing at 36h of age. Blood samples were collected for firocoxib analysis using high pressure liquid chromatography with fluorescence detection at 0 (dose #1 only), 0.25, 0.5, 1, 2, 4, 8, 16 and 24 hours after doses #1, 5 and 9. For all other doses (2, 3, 4, 6, 7 and 8) blood was collected immediately prior to the next dose (24 hour trough). Elimination samples (36, 48, 72, 96, 120 and 144 hours) were collected after dose #9. Safety was assessed via physical examinations, changes in body weight, gastroscopy, complete blood count, serum biochemistry and urinalysis. Firocoxib was rapidly absorbed following oral administration with minimal accumulation after repeat dosing. After the initial dose, an average peak serum concentration (Cmax) of 89.50 ° 53.36 ng/mL (mean ° SD) was achieved (Tmax) in 0.54 ° 0.65 hours. Steady state was obtained after approximately 4 doses and the average maximum concentration (Cavg) in serum was 39.1 ° 8.4 ng/mL. After the final dose, the mean terminal half-life (T½?») was 10.46 ° 4.97 hours. Firocoxib was not detected in plasma 72 hours after the final dose (<2ng/mL). Bioavailability could not be determined as currently, there is no accompanying intravenous dose of firocoxib for this age group to permit the calculation. No significant abnormalities were noted on blood work, urinalysis or gastroscopy. This study demonstrated that firocoxib is absorbed after oral administration in neonatal foals with no observable adverse effects after multiple doses. / Master of Science

Background: International analyses suggest that routine maternal vaccination with seasonal trivalent influenza vaccine is cost-effective, but few studies have been done in middle- to low- income countries. Method: A decision-tree analysis was modelled for the South African public healthcare setting over one year from a payer's perspective. Direct medical costs and consequences were obtained from published literature. Incremental cost effectiveness ratios (ICERs) and univariate sensitivity analyses were then measured. Discounting was excluded due to the seasonality of influenza, limiting the time horizon to a one year period. Findings: The model predicted that to avert influenza-associated hospitalisations amongst pregnant women and their infants less than six months of age, vaccination of pregnant women was not cost-effective. This was irrespective of whether the universal vaccination or HIV-targeted approach was used. A base model simulating 100% vaccine uptake predicted that seasonal vaccination of 100,000 pregnant women results in an estimated net cost of R69,118,114.05 per neonatal influenza-associated hospitalisation averted. Similarly, the model suggested that vaccinating 100,000 pregnant women would cost R1,197,779.79 per maternal hospitalisation averted. Univariate sensitivity analyses reinforced that influenza vaccination of pregnant women was not cost-effective, except when lower incidence of maternal influenzaassociated hospitalisations associated with antenatal influenza vaccination were simulated where the targeted approach became dominant. The latter analysis predicted savings of R770,530.86 per maternal influenza-associated hospitalisation averted. Interpretation: The ICERs suggest that influenza vaccination amongst pregnant women is not cost-effective in the South African public healthcare sector compared to no vaccination, with respect to averting influenza-associated hospitalisations amongst pregnant women and their infants less than six months of age. However, these estimates should be re-evaluated, pending vaccine effectiveness studies of higher methodological quality for low- and middle- income countries and using cost inputs relevant to South African public healthcare setting. This analysis may provide preliminary information regarding the upscaling of influenza vaccination amongst pregnant women as a priority in the constraints of a limited healthcare budget and careful consideration is required regarding vaccine mobilisation amongst pregnant women. / Dissertation (MSc)--University of Pretoria, 2016. / School of Health Systems and Public Health (SHSPH) / MSc / Unrestricted

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