No description available.

Introduction: Despite evidence in favour of cholecystectomy early during first presenting admission for most patients with acute calculous cholecystitis, variation in the timing of cholecystectomy remains evident worldwide. This dissertation characterizes the extent of variation within a large regional healthcare system, as well as addresses gaps in our current understanding of the clinical consequences and costs associated with early versus delayed cholecystectomy for acute cholecystitis. Methods: A population-based retrospective cohort of patients admitted emergently with acute cholecystitis was identified from administrative databases for the province of Ontario, Canada. First, the extent of variation across hospitals in the performance of early cholecystectomy (within 7 days of emergency department presentation) was characterized. Second, among patients discharged without cholecystectomy following index admission, the risk of recurrent gallstone symptoms over time was quantified. Third, operative outcomes of early cholecystectomy were compared to those of delayed cholecystectomy. Finally, a cost-utility analysis compared healthcare costs and quality-adjusted life-year gains associated with three management strategies for acute cholecystitis: early cholecystectomy, delayed cholecystectomy and watchful waiting, where cholecystectomy is performed urgently if recurrent gallstone symptoms arise. Results: The rate of early cholecystectomy varied widely across hospitals in Ontario (median rate 51%, interquartile range 25-71%), even after adjusting for patient characteristics (median odds ratio 3.7). Among patients discharged without cholecystectomy following an index cholecystitis admission, the probability of a gallstone-related emergency department visit or hospital admission was 19% by 12 weeks following discharge. Early cholecystectomy was associated with a lower risk of major bile duct injury (0.28%vs.0.53%, RR=0.53, 95%CI 0.31–0.90, p=0.025). No significant differences were observed in terms of open cholecystectomy (15%vs.14%, RR=1.07, 95%CI 0.99–1.16, p=0.10) or in conversion among laparoscopic cases (11%vs.10%, RR=1.02, 95%CI 0.93–1.13, p=0.68). Early cholecystectomy was on average less costly ($6,905 per person) and more effective (4.20 QALYs per person) than delayed cholecystectomy ($8,511; 4.18 QALYs per person) or watchful waiting ($7,274; 3.99 QALYs per person). Conclusions: Early cholecystectomy offers a benefit over delayed cholecystectomy in terms of major bile duct injury, mitigates the risk of recurrent symptoms, and is associated with the greatest QALY gains at the least cost.

In medical practice today, diabetic ketoacidosis results in a fatal outcome for 10% of patients, and in the hyperosmolar non-ketoacidosis syndrome 50% die. Thrombotic complications account for a considerable proportion of the deaths of these patients and cerebral manifestations are characteristic of their hyperosmolar state. A strategy which leads to improved management and survival of these severely decompensated patients remains to be found. Recommendations for management of these patients are presently controversial because the aetiology of their cerebral disturbance is ill-defined. This thesis describes novel alterations in blood from patients with ketoacidosis which are particularly associated with the development of the hyperosmolar state. The combination of these abnormalities with other factors present, leads to an unique summated effect on the flow properties of blood during severe diabetic decomposition. Subsequently impaired perfusion could therefore account for the depressed conscious level, strokes and fatal thrombotic phenomena commonly associated with diabetic ketoacidosis. The biochemical alterations underlying the blood abnormalities were studied both in humans and in animals with severe diabetic ketoacidosis. The findings which emerged from the study are particularly relevant to planning treatment and monitoring the pathophysiological response of vital tissue in these patients. It is possible that we can reduce the mortality of these serious medical conditions and improve the outlook for the diabetic individual if we elucidate the underlying pathophysiological changes and adjust treatment accordingly.

No description available.

Background: Survivors of severe acute kidney injury remain at high risk of death well-after apparent recovery from the initial event. Methods: We conducted a cohort study of hospitalized adults in Ontario from 1996 to 2008 with acute kidney injury who received temporary dialysis and survived for 90 days following discharge independent from dialysis. The exposure was nephrology follow-up. We used propensity scores to match individuals with early nephrology follow-up to those without. The primary outcome was time to mortality. Results : We identified 3877 patients with acute kidney injury who met the eligibility criteria. A total of 1583 patients had nephrology follow. The incidence of all-cause mortality was lower in those with early nephrology follow-up as compared to those without early follow-up (8.4 vs. 10.6 per 100 person-years, HR 0.76 (95% CI 0.62-0.93)). Conclusions: Nephrology follow-up after hospitalization with acute kidney injury and temporary dialysis was associated with improved survival.

Background: Survivors of severe acute kidney injury remain at high risk of death well-after apparent recovery from the initial event. Methods: We conducted a cohort study of hospitalized adults in Ontario from 1996 to 2008 with acute kidney injury who received temporary dialysis and survived for 90 days following discharge independent from dialysis. The exposure was nephrology follow-up. We used propensity scores to match individuals with early nephrology follow-up to those without. The primary outcome was time to mortality. Results : We identified 3877 patients with acute kidney injury who met the eligibility criteria. A total of 1583 patients had nephrology follow. The incidence of all-cause mortality was lower in those with early nephrology follow-up as compared to those without early follow-up (8.4 vs. 10.6 per 100 person-years, HR 0.76 (95% CI 0.62-0.93)). Conclusions: Nephrology follow-up after hospitalization with acute kidney injury and temporary dialysis was associated with improved survival.

Introduction: Despite evidence in favour of cholecystectomy early during first presenting admission for most patients with acute calculous cholecystitis, variation in the timing of cholecystectomy remains evident worldwide. This dissertation characterizes the extent of variation within a large regional healthcare system, as well as addresses gaps in our current understanding of the clinical consequences and costs associated with early versus delayed cholecystectomy for acute cholecystitis. Methods: A population-based retrospective cohort of patients admitted emergently with acute cholecystitis was identified from administrative databases for the province of Ontario, Canada. First, the extent of variation across hospitals in the performance of early cholecystectomy (within 7 days of emergency department presentation) was characterized. Second, among patients discharged without cholecystectomy following index admission, the risk of recurrent gallstone symptoms over time was quantified. Third, operative outcomes of early cholecystectomy were compared to those of delayed cholecystectomy. Finally, a cost-utility analysis compared healthcare costs and quality-adjusted life-year gains associated with three management strategies for acute cholecystitis: early cholecystectomy, delayed cholecystectomy and watchful waiting, where cholecystectomy is performed urgently if recurrent gallstone symptoms arise. Results: The rate of early cholecystectomy varied widely across hospitals in Ontario (median rate 51%, interquartile range 25-71%), even after adjusting for patient characteristics (median odds ratio 3.7). Among patients discharged without cholecystectomy following an index cholecystitis admission, the probability of a gallstone-related emergency department visit or hospital admission was 19% by 12 weeks following discharge. Early cholecystectomy was associated with a lower risk of major bile duct injury (0.28%vs.0.53%, RR=0.53, 95%CI 0.31–0.90, p=0.025). No significant differences were observed in terms of open cholecystectomy (15%vs.14%, RR=1.07, 95%CI 0.99–1.16, p=0.10) or in conversion among laparoscopic cases (11%vs.10%, RR=1.02, 95%CI 0.93–1.13, p=0.68). Early cholecystectomy was on average less costly ($6,905 per person) and more effective (4.20 QALYs per person) than delayed cholecystectomy ($8,511; 4.18 QALYs per person) or watchful waiting ($7,274; 3.99 QALYs per person). Conclusions: Early cholecystectomy offers a benefit over delayed cholecystectomy in terms of major bile duct injury, mitigates the risk of recurrent symptoms, and is associated with the greatest QALY gains at the least cost.

Understanding the nature and timing of leukaemogenic events during the development of childhood acute lymphoblastic leukaemia (ALL) will enable intervention that could prevent ALL in the future. We hypothesised that 9p21 deletion in childhood ALL may unmask predisposing genetic events that would allow us to determine the "nature" of initiating events in childhood ALL; whereas the inclusion, or exclusion, of random �N� nucleotides in normal immunoglobulin gene rearrangements from the developing fetus and the expression of terminal deoxynucleotidyl transferase (TdT) in fetal lymphocytes may allow us to unmask the developmental window during which the first transforming leukaemic event occurs in a pre-leukaemic B cell. The most frequent genetic abnormality in childhood ALL is deletion of chromosome 9p21, with the minimal region of deletion including the CDKN2-locus, making genes at this locus candidates for a predisposing genetic event in ALL. To determine whether genomic imprinting might be involved in ALL at the 9p21 locus we investigated the imprinting status of the candidate genes CDKN2A, CDKN2B and ARF. No evidence for genomic imprinting of ARF was found in this study. Because no expressed polymorphisms could be identified for CDKN2B, and CDKN2A expression was too low in normal tissues, the imprinting status of these genes could not be evaluated. Furthermore investigations in our laboratory have been unable to find genomic imprinting at any of these genes in mice. However, we have shown variation in allelic expression of ARF, which suggests a role for ARF haploinsufficiency in the onset of childhood ALL. A key feature of early human fetal lymphoid development is the absence of random �N� nucleotides between the rearranged V[H], D[H] and J[H] gene segments. The addition of �N� nucleotides at these junctions requires the enzyme terminal deoxynucleotidyl transferase (TdT). TdT is reported to not be expressed during early fetal lymphopoiesis but has been observed by the end of the first trimester, but data are sparse. The reported absence of N nucleotides in the majority of childhood ALLs suggests an early fetal origin. By defining the window-in-time during which TdT-negative B cell development occurs, we will be able to refine the timing of the origin of the B cells that give rise to ALL. Therefore we have sequenced and analysed the V[H]-DJ[H] and D[H]-J[H] junctions from immunoglobulin rearrangements in developing B cells in normal human fetuses aged from 5.1 to 11 weeks gestation. In this study 73 fetal IgH gene rearrangements were amplified from 21 different fetal liver samples. Only eight of the seventy-three rearrangements (11%) analysed in this study had no �N� nucleotides at the N1 (D[H]-J[H]) junction. This finding contrasts with the 24-28% of fetal rearrangements with no �N� nucleotides that have been reported in the literature. Furthermore, �N� nucleotides were shown to be present in the earliest sample, 5.1 weeks gestation. TdT expression was demonstrated by immunohistochemistry at 7.3 weeks and by RT-PCR at 8.3 weeks. B cell development in the fetal liver was detected as early as 6.5 weeks using flow cytometric analysis. Then, IgH gene rearrangements from 99 cases of childhood ALL were analysed. In total, 134 clone-specific IgH gene rearrangements were examined in this study. No association was found between the number of �N� nucleotides from complete and incomplete rearrangements at either the N1 (D[H]-J[H]) or N2 (V[H]-DJ[H]) junctions. Nor was any association observed between ALLs from children [less than or equal to] 3 years of age and those >3 years of age at diagnosis. These findings indicate that ALL IgH rearrangements do not have the paucity of �N� nucleotides that has been previously reported. The findings in this thesis suggest that there is no TdT-negative timepoint during B cell development and that there is no paucity of �N� nucleotides at the N1 junction in either fetal or childhood ALL IgH gene rearrangements.

Proefschrift Universiteit van Amsterdam. / Met lit.opg. en een samenvatting in het Nederlands.

Thesis Erasmus University Rotterdam. / With bibliogr., with a summary in Dutch.