A model for undertaking effectiveness and cost-effectiveness analyses of primary preventive strategies in cardiovascular disease.

BACKGROUND: Clinical trials generally provide strong evidence of the efficacy of cardiovascular preventive strategies, but poor evidence of their 'real-life' utility, in terms of effectiveness and cost-effectiveness. DESIGN AND METHODS: The Cardiovascular Disease Prevention Model is presented, which represents a means of extrapolating the results of clinical trials to a broader, more relevant context. The model is configured as a decision-analysis tree, and underpinned by life-course analysis and Markov processes. Uncertainty and sensitivity analyses are undertaken by Monte Carlo simulation. RESULTS: The results of effectiveness and cost-effectiveness analyses of a hypothetical preventive intervention are presented to demonstrate the outputs of the model. The potential impact and efficiency of the intervention are made obvious. CONCLUSIONS: The Cardiovascular Disease Prevention Model offers a means to translate the results of trials of cardiovascular preventive interventions, in order to inform clinical and public health practice, as well as health policy.     

Differential cell cycle phase specificity for neoplastic transformation and mutation to ouabain resistance induced by N-methyl-N''-nitro-N-nitrosoguanidine in synchronized C3H10T 1/2 C18 cells.

The transformable mouse embryo fibroblast cell line C3H10T 1/2 C18 has been employed to study the induction by the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) of morphological transformation and mutation to ouabain resistance throughout the cell cycle. Cells were synchronized by means of isoleucine deprivation for 24 hr and initiated DNA synthesis with a high degree of synchrony 7.5 hr after release of the isoleucine block. At various intervals throughout the cell cycle cultures were treated with MNNG at 1.0 microgram/ml and the induction of cytotoxicity, morphological transformation, and ouabain-resistant colonies was determined. All three phenomena exhibited marked cell-cycle phase dependency. Maximal induction of transformation occurred in cultured treated 7.5 hr after release from isoleucine deprivation, when the cells were at the G1/S boundary. In contrast, induction of ouabain-resistant colonies was at a minimum at the time of maximal induction of transformation, and peak induction of ouabain resistance did not occur until 16-18 hr after release from the isoleucine block, when cells were in late S phase. A close correlation was observed between the induction of cytotoxicity and of ouabain-resistant mutants. The results suggest that differences exist in the production or cellular processing of the various early lesions.     

Autonomic Arousal During Actigraphically Estimated Waking and Sleep in Male Veterans With PTSD

Physiological hyperarousal is manifested acutely by increased heart rate, decreased respiratory sinus arrhythmia, and increased skin conductance level and variability. Yet it is uncertain to what extent such activation occurs with the symptomatic hyperarousal of posttraumatic stress disorder (PTSD). We compared 56 male veterans with current PTSD to 54 males who never had PTSD. Subjects wore ambulatory devices that recorded electrocardiograms, finger skin conductance, and wrist movement while in their normal environments. Wrist movement was monitored to estimate sleep and waking periods. Heart rate, but not the other variables, was elevated in subjects with PTSD equally during waking and during actigraphic sleep (effect sizes, Cohen's d, ranged from 0.63 to 0.89). The length of the sleep periods and estimated sleep fragmentation did not differ between groups. Group heart rate differences could not be explained by differences in body activity, PTSD hyperarousal symptom scores, depression, physical fitness, or antidepressant use.     

Construct validity of individual and summary performance metrics associated with a computer-based laparoscopic simulator

Background

Computer-based surgical simulators capture a multitude of metrics based on different aspects of performance, such as speed, accuracy, and movement efficiency. However, without rigorous assessment, it may be unclear whether all, some, or none of these metrics actually reflect technical skill, which can compromise educational efforts on these simulators. We assessed the construct validity of individual performance metrics on the LapVR simulator (Immersion Medical, San Jose, CA, USA) and used these data to create task-specific summary metrics.

Methods

Medical students with no prior laparoscopic experience (novices, N = 12), junior surgical residents with some laparoscopic experience (intermediates, N = 12), and experienced surgeons (experts, N = 11) all completed three repetitions of four LapVR simulator tasks. The tasks included three basic skills (peg transfer, cutting, clipping) and one procedural skill (adhesiolysis).

Results

We selected 36 individual metrics on the four tasks that assessed six different aspects of performance, including speed, motion path length, respect for tissue, accuracy, task-specific errors, and successful task completion. Four of seven individual metrics assessed for peg transfer, six of ten metrics for cutting, four of nine metrics for clipping, and three of ten metrics for adhesiolysis discriminated between experience levels. Time and motion path length were significant on all four tasks. We used the validated individual metrics to create summary equations for each task, which successfully distinguished between the different experience levels.

Conclusion

Educators should maintain some skepticism when reviewing the plethora of metrics captured by computer-based simulators, as some but not all are valid. We showed the construct validity of a limited number of individual metrics and developed summary metrics for the LapVR. The summary metrics provide a succinct way of assessing skill with a single metric for each task, but require further validation.     

The role of mycophenolate mofetil in kidney transplantation revisited

Since its regulatory approval in 1995, mycophenolate mofetil (MMF) has largely replaced azathioprine (AZA) as the anti-metabolite immunosuppressive of choice in kidney transplantation. While the initial industry-sponsored clinical trials suggested strong reductions in the incidence of acute rejection in the first six months post transplantation, long-term follow-up studies have failed to demonstrate a similar degree of benefit in overall graft and patient survival. In addition, several subsequent studies have raised questions on the potential attenuating effects of calcineurin inhibitor choice on MMF efficacy when compared to AZA. This review will revisit the question of whether the available evidence continues to support the superiority of MMF over AZA in kidney transplantation outcomes while comprehensively reviewing the available evidence from clinical trial data, systematic reviews, and registry studies.     

Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia

Autosomal-dominant familial hypercholesterolemia (FH) is characterized by increased plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and a substantial risk to develop cardiovascular disease. Causative mutations in three major genes are known: the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB) and the proprotein convertase subtilisin/kexin 9 gene (PCSK9). We clinically characterized 336 patients suspected to have FH and screened them for disease causing mutations in LDLR, APOB, and PCSK9. We genotyped six single nucleotide polymorphisms (SNPs) to calculate a polygenic risk score for the patients and 1985 controls. The 117 patients had a causative variant in one of the analyzed genes. Most variants were found in the LDLR gene (84.9%) with 11 novel mutations. The mean polygenic risk score was significantly higher in FH mutation negative subjects than in FH mutation positive patients (P < .05) and healthy controls (P < .001), whereas the score of the two latter groups did not differ significantly. However, the score explained only about 3% of the baseline LDL-C variance. We verified the previously described clinical and genetic variability of FH for German hypercholesterolemic patients. Evaluation of a six-SNP polygenic score recently proposed for clinical use suggests that it is not a reliable tool to classify hypercholesterolemic patients.     

Progressive Nephron Loss in Aging Kidneys: Clinical–Structural Associations Investigated by Two Anatomical Methods

Two major studies of structural changes associated with aging in human kidneys are reviewed and new information presented. The studies are the Monash University stereologically analyzed series of 319 autopsy kidneys from the United States in which 44% were white and the Mayo Clinic CT angiogram/biopsy analysis of 1,388 US kidney donors in which 97% were white. Hypertension rates in the Monash series were 48% and included moderate and severe hypertension. In the Mayo Clinic study, 12% had mild hypertension. The studies showed no relationship between glomerular number and hypertension except for a weak relationship with older white women in the Monash series. An inverse relationship was present between glomerular number and glomerular volume, a reciprocity that tended to enhance glomerular mass and by inference filtration capacity with lower nephron numbers. This relationship seemed to be present whether low nephron numbers were intrinsic or acquired. In the Mayo Clinic studies, pretransplant iothalamate clearances demonstrated that single nephron (SN) glomerular filtration rates (GFR) were similar throughout the range of glomerular number in subjects younger than 70 years, but that increased SNGFR correlated with nephron hypertrophy and increased nephrosclerosis particularly at 70 years of age and over. Hypertension at least through middle age cannot be related to a deficiency of glomeruli, but glomeruli are lost with later aging in association with adaptive nephron hypertrophy that can maintain GFR near normal. These studies help define an age-related nephropathy that overlaps with hypertension as a potential cause of end-stage renal disease when glomerulosclerosis is advanced.     

Analysis of structure and gene expression in developing kidneys of male and female rats exposed to low protein diets in utero

A maternal low protein (LP) diet in rodents often results in low nephron endowment and renal pathophysiology in adult life, with outcomes often differing between male and female offspring. Precisely how a maternal LP diet results in low nephron endowment is unknown. We conducted morphological and molecular studies of branching morphogenesis and nephrogenesis to identify mechanisms and timepoints that might give rise to low nephron endowment. Sprague–Dawley rats were fed a normal protein (19.4% protein, NP) or LP (9% protein) diet for 3 weeks prior to mating and throughout gestation. Embryonic day 14.25 (E14.25) kidneys from males and females were either cultured for 2 days after which branching morphogenesis was quantified, or frozen for gene expression analysis. Real-time PCR was used to quantify expression of key nephrogenesis and branching morphogenesis genes at E14.25 and 17.25. At E17.25, nephron number was determined in fixed tissue. There was no effect of either maternal diet or sex on branching morphogenesis. Nephron number at E17.25 was 14% lower in male and female LP offspring than in NP controls. At E14.25 expression levels of genes involved in branching morphogenesis (Gfrα1, Bmp4, Gdnf) and nephrogenesis (Hnf4a, Pax2, Wnt4) were similar in the dietary groups, but significant differences between sexes were identified. At E17.25, expression of Gfrα1, Gdnf, Bmp4, Pax2 and Six2 was lower in LP offspring than NP offspring, in both male and female offspring. These findings provide new insights into how a LP diet leads to low nephron endowment and renal sexual dimorphism.