One Community’s Effort to Control Genetic Disease

In 1989, we established a small community health clinic to provide care for uninsured Amish and Mennonite children with genetic disorders. Over 20 years, we have used publicly available molecular data and sophisticated technologies to improve diagnostic efficiency, control laboratory costs, reduce hospitalizations, and prevent major neurological impairments within a rural underserved community. These actions allowed the clinic’s 2010 operating budget of $1.5 million to save local communities an estimated $20 to $25 million in aggregate medical costs. This exposes an unsettling fact: our failure to improve the lot of most people stricken with genetic disease is no longer a matter of scientific ignorance or prohibitive costs but of choices we make about how to implement existing knowledge and resources.KEY FINDINGS

• ▪ Successful integration of molecular technologies into primary care can improve diagnostic efficiency, control laboratory costs, reduce hospitalizations, and prevent catastrophic clinical outcomes.
• ▪ Population-specific genetic information is a strong foundation for regional preventative health services. New high-density, low-cost genotyping methods afford the opportunity to actuate this model of care in small underserved communities throughout the world.
• ▪Scaling molecular studies to small populations and even individual families is a reasonable scientific alternative to large scale genome wide association studies, and may help solve some intractable problems in human disease research and public health.

“I have no doubt that it is possible to give a new direction to technological development, a direction that shall lead it back to the real needs of man.”E. F. Schumacher, 19741“Stunning scientific and technological advances in genetics will mean little if they do not benefit people.”A. Guttmacher et al., 20012

     

Maternal Concentrations of Polyfluoroalkyl Compounds during Pregnancy and Fetal and Postnatal Growth in British Girls

Background: Prenatal exposures to polyfluoroalkyl compounds (PFCs) may be associated with adverse changes in fetal and postnatal growth.Objective: We explored associations of prenatal serum concentrations of perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexane sulfonate (PFHxS) with fetal and postnatal growth in girls.Methods: We studied a sample of 447 singleton girls and their mothers participating in the Avon Longitudinal Study of Parents and Children (ALSPAC). Data on weight and length were obtained at birth and at 2, 9, and 20 months. Serum samples were obtained in 1991–1992, from mothers during pregnancy. We explored associations between prenatal PFC concentrations and weight at birth as well as longitudinal changes in weight-for-age SD scores between birth and 20 months.Results: PFOS (median, 19.6 ng/mL), PFOA (median, 3.7 ng/mL), and PFHxS (median, 1.6 ng/mL) were detected in 100% of samples. On average, girls born to mothers with prenatal concentrations of PFOS in the upper tertile weighed 140 g less [95% confidence interval (CI): –238, –42] at birth than girls born to mothers with concentrations in the lower tertile in adjusted models. Similar patterns were seen for PFOA (–133 g; 95% CI: –237, –30) and PFHxS (–108 g; 95% CI: –206, –10). At 20 months, however, girls born to mothers with prenatal concentrations of PFOS in the upper tertile weighed 580 g more (95% CI: 301, 858) when compared with those in the lower tertile. No differences in weight were found for PFOA and PFHxS.Conclusions: Girls with higher prenatal exposure to each of the PFCs examined were smaller at birth than those with lower exposure. In addition, those with higher exposure to PFOS were larger at 20 months.     

Handling Cases of ‘Medical Futility’

Medical futility is commonly understood as treatment that would not provide for any meaningful benefit for the patient. While the medical facts will help to determine what is medically appropriate, it is often difficult for patients, families, surrogate decision-makers and healthcare providers to navigate these difficult situations. Often communication breaks down between those involved or reaches an impasse. This paper presents a set of practical strategies for dealing with cases of perceived medical futility at a major cancer center.     

Effect of plant sterols in combination with other cholesterol-lowering foods

The National Cholesterol Education Program Adult Treatment Panel III guidelines advocate effective combinations of cholesterol-lowering dietary components. This approach (dietary portfolio) produces large reductions in serum cholesterol, but the contribution of individual components remains to be established. We therefore assessed the effect of eliminating one out of the 4 dietary portfolio components. Plant sterols were selected because at 2 g/d, they have been reported to reduce low-density lipoprotein cholesterol (LDL-C) by 9% to 14%. Forty-two hyperlipidemic subjects were prescribed diets high in soy protein (22.5 g/1000 kcal), viscous fibers (10 g/1000 kcal), and almonds (23 g/1000 kcal) for 80 weeks. Subjects were instructed to take these together with plant sterols (1.0 g/1000 kcal) except between weeks 52 and 62. While taking the full dietary portfolio, including plant sterols, mean LDL-C reduction from baseline was 15.4% +/- 1.6% (P < .001). After sterol elimination, mean LDL-C reduction was 9.0% +/- 1.5% (P < .001). Comparable LDL-C reductions were also seen for the 18 subjects with a complete data set: on plant sterols, 16.7% +/- 3.1% (P < .001) and off plant sterols, 10.3% +/- 2.6% (P < .001), resulting in a 6.3% +/- 2.0% (P = .005) difference attributable to plant sterols. Compliance in this group of 18 was 67.0% +/- 5.9% for plant sterols and 61.9% +/- 4.8% for the other components. In combination with other cholesterol-lowering foods and against the background of a low-saturated fat diet, plant sterols contributed over one third of the LDL-C reduction seen with the dietary portfolio after 1 year of following dietary advice.     

Consequences of restenosis after coronary angioplasty

The consequences of restenosis after angioplasty were evaluated in 466 patients who had coronary angiography 3 to 12 months after successful coronary angioplasty and were followed long term. The 236 subjects with restenosis resembled the 230 without restenosis with respect to age, sex, presence of multivessel disease, mean ejection fraction, prior myocardial infarction, prior coronary artery bypass grafting, and completeness of revascularization. The 5-year relative risk of revascularization for patients with restenosis markedly exceeded that for patients without restenosis. The relative risk of repeat angioplasty in the former group was 4.26 times that in the latter group (95% confidence interval, 2.80 to 6.51), and the risk of coronary artery bypass grafting in patients with restenosis was 3.68 (95% confidence interval, 2.16 to 6.28). There was no difference between the 2 groups in the relative risk of myocardial infarction or death. When the completeness of revascularization was considered, patients with incomplete revascularization and restenosis had the worst outcomes, with 50% needing coronary artery bypass grafting within 5 years. Early restenosis markedly increases the probability of revascularization, but it has little effect on infarction or mortality. Even when early restenosis is absent, further revascularization procedures are still frequent. A solution to the problem of restenosis might reduce by half the need for revascularization during the subsequent 5 years.     

Atrial resting membrane potential confers sodium current sensitivity to propafenone,flecainide and dronedarone

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Percutaneous transluminal angioplasty in patients with multivessel coronary disease: how important is complete revascularization for cardiac event-free survival?

The relative influences of revascularization status and baseline characteristics on long-term outcome were examined in 867 patients with multivessel coronary disease who had undergone successful coronary angioplasty. These patients represented 83% of a total of 1,039 patients in whom angioplasty had been attempted with an in-hospital mortality and infarction rate of 2.5% and 4.8%, respectively. Emergency coronary bypass surgery was needed in 4.9%. Of the 867 patients, 41% (group 1) were considered to have complete revascularization and 59% (group 2) to have incomplete revascularization. Univariate analysis revealed major differences between these two groups with patients in group 2 characterized by advanced age, more severe angina, a greater likelihood of previous coronary surgery and infarction, more extensive disease and poorer left ventricular function. Over a mean follow-up period of 26 months, the probability of event-free survival was significantly lower for group 2 only with respect to the need for coronary artery surgery (p = 0.004) and occurrence of severe angina (p = 0.04). The difference in mortality was of borderline significance (p = 0.051) and there were no significant differences between groups 1 and 2 in either the incidence of myocardial infarction or the need for repeat angioplasty. Multivariate analysis identified independent baseline predictors of late cardiac events that were then used to adjust the probabilities of event-free survival. This adjustment effectively removed any significant influence of completeness of revascularization on event-free survival for any of the above end points including the combination of death, myocardial infarction and need for coronary artery surgery. Therefore, late outcome in these patients is not significantly influenced by revascularization status but depends more on baseline patient characteristics.     

Evaluation of long-term survival after successful percutaneous coronary intervention among patients with chronic renal failure

We studied the long-term outcomes after percutaneous coronary intervention in dialysis patients and in patients with chronic renal failure (CRF) (serum creatinine > or = 3.0 mg/dl). All-cause mortality at 1 year was 2.9% for the control group, 16.2% for the group with CRF, and 14.1% for dialysis patients. Cardiac mortality at 1 year was 1.9% for ther control group, 15.2% for the group with CRF, and 10.0% for dialysis patients.