Characterizing a "Big Data" Cohort of Over 200,000 Low-Income U.S. Infants and Children for Obesity Research: The ADVANCE Early Life Cohort.

Introduction Low-income populations have elevated exposure to early life risk factors for obesity, but are understudied in longitudinal research. Our objective was to assess the utility of a cohort derived from electronic health record data from safety net clinics for investigation of obesity emerging in early life. Methods We examined data from the PCORNet ADVANCE Clinical Data Research Network, a national network of Federally-Qualified Health Centers serving >1.7 million safety net patients across the US. This cohort includes patients who, in 2012-2014, had ≥1 valid body mass index measure when they were 0-5 years of age. We characterized the cohort with respect to factors required for early life obesity research in vulnerable subgroups: sociodemographic diversity, weight status based on World Health Organization (<2 years) or Centers for Disease Control (≥2 years) growth curves, and data longitudinality. Results The cohort includes 216,473 children and is racially/ethnically diverse (e.g., 17.9% Black, 45.4% Hispanic). A majority (56.9%) had family incomes below the Federal Poverty Level (FPL); 32% were <50% of FPL. Among children <2 years, 7.6 and 5.3% had high and low weight-for-length, respectively. Among children 2-5 years, 15.0, 12.7 and 2.4% were overweight, obese, and severely obese, respectively; 5.3% were underweight. In the study period, 79.2% of children had ≥2 BMI measures. Among 4-5 year olds, 21.9% had >1 BMI measure when they were <2 years. Discussion The ADVANCE Early Life cohort offers unique opportunities to investigate early life determinants of obesity in the understudied population of low income and minority children.

Evaluating community health centers' adoption of a new global capitation payment (eCHANGE) study protocol.

Primary care patient-centered medical homes (PCMHs) are an effective healthcare delivery model. Evidence regarding the most effective payment models for increased coordination efforts is sparse. This protocol paper describes the evaluation of an Alternative Payment Methodology (APM) implemented in a subset of Oregon community health centers (CHCs), using a prospective matched observational design. The APM is a primary care payment reform intervention that changed Oregon's Medicaid payment for several CHCs from fee-for-service reimbursement to a per-member-per-month capitated payment. We will implement a difference-in-difference analytic approach to evaluate pre-post APM changes between intervention and control groups, including: 1) clinic-level outcomes, 2) patient-level clinical outcomes, and 3) patient-level econometric outcomes. Findings from the project will be of national significance, as there is a need for evidence regarding how novel payment methods might enhance PCMH capabilities and support their capacity to produce better quality and outcomes. If this capitated payment method is proven effective, study findings will inform dissemination of similar APMs nationwide.

Angiotensin-converting enzyme and cardiovascular disease risk.

The published studies of the association of the angiotensin-converting enzyme (ACE) genotype with cardiovascular disease have used many different diagnostic criteria for cardiovascular disease and have drawn their samples from different patient groups and different populations. This review examines the association of the ACE DD genotype with cardiovascular disease risk in studies grouped by their case criterion, the geographical region of the population samples, and by the cardiovascular risk level of the patient sample. In studies where the underlying odds ratios are determined to be homogeneous, the overall odds ratios for myocardial infarction and coronary artery disease with regard to the ACE DD genotype are estimated using the Mantel-Haenszel method.

In vivo observations of terminal Schwann cells at normal, denervated, and reinnervated mouse neuromuscular junctions.

We found a low-molecular-mass, fluorescent dye, Calcein blue am ester (CB), that labels terminal Schwann cells at neuromuscular junctions in vivo without damaging them. This dye was used to follow terminal Schwann cells at neuromuscular junctions in the mouse sternomastoid muscle over periods of days to months. Terminal Schwann cell bodies and processes were stable in their spatial distribution over these intervals, with processes that in most junctions were precisely aligned with motor nerve terminal branches. Three days after nerve cut, the extensive processes elaborated by terminal Schwann cells in denervated muscle were labeled by CB. The number and length of CB-labeled terminal Schwann cell processes decreased between 3 days and 1 month after denervation, suggesting that terminal Schwann cell processes are only transiently maintained in the absence of innervation. During reinnervation after nerve crush, however, terminal Schwann cell processes were extended in advance of axon sprouts, and these processes persisted until reinnervation was completed. By viewing the same junctions twice during reinnervation, we directly observed that axon sprouts used existing Schwann cell processes and chains of cell bodies as substrates for outgrowth. Thus, CB can be used to monitor the dynamic behavior of terminal Schwann cells, whose interactions with motor axons and their terminals are important for junction homeostasis and repair.

Angiotensin-converting enzyme DD genotype and cardiovascular disease in heterozygous familial hypercholesterolemia.

BACKGROUND: Controversy exists as to whether the deletion/deletion genotype (DD) of the ACE gene polymorphism increases the risk of myocardial infarction (MI). Studies have suggested that the ACE DD genotype is associated with increased plaque instability. We hypothesized that the ACE DD genotype may increase the risk of myocardial infarction and coronary heart disease (CHD) in patients with heterozygous familial hypercholesterolemia (FH) or familial defective apolipoprotein B-100 (FDB) who, as a group, are at high risk of having lipid-rich plaques in their coronary arteries. METHODS AND RESULTS: We determined the ACE genotypes and incidence of MI or surgical intervention for CHD in 213 adult patients with heterozygous FH or FDB. The incidence of MI in 35 male patients who carried the ACE DD genotype was 2.5 times that observed in male patients with the II or DI genotypes, and the incidence of CHD in male patients with the DD genotype was 2.2 times higher than in those who had ACE DI+II. The potential effects of ACE genotype on CHD could not be directly compared in female patients because of a disparity in the smoking history of the genotypic groups. From logistic regression analysis, the estimated odds ratio associated with the ACE DD genotype was 2.57 for MI and 2.21 for CHD adjusted for age, sex, and smoking history. CONCLUSIONS: The ACE DD genotype is associated with an increased risk of MI and CHD in patients with heterozygous FH or FDB. Determination of the ACE genotype in asymptomatic FH and FDB patients provides an additional means to identify those patients at greatest risk for the premature development of CHD.

Stabilization of acetylcholine receptors by exogenous ATP and its reversal by cAMP and calcium.

Innervation of the neuromuscular junction (nmj) affects the stability of acetylcholine receptors (AChRs). A neural factor that could affect AChR stabilization was studied using cultured muscle cells since they express two distinct populations of AChRs similar to those seen at the nmjs of denervated muscle. These two AChR populations are (in a ratio of 9 to 1) a rapidly degrading population (Rr) with a degradation half-life of approximately 1 d and a slowly degrading population (Rs) that can alternate between an accelerated form (half-life approximately 3-5 d) and a stabilized form (half-life approximately 10 d), depending upon the state of innervation of the muscle. Previous studies have shown that elevation of intracellular cAMP can stabilize the Rs, but not the Rr. We report here that in cultured rat muscle cells, exogenous ATP stabilized the degradation half-life of Rr and possibly also the Rs. Furthermore, pretreatment with ATP caused more stable AChRs to be inserted into the muscle membrane. Thus, in the presence of ATP, the degradation rates of the Rr and Rs overlap. This suggests that ATP released from the nerve may play an important role in the regulation of AChR degradation. Treatment with either the cAMP analogue dibutyryl-cAMP (dB-cAMP) or the calcium mobilizer ryanodine caused the ATP-stabilized Rr to accelerate back to a half-life of 1 d. Thus, at least three signaling systems (intracellular cAMP, Ca2+, and extracellular ATP) have the potential to interact with each other in the building of an adult neuromuscular junction.

Creutzfeldt-Jakob disease: current U.S. policy to further reduce the possible risk of transmission by transfusion.

Because the results of epidemiological and subhuman primate studies conducted over the last quarter of a century have failed to show a statistically significant risk of transmission of CJD by transfusion of blood components or plasma derivatives, the FDA's position is that only a theoretical low risk of CJD transmission cannot be excluded at this time. Consequently, FDA issued two memoranda on 8 August 1995 as updated interim policy documents recommending: (1) permanent deferral from donating blood or plasma for all persons who state at the time of donation, or for whom post donation information becomes available, that they have ever received pit-hGh, a dura mater transplant graft, or have a blood relative history of CJD, unless this increased risk for CJD is excluded on the basis of genetic analysis testing; (2) the quarantining of all undistributed in-date units of blood or blood components collected from either of these three groups of donors together with notification of all consignees of such in-date units so that distributed units also can be quarantined and recipient tracing and notification may be effected, and (3) the withdrawal from distribution and quarantining of in-date plasma derivative products derived from plasma pools containing a unit from either of these three groups of donors at known high risk for CJD, or donors subsequently diagnosed as having CJD. Consignees of these products are to be notified in order that they, in turn, may inform physicians or other qualified personnel responsible for the care of product recipients to provide counseling as deemed medically appropriate. The 'family history of CJD' criterion was further clarified to mean a 'history of CJD in 2 or more family members' during the BPAC meeting of 14 December 1995. In a workshop meeting on 29 January 1996 the FDA urged that additional laboratory animal data be generated by plasma derivative manufacturers in order to ascertain if the sterilization steps used in their production of plasma derivatives further reduce the risk of transmission of CJD.

Safety monitoring and epidemiological surveillance of blood transfusion in the United States.

Safety monitoring and epidemiological surveillance of blood transfusion in the United States is complex and involves government agencies and independent organizations. Several systems of control are in place nationwide to ensure that blood, blood components, and plasma derivatives meet prescribed standards. Control and surveillance of drugs that are biologics, which include human blood, blood components and plasma derivatives, are exercised by the Food and Drug Administration. Epidemiological surveillance involves several agencies and organizations that constitute a network capable of rapidly detecting unusual adverse events.

Diagnosis of intracranial lymphoma in patients with AIDS: value of 201TI single-photon emission computed tomography.

OBJECTIVE: Although the prevalence of intracranial lymphoma is high among patients with AIDS, current imaging techniques are not reliable for differentiating this tumor from other common nonneoplastic lesions, such as those seen in toxoplasmosis. The purpose of this study was to prospectively investigate the use of 201Tl single-photon emission computed tomography (SPECT) in identifying intracranial lymphoma in patients with AIDS. SUBJECTS AND METHODS: Thirteen patients with AIDS and intracranial masses underwent 201Tl imaging with a three-headed SPECT camera. Sic of the 13 were subsequently proved to have lymphoma. Studies were interpreted prospectively as showing tumor if uptake of 201Tl was increased in the region where the lesion was seen on MR images. A lesion-to-nonlesion uptake ratio (counts/pixel) was calculated retrospectively. RESULTS: The SPECT images of six patients were interpreted prospectively as showing no lymphoma. Uptake ratios in these six patients were 0.77-1.95 (mean, 1.45). In each, tumor was excluded as a final diagnosis (four had toxoplasmosis, one had progressive multifocal leukoencephalopathy, and one had venous angioma). Among the seven patients with SPECT images interpreted as showing lymphoma, six were later proved to have lymphoma (uptake ratio: mean, 3.65; range, 2.95-4.30; p < .005). The SPECT findings in the seventh patient were classified as false-positive for tumor on the basis of the prospective interpretation of the images; three concurrent infections were found at autopsy. The uptake ratio in this patient was low (1.81), suggesting that quantification might have diagnostic usefulness for improving accuracy. CONCLUSION: This preliminary study indicates that 201Tl SPECT might be a useful, noninvasive method for differentiating intracranial lymphoma from nonneoplastic lesions in patients with AIDS.

Comparative effects of gemfibrozil and clofibrate in type III hyperlipoproteinemia.

Type III hyperlipoproteinemia (dysbetalipoproteinemia) is characterized by elevated concentrations of plasma cholesterol and triglycerides due to an increase in very low density lipoprotein (VLDL) remnant lipoproteins. In a retrospective analysis we observed that in 12 patients with this disorder, gemfibrozil reduced concentrations of total cholesterol, VLDL cholesterol and triglycerides by 48%, 72% and 68%, respectively. These changes were greater than those reported in a similar number of patients treated with clofibrate. Comparative data on the efficacy of different fibrates in this disorder are very limited; to assess this further we have compared the hypolipidemic effects of gemfibrozil (600 mg twice daily) and clofibrate (1 g twice daily) in six patients with well-characterized type III hyperlipoproteinemia. Baseline values were obtained after at least 8 weeks on diet and treatment values were obtained after 6 and 8 weeks of treatment with each drug. Treatment with clofibrate and gemfibrozil both resulted in significant reductions in the plasma concentrations of total cholesterol (40% and 54%), VLDL cholesterol (59% and 79%) and total triglycerides (48% and 70%), as well as a significant increase in HDL cholesterol (9% and 7%). Gemfibrozil was, however, significantly (P < 0.05) more effective in reducing plasma concentrations of total cholesterol, VLDL cholesterol and triglycerides than was clofibrate, in the same patients.

Two populations of AChR in rat myotubes have different degradation rates and responses to cAMP.

Acetylcholine receptors (AChRs) of rat muscle cells grown in culture for 4 days were labeled with 125I-alpha-bungarotoxin and their degradation rate measured. Two AChR populations, a rapidly degrading one (Rr,t1/2 approximately 1 day) and a slowly degrading one (Rs, t1/2 approximately 4 days) were identified at a ratio of approximately 9 to 1. The degradation rate of the Rs was slowed to a t1/2 of approximately 10 days by cAMP while that of the Rr remained unchanged. These data provide further evidence that two AChR populations with different degradation rates can exist in noninnervated muscle and that they can be further distinguished by their differing response to cAMP. We suggest that the two AChR populations seen in myotubes may be physiologically equivalent to the Rs and Rr components seen at the neuromuscular junction of denervated adult muscle and could thus provide a good model for characterizing the Rr and Rs AChRs.

Quantitation of renal function using radioisotopic techniques.

Radioisotopic methods are practical for clinical use because they do not require continuous intravenous infusion or urine collection. This obviously is of great advantage in infants and small children, in whom accurate urine collection is difficult, but the techniques apply to adults as well. The ability to determine individual kidney function is a major benefit. Accuracies of the radioisotopic techniques vary but generally are within clinically acceptable ranges. The need for accuracy and reproducibility can be balanced with the desire for speed and convenience when choosing among the different techniques. Methods that use plasma sampling provide greater accuracy and are recommended in cases of severe dysfunction, whereas methods such as Gates' camera method, which eliminates plasma samples, can be completed in minutes. Radioisotopic techniques are most useful in the ranges of mild to moderately decreased function, in which serum creatinine concentration is nondiagnostic, and although they are much less accurate at markedly low renal function levels, so is 24-hour creatinine clearance. In conclusion, radiopharmaceutical agents offer a wide array of possible techniques for simple, accurate, and noninvasive measurement of global as well as individual GFR and ERPF.

Tc-99m MAG3 as an alternative to Tc-99m DTPA and I-131 Hippuran for renal transplant evaluation.

This study investigated the new radiopharmaceutical, Tc-99m mercaptoacetyltriglycine (MAG3), as a possible alternative to Tc-99m DTPA and I-131 Hippuran for renal transplant evaluation. Tc-99m MAG3 and I-131 Hippuran were used sequentially in 19 consecutive patient studies and compared qualitatively and quantitatively. Serum creatinine values ranged from 1.6 mg/dL to 10.3 mg/dL (mean, 5.4 mg/dL). The Tc-99m MAG3 images and time-activity curves were of superior quality (3+) compared to I-131 Hippuran (1-2+). Quantitative analysis of the time to peak activity (Tmax) demonstrated a high correlation and no significant difference for Tc-99m MAG3 (mean, 11.4 min) compared to I-131 Hippuran (mean, 11.2 min). The percentage of peak activity retained at 20 minutes (T20) also showed a high correlation between the two agents; however, Tc-MAG3 showed a significantly slower clearance (T20 mean, 77%) than I-131 Hippuran (mean, 71%). Flow images were judged to be of good quality; however, the first-pass time-activity curves were often different from that seen with Tc-99m DTPA. Interpretation of delayed Tc-99m MAG3 images, for example to diagnose a slow urinary leak, were sometimes complicated by bowel clearance. In conclusion, Tc-99m MAG3 is superior to I-131 Hippuran for evaluation of renal transplant function. Tc-99m is the agent of choice for evaluation of renal transplant blood flow and function.

Effects of electrical stimulation and tetrodotoxin paralysis on antigenic properties of acetylcholine receptors in rat skeletal muscle.

To examine the role of muscle activity in the expression of fetal- and adult-type acetylcholine receptors (AChRs), we studied the effects of muscle stimulation in cell culture and of tetrodotoxin (TTX)-induced paralysis and denervation in adult rat muscles. The AChR content of these muscles was determined using [125I]alpha-bungarotoxin and the proportion of fetal-type receptors was estimated using a radioimmunoprecipitation assay with a myasthenic serum that was highly specific for fetal-type receptors. We found that both stimulated, aneural muscle cells in vitro and inactive muscles in vivo produced predominantly fetal-type AChRs. However the TTX-paralysed muscles had a lower proportion of fetal-type receptors than the denervated muscles. We conclude that neither muscle activity nor innervation alone, but a combination of both, is required for full regulation of AChR antigenicity.

The hypolipidemic effects of lovastatin and clofibrate alone and in combination in patients with type III hyperlipoproteinemia.

The hypolipidemic effects of lovastatin and clofibrate have been evaluated in 12 patients with type III hyperlipoproteinemia. In these patients plasma concentrations of total cholesterol decreased from 500 +/- 56 mg/dL (mean +/- SEM) at baseline to 278 +/- 23 mg/dL on lovastatin (20 mg twice daily), and were 299 +/- 15 mg/dL during treatment with clofibrate (1 g twice daily). Nine patients were treated sequentially with lovastatin at doses of 20 and 40 mg twice daily and clofibrate; in these patients total plasma cholesterol concentrations decreased from 549 +/- 67 mg/dL at baseline to 291 +/- 24 mg/dL on lovastatin (20 mg twice daily), 247 +/- 20 mg/dL (40 mg twice daily) and were 297 +/- 18 mg/dL on monotherapy with clofibrate. Concentrations of very-low-density lipoprotein (VLDL) cholesterol were similar on clofibrate and the higher dose of lovastatin, whereas concentrations of low-density lipoprotein (LDL) cholesterol were significantly lower on lovastatin. In six patients who remained hyperlipidemic on monotherapy with either drug, combination drug therapy with lovastatin (20 mg twice daily) plus clofibrate reduced plasma concentrations of total cholesterol from 635 +/- 79 mg/dL to 205 +/- 11 mg/dL. No patients were discontinued from single or combined drug therapy and no significant biochemical abnormalities were observed. The results of this study demonstrate the potential usefulness of lovastatin in the therapy of type III hyperlipoproteinemia and indicate that, in selected patients who remain hypercholesterolemic on monotherapy with either clofibrate or lovastatin, combination drug therapy with both of these drugs is effective in further reducing plasma concentrations of total, VLDL, and LDL cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of apolipoprotein E phenotype on the response to lovastatin therapy in patients with heterozygous familial hypercholesterolemia.

Apolipoprotein E (apo E) phenotypes have been previously shown to influence plasma lipoprotein concentrations in normal populations and to affect the response to some lipid lowering drugs. The purpose of the present study was to determine if variations in the apo E phenotype also affect basal lipoprotein concentrations in patients with heterozygous familial hypercholesterolemia (FH) and if the apo E phenotype influenced their subsequent response to lovastatin. Apo E phenotypes were determined on plasma from 134 FH patients. The relative frequencies of the epsilon 2, epsilon 3, and epsilon 4 alleles were .090, .772, and .138, respectively. Plasma triglycerides were found to be 34% higher in E3/2 heterozygotes relative to E3/3 patients. Baseline concentrations of low-density lipoprotein (LDL) cholesterol in untreated FH patients were not influenced by the apo E phenotype; the hypolipidemic response to lovastatin (20 or 40 mg twice daily) was also independent of the apo-E phenotype of the patients.

Evaluation of the safety, recovery, half-life, and clinical efficacy of antithrombin III (human) in patients with hereditary antithrombin III deficiency. Cooperative Study Group.

Antithrombin III (Human) (AT III) was administered to 18 patients with documented hereditary AT III deficiency. In eight patients with no ongoing clinical symptoms of thrombosis, the percent increase per unit AT III infused per kilogram of body weight ranged from 1.56% to 2.74%, and the half-life from 43.3 to 77.0 hours. No significant difference was noted between patients receiving and those not receiving coumarin therapy. In clinically ill patients, the in vivo recovery was significantly lower and ranged from 0.64% to 1.90% increase per unit AT III infused/kg. Efficacy of AT III was evaluated in 13 patients for the prevention or treatment of thrombosis. AT III was efficacious as assessed by the absence of thrombotic complications after surgery and/or parturition, and the nonextension and nonrecurrence of thrombosis in patients exhibiting an acute thrombotic episode. No side effects were noted. Follow-up studies indicated no hepatitis B seroconversion and no alanine aminotransferase elevations in patients who were not transfused with other blood products.

Loss of antigenic properties of acetylcholine receptors in rat skeletal muscle after birth.

Antibodies in a myasthenic serum were used to follow the changes in antigenic properties of acetylcholine receptors in rat skeletal muscle during development. In binding assays at saturating concentrations of antigen or antibody, the antibodies reacted with extrajunctional receptors of fetal and denervated adult muscle but showed little binding to junctional receptors of adult rat muscle. They did, however, bind to junctional receptors of adult chicken muscle which, unlike rat receptors, do not appear to undergo a change in their channel properties during development. Binding studies with acetylcholine receptors of developing rat muscle carried out at saturating concentrations of antibody showed that the loss of antigenic determinant(s) begins at 1-2 days after birth.