Designing Trials of Disease Modifying Agents for Early and Preclinical Alzheimer's Disease Intervention: What Evidence is Meaningful to Patients, Providers, and Payers?

BACKGROUND: Drug development for disease modifying agents in Alzheimer's disease (AD) is focused increasingly on targeting underlying pathology in very early stages of AD or in cognitively normal patients at elevated risk of developing dementia due to Alzheimer's. Very early interventional studies of this type have many uncertainties, including whether they can provide the clinical results that payers, providers, and patients will wish to see for decisions. This paper describes an initiative to create greater transparency for researchers to anticipate these decision needs. OBJECTIVE: To create multi-stakeholder-vetted recommendations for the design of studies in later phases of drug development to evaluate the ability of disease modifying agents to delay or prevent the onset of dementia due to Alzheimer's disease (AD). DESIGN: A multi-stakeholder expert workgroup and overseeing steering group were convened to discuss current advances in early interventional clinical trial design and the evidence needs of patients, providers, and payers. Eight teleconferences and one in-person all-day meeting were held. Meetings were recorded and summary notes prepared between sessions. Final conclusions were consolidated by the project team with the workgroup Chair based on these discussions and were reviewed by group members. SETTING: The in-person meeting was held in Baltimore, MD. PARTICIPANTS: In total, 36 stakeholders representing life sciences industry, payers or health technology assessors, patient advocates and research advocacy organizations, regulators, clinical experts and academic or NIH researchers. INTERVENTION: N/A. MEASUREMENTS: N/A. RESULTS: Certain aspects of clinical trial design were deemed important to address stakeholder decision needs for future Alzheimer's prevention drugs even as the field rapidly progresses. These include the need for more robust behavioral and psychological outcome data in early symptomatic disease and the need to update activities of daily living measures to include "digital independence." CONCLUSIONS: Amyloid, tau, and biomarkers of neurodegeneration should be included in trials and studied in relation to other early measures of change meaningful to individuals with AD, their families, and health plans. These measures include early sensitive changes in behavioral and psychological measures and ability to navigate the contemporary digital landscape. Additional work is needed to generate more robust behavioral and psychological outcome data in early symptomatic disease, and to generate multi-stakeholder consensus on early measures of change and magnitudes of change that will be meaningful to patients, providers, and payers.

Magnetic-film atom chip with 10 µm period lattices of microtraps for quantum information science with Rydberg atoms.

We describe the fabrication and construction of a setup for creating lattices of magnetic microtraps for ultracold atoms on an atom chip. The lattice is defined by lithographic patterning of a permanent magnetic film. Patterned magnetic-film atom chips enable a large variety of trapping geometries over a wide range of length scales. We demonstrate an atom chip with a lattice constant of 10 µm, suitable for experiments in quantum information science employing the interaction between atoms in highly excited Rydberg energy levels. The active trapping region contains lattice regions with square and hexagonal symmetry, with the two regions joined at an interface. A structure of macroscopic wires, cutout of a silver foil, was mounted under the atom chip in order to load ultracold (87)Rb atoms into the microtraps. We demonstrate loading of atoms into the square and hexagonal lattice sections simultaneously and show resolved imaging of individual lattice sites. Magnetic-film lattices on atom chips provide a versatile platform for experiments with ultracold atoms, in particular for quantum information science and quantum simulation.

Antenatal corticosteroids and newborn screening for congenital adrenal hyperplasia.

OBJECTIVE: To assess the effect of reported corticosteroid exposure on neonatal levels of 17-hydroxyprogesterone (17-OHP), the cortisol precursor used in newborn screening for congenital adrenal hyperplasia, in newborns weighing less than 2500 g at birth. DESIGN: A retrospective study of newborns weighing less than 2500 g at birth and exposed to corticosteroids as reported on their newborn screening card compared with newborns weighing less than 2500 g at birth and reported as not exposed to corticosteroids. METHODS: Birth weight, gestational age, age at screening, special care information, and name of screening hospital were obtained from newborn screening cards for 16 115 newborns screened in Michigan during the first 3 months of 2000. Levels of 17-OHP, measured by fluoroimmunoassay, were obtained from Michigan's Newborn Screening Program database. RESULTS: The mean 17-OHP level for the 69 low-birth-weight newborns in the corticosteroid-exposed group was 52 ng/mL, which was higher than that for the 771 low-birth-weight newborns in the unexposed group (35 ng/mL) (P<.001). Reported corticosteroid use did not decrease the number of expected borderline positive screening results for congenital adrenal hyperplasia (P>.05). Levels of 17-OHP varied by birth weight in corticosteroid-exposed and unexposed newborns. CONCLUSIONS: Corticosteroid exposure may not suppress screening 17-OHP levels. Therefore, newborn screening should not be delayed in premature newborns because of antenatal exposure to corticosteroids.

Independent associations among maternal alcohol consumption and infant thyroxine levels and pregnancy outcome.

Studies with animal models of alcohol-related birth defects (ARBDs) suggest that reductions in circulating thyroid hormones, including thyroxine (T4), may be a persistent postnatal effect of fetal alcohol exposure. The few clinical reports of children with fetal alcohol syndrome (FAS) that address thyroid system function generally reported that FAS children have thyroid hormone levels within normal limits. For the current study, data bases from the Fetal Alcohol Research Center and the Michigan Department of Public Health Newborn Screening Program were assessed to correlate measures of maternal drug use during pregnancy and infant outcome (gestational age at birth, birthweight, "fetal growth"), with infant whole-blood T4 levels. Multiple regression analyses accounted for demographic factors, infant age at testing, and variation in the T4 assay. As expected, alcohol intake and smoking each had a substantial negative impact on birthweight, gestational age at birth, and fetal growth, assessed as birthweight corrected for gestational age. Infant T4 levels were positively related to birthweight and gestational age and were more strongly related to fetal growth. Infant T4 levels were not influenced significantly by either maternal smoking or alcohol consumption. Smoking- and alcohol-related reductions in birthweight, gestational age, or fetal growth were not associated significantly with variations in infant T4. Interesting questions remain regarding species differences and the influences of maternal alcohol consumption on T4 metabolism as a mechanism for ARBDs. However, the current data do not support the hypothesis that maternal alcohol consumption, or smoking, during pregnancy leads to compromised thyroid system function in newborn humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction, localization and metal content of hydrogenase in the green alga Chlamydomonas reinhardtii.

The hydrogenase enzyme occurring in Chlamydomonas reinhardtii is induced by anaerobic adaptation of the cells. In aerobically growing cells, antibodies against the hydrogenase failed to detect either active or inactive enzyme. However, already 10 min after the onset of anaerobic adaptation, the protein could be detected. The maximal amount of enzyme was reached after 2-3 hours anaerobiosis. Addition of nickel or iron to the growth medium did not influence activity. In atomic absorption experiments, a Ni/Fe ratio of about 1:250 was measured. We, therefore, propose the hydrogenase from C. reinhardtii to be of the Fe-only type. Adaptation in the presence of uncouplers of phosphorylation showed this process to be energy-dependent. From protein synthesis inhibition experiments, it is concluded that the protein is synthesized on cytoplasmic ribosomes and, therefore, must be nuclear encoded. After isolation of intact chloroplasts from adapted cells, the active enzyme was shown, by Western-blotting analysis, to be located in the chloroplasts.

Isolation, characterization and N-terminal amino acid sequence of hydrogenase from the green alga Chlamydomonas reinhardtii.

Hydrogenase from Chlamydomonas reinhardtii was purified to homogeneity by five column-chromatography steps under strict anaerobic conditions. The cells were disrupted by mild treatment with detergent. The enzyme was purified 6100-fold, resulting in a specific activity for H2 evolution of 935 mumol.min-1.mg protein-1 at 25 degrees C, using reduced methyl viologen as electron donor. The optimal temperature for hydrogen evolution is 60 degrees C, the optimal pH value is 6.9. The Km value for methyl viologen is 0.83 mM, for ferredoxin, 35 microM. From SDS/PAGE gels, the protein was judged to be pure. On non-denaturing gels, run under nitrogen, a single band was detected after activity staining. This band corresponded to the single band observed on denaturing SDS gels, which had an apparent molecular mass of 48 kDa. If the band was cut out of the native gel and incubated with reduced methyl viologen, hydrogen evolution could be measured. The purified enzyme contains 4 Fe atoms/mol. The amino acid composition and the N-terminal amino acid sequence (24 residues) of the protein were determined. No significant amino acid sequence homologies could be found to any sequences from prokaryotic hydrogenases.

High misses after odd flashes in oxygen evolution in thoroughly dark-adapted thylakoids from pea and Chenopodium album.

In Photosystem II (PS II), water is oxidized to molecular oxygen and plastoquinone is reduced to plastoquinol. The oxidation of water requires the accumulation of four oxidizing equivalents, through the so-called S-states of the oxygen evolving complex; the production of plastoquinol requires the accumulation of two reducing equivalents on a bound plastoquinone, QB. It has been generally believed that during the flash-induced transition of each of the S-states (Sn → Sn+1, where n=0, 1, 2 and 3), a certain small but equal fraction of the PS II reaction centers are unable to function and, thus, 'miss' being turned over. We used thoroughly dark-adapted thylakoids from peas (Pisum sativum) and Chenopodium album (susceptible and resistant to atrazine) starting with 100% of the oxygen evolving complex in the S1 state. Thylakoids were illuminated with saturating flashes, providing a double hit parameter of about 0.07. Our experimental data on flashnumber dependent oscillations in the amount of oxygen per flash fit very well with a binary pattern of misses: 0, 0.2, 0, 0.4 during S0 → S1, S1 → S2, S2 → S3 and S3 → S0 transitions. Addition of 2 mM ferricyanide appears to shift this pattern by one flash. These results are consistent with the 'bicycle' model recently proposed by V. P. Shinkarev and C. A. Wraight (Oxygen evolution in photosynthesis: From unicycle to bicycle, 1993, Proc Natl Acad Sci USA 90: 1834-1838), where misses are due to the presence of P(+) or QA (-) among the various equilibrium states of PS II centers.

The utilization of genetic counselors within a newborn screening program.

Genetic counselors have participated in the Michigan Newborn Screening Program on a contractual basis since 1988. Their role includes newborn screening education and training, newborn nursery site visits, and monitoring newborn screening in hospitals. Their impact has been to improve the quality of newborn screening services by reducing errors and increasing completion of data fields on newborn screening cards, improving hospital nursery cooperation and problem solving, and enhancing health department response to specific problems.

Temporal changes in Ohio amniocentesis utilization during the first twelve years (1972-1983), and frequency of chromosome abnormalities observed.

The history of amniocentesis utilization in the seventh largest state of the United States is documented from its inception in 1972 through the first half of 1984. Amniocentesis utilization ratios for Ohio residents aged greater than or equal to 35 have increased from 0.21 per cent (19/9091) in 1972 to 23.4 per cent (1655/7531) in 1983, representing an average annual growth rate of 43.1 per cent. Of the amniocenteses performed from January 1, 1978-July 1, 1984, 71 per cent were referred for advanced maternal age (greater than or equal to 35), 15 per cent for maternal anxiety (30-34), 10 per cent for family history or previous child with a genetic defect, and 4 per cent for other reasons. Between 1978-1983 utilization by women 45 years of age was only 20 per cent higher than women 35 even though their risk of giving birth to a Down syndrome child was bout one order of magnitude higher. In addition, various factors were tested as to whether they affected utilization of amniocentesis by women greater than or equal to 35 during 1978-1983. A strong correlation of +0.89 existed between county population size and utilization ratios. No difference in utilization was found between whites and nonwhites, regardless of county population size. When utilization ratios were compared separately between Protestants, Catholics and other religions in Ohio's most populated county, no statistical differences were found. From 1978-July 1, 1984, the frequency of all cytogenetically abnormal chromosome results observed in Ohio amniocenteses to women greater than or equal to 35 was 2.48 per cent (187/7536). Of these, 2.15 per cent (162/7536) had unbalanced karyotypes. Future maximum amniocentesis utilization for women greater than or equal to 35 is estimated at 60-70 per cent.