Further results on covariate measurement errors in cohort studies with time to response data

The impact of covariate measurement errors on the estimation of relative risk regression parameters is discussed. First the dependence of the induced relative risk process on the cumulative baseline failure rate function is noted. Next induced relative risk models under some specific failure time and measurement error models are described, including the much simplified models that are appropriate under a 'rare disease' assumption. The presentation then turns to the joint estimation of relative risk parameters of primary interest along with measurement error parameters. A partial likelihood product is proposed for such estimation and asymptotic properties are indicated. Guidance is also presented as to the appropriate size of a 'validation' sample relative to the full cohort size. Finally some more general considerations are presented as to the usefulness and interpretation of deattenuated regression coefficients.     

The effect of local controlled release of sodium fluoride on the stimulation of bone growth

This study was performed to test the feasibility of using a biodegradable delivery system for the local controlled release of sodium fluoride as a mechanism for the stimulation of local bone growth. Sodium fluoride grains were mixed with poly-DL-lactic acid (PLA), and the mixture was then dissolved in acetone. After driving off the solvent, sheets of this material were rolled into rods 3.2 mm in diameter and 28.6 mm long. These were inserted into the intramedullary canals of the right femora of adult New Zealand White rabbits. A sham implant, made the same way but containing no fluoride, was inserted into the contralateral left leg. The effects of three different concentrations of sodium fluoride, 0.125 g NaF/g PLA, 0.250 g NaF/g PLA, and 0.500 g NaF/g PLA, were determined after a 4-week implantation period. In a second set of experiments, the concentration was fixed at 0.500 g NaF/g PLA with implantation durations of 4, 8, and 16 weeks. Expressed in terms of property ratios (experimental/control), bending strengths of the femora were significantly raised in most groups with the notable exception of Group 3 (0.500 g NaF/g PLA, 4 weeks). Cross-sectional area ratios in the distal femora were increased in all groups compared to right/left values for a normal unoperated group (p less than 0.05), with the highest ratio being 1.50 (SD = 0.44) for Group 4 (0.500 g NaF/g PLA, 8 weeks). Only Group 4 animals showed significant (p less than 0.05) increases in midshaft area ratio and none had responses proximally. Growth rates, measured by sequential fluorochrome labeling of bone followed the area ratio data and were only significant for the distal femora.     

Safety and immunogenicity of a canarypox-vectored human immunodeficiency virus Type 1 vaccine with or without gp120: a phase 2 study in higher- and lower-risk volunteers

Live attenuated viral vectors that express human immunodeficiency virus (HIV) antigens are being developed as potential vaccines to prevent HIV infection. The first phase 2 trial with a canarypox vector (vCP205, which expresses gp120, p55, and protease) was conducted in 435 volunteers with and without gp120 boosting, to expand the safety database and to compare the immunogenicity of the vector in volunteers who were at higher risk with that in volunteers at lower risk for HIV infection. Neutralizing antibodies to the MN strain were stimulated in 94% of volunteers given vCP205 plus gp120 and in 56% of volunteers given vCP205 alone. CD8(+) cytotoxic T lymphocyte cells developed at some time point in 33% of volunteers given vCP205, with or without gp120. Phase 3 field trials with these or similar vaccines are needed, to determine whether efficacy in preventing HIV infection or in slowing disease progression among vaccinees who become infected is associated with the level and types of immune responses that were induced by the vaccines in this study.     

Clonal diversity analysis using SNP microarray: a new prognostic tool for chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease. The methods currently used for monitoring CLL and determining conditions for treatment are limited in their ability to predict disease progression, patient survival, and response to therapy. Although clonal diversity and the acquisition of new chromosomal abnormalities during the disease course (clonal evolution) have been associated with disease progression, their prognostic potential has been underappreciated because cytogenetic and fluorescence in situ hybridization (FISH) studies have a restricted ability to detect genomic abnormalities and clonal evolution. We hypothesized that whole genome analysis using high resolution single nucleotide polymorphism (SNP) microarrays would be useful to detect diversity and infer clonal evolution to offer prognostic information. In this study, we used the Infinium Omni1 BeadChip (Illumina, San Diego, CA) array for the analysis of genetic variation and percent mosaicism in 25 non-selected CLL patients to explore the prognostic value of the assessment of clonal diversity in patients with CLL. We calculated the percentage of mosaicism for each abnormality by applying a mathematical algorithm to the genotype frequency data and by manual determination using the Simulated DNA Copy Number (SiDCoN) tool, which was developed from a computer model of mosaicism. At least one genetic abnormality was identified in each case, and the SNP data was 98% concordant with FISH results. Clonal diversity, defined as the presence of two or more genetic abnormalities with differing percentages of mosaicism, was observed in 12 patients (48%), and the diversity correlated with the disease stage. Clonal diversity was present in most cases of advanced disease (Rai stages III and IV) or those with previous treatment, whereas 9 of 13 patients without detected clonal diversity were asymptomatic or clinically stable. In conclusion, SNP microarray studies with simultaneous evaluation of genomic alterations and mosaic distribution of clones can be used to assess apparent clonal evolution via analysis of clonal diversity. Since clonal evolution in CLL is strongly correlated with disease progression, whole genome SNP microarray analysis provides a new comprehensive and reliable prognostic tool for CLL patients.     

Blood usage in lung transplantation

BACKGROUND: Few published data are available regarding perioperative blood usage in lung transplantation. STUDY DESIGN AND METHODS: The medical records of all patients undergoing lung transplantation at a university medical center in 1994 and 1995 were reviewed. RESULTS: Ninety patients underwent lung transplantation during this period. Six patients were excluded: two received a living related-donor lung, three underwent retransplantation and one underwent concomitant repair of a tetralogy of Fallot. Of the 84 evaluable patients, 59 underwent single lung transplantation and 25 double lung transplantation. Double-lung recipients used more red cells (6.4 vs. 1.7 units, p = 0.0002) and were more likely to receive red cells, platelets, plasma, or any component (92 vs. 32%, p< or =0.0001) than were single-lung recipients. Double- lung recipients were more likely to require cardiopulmonary bypass (40 vs. 12%, p = 0.003), and cardiopulmonary bypass was associated with greater transfusion requirements (p< or =0.0001). However, among patients requiring cardiopulmonary bypass, blood use did not differ between those undergoing double lung transplantation and those undergoing single lung transplantation. In the subset of patients not requiring cardiopulmonary bypass, double-lung recipients received more red cells (4.5 vs. 0.7 units, p< or =0.0001) and more plasma (2.0 vs. 0.2 units, p = 0.006). CONCLUSION: Double-lung recipients require more perioperative transfusions than single-lung recipients. The greater transfusion requirement is due to the more frequent need for cardiopulmonary bypass as well as the greater complexity of the procedure. These data are useful for developing surgical blood ordering guidelines for lung transplantation.     

High technology medicine and the physician-patient relationship

While technologic problems in critical care have become highly refined with precise solutions, ethical problems and solutions have remained fairly primitive. A useful distinction between technology and techniques is made with individual technologies being the parts that make up the therapeutic techniques as a whole. The phenomena of “technical convergence” is discussed wherein we may control each part of the system, but the system itself may be out of control. This is explained in terms of the logical fallacy of composition, noting that a whole may not necessarily have the same characteristics of its parts. Resolution of some of the ethical problems in critical care is suggested through a reexamination of the physician-patient relationship. It is noted that the relationship needs to be personal-technologic rather than sociotechnologic in nature, with the former focusing solely on the best interest of the individual patient and the latter focusing more on the broader concerns of society in the allocation of limited resources. The detrimental effects for the physician as well as the patient of the shift toward the sociotechnologic relationship is explored, especially the dehumanization of the physician. A call for a reaffirmation of the traditional professional model of medicine emphasizing the best interest of patients as opposed to the more popular business model emphasizing materialism and efficiency is given.     

Pulp revascularization for immature replanted teeth: a case report

Immature avulsed teeth are not usually treated with pulp revascularization because of the possibility of complications. However, this therapy has shown success in the treatment of immature teeth with periapical lesions. This report describes the case of an immature replanted tooth that was successfully treated by pulp revascularization. An 8‐year‐old boy suffered avulsion on his maxillary left lateral incisor. The tooth showed incomplete root development and was replanted after 30 minutes. After diagnosis, revascularization therapy was performed by irrigating the root canal and applying a calcium hydroxide paste and 2% chlorhexidine gel for 21 days. In the second session, the intracanal dressing was removed and a blood clot was stimulated up to the cervical third of the root canal. Mineral trioxide aggregate was placed as a cervical barrier at the entrance of the root canal and the crown was restored. During the follow‐up period, periapical repair, apical closure and calcification in the apical 4 mm of the root canal was observed. An avulsed immature tooth replanted after a brief extra‐alveolar period and maintained in a viable storage medium may be treated with revascularization.