Publications

BACKGROUND

Substantial gaps often exist between every day practice and best practice as defined by research evidence. We present a framework for defining, analyzing, and quantifying such proof-to-practice gaps.

METHOD

An intervention's use can be plotted over time as ideal and actual uptake curves among candidates and noncandidates. Gaps of underuse are deviations from ideal uptake among candidates and can be quantified as underuse NNPs (Number Not Prevented): the number of disease events each year that would have been prevented, but were not, because of underuse among candidates of the intervention. Gaps of overuse are deviations from ideal uptake among non candidates and can be similarly quantified as overuse NNPs.

RESULTS

Applying our method to the underuse of beta-blockers at hospital discharge postmyocardial infarction (MI) in the United States demonstrates an annual NNP of 2995 first-year post-MI deaths not prevented (sensitivity analysis range 455-20,409). Our NNP analysis framework highlights challenges to the determination of efficacy and efficiency, the definition of what constitutes proof, rapid recognition of proof when it does occur, the definition of eligible candidates, and the definition of the proportion of candidates treated.

CONCLUSION

League tables of NNPs can help policy makers compare the clinical consequences of underuse and overuse of diverse interventions, while the NNP framework provides a systematic approach for describing and analyzing the components of proof-to-practice gaps. Such gap analyses can help organizations direct their resources to reducing gaps of greatest clinical consequence.

Both exposure of stratum corneum to neutral pH buffers and blockade of acidification mechanisms disturb cutaneous permeability barrier homeostasis and stratum corneum integrity/cohesion, but these approaches all introduce potentially confounding variables. To study the consequences of stratum corneum neutralization, independent of hydration, we applied two chemically unrelated superbases, 1,1,3,3-tetramethylguanidine or 1,8-diazabicyclo [5,4,0] undec-7-ene, in propylene glycol:ethanol (7:3) to hairless mouse skin and assessed whether discrete pH changes alone regulate cutaneous permeability barrier function and stratum corneum integrity/cohesion, as well as the responsible mechanisms. Both 1,1,3,3-tetramethylguanidine and 1,8-diazabicyclo [5,4,0] undec-7-ene applications increased skin surface pH in parallel with abnormalities in both barrier homeostasis and stratum corneum integrity/cohesion. The latter was attributable to rapid activation (<20 min) of serine proteases, assessed by in situ zymography, followed by serine-protease-mediated degradation of corneodesmosomes. Western blotting revealed degradation of desmoglein 1, a key corneodesmosome structural protein, in parallel with loss of corneodesmosomes. Coapplication of serine protease inhibitors with the superbase normalized stratum corneum integrity/cohesion. The superbases also delayed permeability barrier recovery, attributable to decreased beta-glucocerebrosidase activity, assessed zymographically, resulting in a lipid-processing defect on electron microscopy. These studies demonstrate unequivocally that stratum corneum neutralization alone provokes stratum corneum functional abnormalities, including aberrant permeability barrier homeostasis and decreased stratum corneum integrity/cohesion, as well as the mechanisms responsible for these abnormalities.

OBJECTIVE

Strong evidence indicates that at least one key tumour suppressor gene important for the development of malignant parathyroid tumours is located on chromosome 13, but the critical target gene remains unknown. Importantly, the region of acquired DNA loss includes two established tumour suppressor genes, the retinoblastoma gene, RB (RB1) and BRCA2. Resolution of whether RB or BRCA2 is the critical 13q tumour suppressor gene in parathyroid cancer requires analysis of these genes' sequences for intragenic inactivating mutations. Therefore, RB and BRCA2 were analysed in a group of parathyroid carcinomas in which mutations of these genes should be most readily detectable.

PATIENTS AND DESIGN

Six parathyroid carcinomas from four patients which showed loss of heterozygosity (LOH) at the RB locus and/or 13q loss by comparative genomic hybridazation (CGH) were selected from a CGH/LOH-screened panel of 16 carcinoma specimens from 10 patients. These tumours were examined for mutations by direct sequencing of the complete 27-exon coding region, intron-exon boundaries and promoter of RB. The 26 coding exons and intron-exon boundaries of BRCA2 were also directly sequenced in seven parathyroid carcinomas with loss in the BRCA2 region.

RESULTS

No microdeletions, insertions, or point mutations were detected in either RB or BRCA2 in any of the carcinomas.

CONCLUSION

The absence of tumour-specific somatic mutations in RB and BRCA2 suggests that they are unlikely to act as classic tumour suppressor genes in the pathogenesis of parathyroid carcinomas. While decreased expression of these genes might contribute to parathyroid carcinomatosis in a secondary fashion and 13q loss warrants further study as a diagnostic marker for parathyroid carcinoma, the putative 13q tumour suppressor awaits identification.

OBJECTIVES

There is increasing evidence that polymorphism of the ABCB1 (MDR1) gene contributes to interindividual variability in bioavailability and tissue distribution of P-glycoprotein substrates. The aim of the present study was to (1) identify and describe novel variants in the ABCB1 gene, (2) understand the extent of variation in ABCB1 at the population level, (3) analyze how variation in ABCB1 is structured in haplotypes, and (4) functionally characterize the effect of the most common amino acid change in P-glycoprotein.

METHODS AND RESULTS

Forty-eight variant sites, including 30 novel variants and 13 coding for amino acid changes, were identified in a collection of 247 ethnically diverse DNA samples. These variants comprised 64 statistically inferred haplotypes, 33 of which accounted for 92% of chromosomes analyzed. The two most common haplotypes, ABCB1*1 and ABCB1*13, differed at six sites (three intronic, two synonymous, and one non-synonymous) and were present in 36% of all chromosomes. Significant population substructure was detected at both the nucleotide and haplotype level. Linkage disequilibrium was significant across the entire ABCB1 gene, especially between the variant sites found in ABCB1*13, and recombination was inferred. The Ala893Ser change found in the common ABCB1*13 haplotype did not affect P-glycoprotein function.

CONCLUSION

This study represents a comprehensive analysis of ABCB1 nucleotide diversity and haplotype structure in different populations and illustrates the importance of haplotype considerations in characterizing the functional consequences of ABCB1 polymorphisms.

Sporadic Creutzfeldt-Jakob disease (CJD) is the most common prion disease. The diagnosis can be confirmed only by histological examination of brain tissue obtained at biopsy or at autopsy. Because of the transmissible nature of the disease, autopsy or brain biopsy cannot be performed at many institutions, which poses numerous challenges in confirming the diagnosis. We report the case of a patient with CJD in which autopsy to confirm the diagnosis was performed after overcoming numerous obstacles and advocating with hospital leadership. This case illustrates the numerous challenges that exist in achieving a definitive diagnosis of CJD and in postmortem disposition of the body, and we provide recommendations to clinicians who face similar challenges.

OBJECTIVE

Aimed at reducing surgical deaths, several recent initiatives have attempted to establish volume-based referral strategies in high-risk surgery. Although payers are leading the most visible of these efforts, it is unknown whether volume standards will also reduce resource use.

METHODS

We studied postoperative length of stay and 30-day readmission rate after 14 cardiovascular and cancer procedures using the 1994-1999 national Medicare database (total n = 2.5 million). We used regression techniques to examine the relationship between length of stay, 30-day readmission, and hospital volume, adjusting for age, gender, race, comorbidity score, admission acuity, and mean social security income.

RESULTS

Mean postoperative length of stay ranged from 3.4 days (carotid endarterectomy) to 19.6 days (esophagectomy). There was no consistent relationship between volume and mean length of stay; it significantly increased across volume strata for 7 of the 14 procedures and significantly decreased across volume strata for the other 7. Mean length of stay at very-low-volume and very-high-volume hospitals differed by more than 1 day for 6 procedures. Of these, the mean length of stay was shorter in high-volume hospitals for 3 procedures (pancreatic resection, esophagectomy, cystectomy), but longer for other procedures (aortic and mitral valve replacement, gastrectomy). The 30-day readmission rate also varied widely by procedure, ranging from 9.9% (nephrectomy) to 22.2% (mitral valve replacement). However, volume was not related to 30-day readmission rate with any procedure.

CONCLUSION

Although hospital volume may be an important predictor of operative mortality, it is not associated with resource use as reflected by length of stay or readmission rates.