Faculty Bibliography

Three Americans won the Nobel Prize in Physiology or Medicine on Monday for discovering the machinery that regulates how cells transport major molecules in a cargo system that delivers them to the right place at the right time

Their research solved the mystery of how cells organize their transport system, the Karolinska committee said. Dr. [Randy W. Schekman] discovered a set of genes that were required for vesicle traffic. Dr. [James E. Rothman] unraveled protein machinery that allows vesicles to fuse with their targets to permit transfer of cargo. Dr. Sudhof revealed how signals instruct vesicles to release their cargo with precision. Dr. Rothman, 63, who was born in Haverhill, Mass., studied vesicle transport in mammalian cells in the 1980s and 1990s. He discovered that a protein complex allows vesicles to dock and fuse with their target membranes. In the fusion process, proteins on the vesicles and target membranes bind to each other like the two sides of a zipper. The fact that there are many such proteins and that they bind only in specific combinations ensures that cargo is delivered to a precise location. The same principle operates inside the cell and when a vesicle binds to the cell's outer membrane to release its contents. Dr. Rothman received a Ph.D. from Harvard Medical School in 1976, was a postdoctoral fellow at Massachusetts Institute of Technology, and moved in 1978 to Stanford, where he started his research on the vesicles of the cell. Dr. Rothman has also worked at Princeton University, Memorial Sloan-Kettering Cancer Institute and Columbia University

Clinical practice guidelines are a common way of summarizing the standard recommendations for medical conditions. After the research was initially published last year, I grappled with the evidence, or lack thereof, reaching a conclusion that I mainly still supported the annual visit, if only because it establishes a solid doctor-patient relationship

BACKGROUND: Pyrazinamide (PZA) is essential in tuberculosis treatment. We describe the prevalence, trends, and predictors of PZA resistance in Mycobacterium tuberculosis complex (MTBC) in the United States. METHODS: We analyzed culture-positive MTBC cases with reported drug susceptibility tests for PZA in 38 jurisdictions routinely testing for PZA susceptibility from 1999 to 2009. National Tuberculosis Genotyping Service data for 2004-2009 were used to distinguish M. tuberculosis from Mycobacterium bovis and determine phylogenetic lineage. RESULTS: Overall 2.7% (2167/79 321) of MTBC cases had PZA resistance, increasing annually from 2.0% to 3.3% during 1999-2009 (P < .001), largely because of an increase in PZA monoresistance. PZA-monoresistant MTBC (vs drug-susceptible) was associated with an age of 0-24 years (adjusted prevalence ratio [aPR],1.50; 95% confidence interval [CI], 1.31-1.71), Hispanic ethnicity (aPR, 3.52; 95% CI, 2.96-4.18), human immunodeficiency virus infection (aPR, 1.43; 95% CI, 1.15-1.77), extrapulmonary disease (aPR, 3.02; 95% CI, 2.60-3.52), and normal chest radiograph (aPR, 1.88; 95% CI, 1.63-2.16) and was inversely associated with Asian (aPR, 0.59; 95% CI, .47-.73) and black (aPR, 0.37; 95% CI, .29-.49) race. Among multidrug-resistant (MDR) cases, 38.0% were PZA-resistant; PZA resistance in MDR MTBC was associated with female sex (aPR, 1.25; 95% CI, 1.08-1.46) and previous tuberculosis diagnosis (aPR, 1.37; 95% CI, 1.16-1.62). Of 28 080 cases with genotyping data, 925 (3.3%) had PZA resistance; 465 of 925 (50.3%) were M. bovis. In non-MDR M. tuberculosis cases, PZA resistance was higher in the Indo-Oceanic than the East Asian lineage (2.2% vs 0.9%, respectively; aPR, 2.26; 95% CI, 1.53-3.36), but in MDR cases it was lower in the Indo-Oceanic lineage (22.0% vs 43.4%, respectively; aPR, 0.54; 95% CI, .32-.90). CONCLUSIONS: Specific human and mycobacterial characteristics were associated with PZA-resistant MTBC, reflecting both specific subgroups of the population and phylogenetic lineages of the mycobacteria.

The risk of progression to multiple myeloma (MM) from the precursor condition smoldering MM (SMM) varies considerably among individual patients. Reliable markers for progression to MM are vital to advance the understanding of myeloma precursor disease and for the development of intervention trials designed to delay/prevent MM. The Mayo Clinic and Spanish PETHEMA have proposed models to stratify patient risk based on clinical parameters. The aim of our study was to define the degree of concordance between these two models by comparing the distribution of patients with SMM classified as low, medium and high risk for progression. A total of 77 patients with SMM were enrolled in our prospective natural history study. Per study protocol, each patient was assigned risk scores based on both the Mayo and the Spanish models. The Mayo Clinic model identified 38, 35 and four patients as low, medium and high risk, respectively. The Spanish PETHEMA model classified 17, 22 and 38 patients as low, medium and high risk, respectively. There was significant discordance in overall patient risk classification (28.6% concordance) and in classifying patients as low versus high (p < 0.0001), low versus non-low (p = 0.0007) and high versus non-high (p < 0.0001) risk. There is a need for prospectively validated models to characterize individual patient risk of transformation to MM.

BACKGROUND:Many Veterans Affairs (VA) primary care (PC) patients prefer telephone-delivered care to other health care delivery modalities. OBJECTIVE:To evaluate PC patients' telephone experiences and outcomes before and after a national telephone transformation quality improvement (QI) collaborative. METHODS:Cross-sectional surveys were conducted pre- and post-collaborative. We used bivariate analyses to assess differences in pre/post outcomes and multivariate regression to identify variables associated with patients' perceptions of poor quality care. RESULTS:Patients from 13 VA facilities participated (n = 730; pre-intervention = 314, post-intervention = 416); most of them were males (90%) with a mean age of 62 years. After the collaborative (versus pre-collaborative), few experienced transfers (52% versus 62%, P = 0.0006) and most reported timely call answer (88% versus 80%, P = 0.003). Improvements in staff understanding why patients were calling and providing needed medical information were also found. There were measurable improvements in patient satisfaction (87% versus 82% very/mostly satisfied, P = 0.04) and perceived quality of telephone care (85% versus 78% excellent/good quality, P = 0.01) post- collaborative. The proportion of veterans who reported delayed care due to telephone access issues decreased from 41% to 15% after the collaborative, P < 0.0001. Perceptions of poor quality care were higher when calls were for urgent care needs did not result in receipt of needed information and included a transfer or untimely answer. CONCLUSIONS:The QI collaborative led to improvements in timeliness of answering calls, patient satisfaction and perceptions of high-quality telephone care and fewer reports of health care delays. Barriers to optimal telephone care 'quality' include untimely answer, transfers, non-receipt of needed information and urgent care needs.

The integration of genetics and the social sciences will lead to a more complex understanding of the articulation between social and biological processes, although the empirical difficulties inherent in this integration are large. One key challenge is the implications of moving "outside the lab" and away from the experimental tools available for research with model organisms. Social science research methods used to examine human behavior in nonexperimental, real-world settings to date have not been fully taken advantage of during this disciplinary integration, especially in the form of gene-environment interaction research. This article outlines and provides examples of several prominent research designs that should be used in gene-environment research and highlights a key benefit to geneticists of working with social scientists.