The Stanford Biodesign Program began in 2001 with a mission of helping to train leaders in biomedical technology innovation. A key feature of the program is a full-time postgraduate fellowship where ...multidisciplinary teams undergo a process of sourcing clinical needs, inventing solutions and planning for implementation of a business strategy. The program places a priority on needs identification, a formal process of selecting, researching and characterizing needs before beginning the process of inventing. Fellows and students from the program have gone on to careers that emphasize technology innovation across industry and academia. Biodesign trainees have started 26 companies within the program that have raised over $200 million and led to the creation of over 500 new jobs. More importantly, although most of these technologies are still at a very early stage, several projects have received regulatory approval and so far more than 150,000 patients have been treated by technologies invented by our trainees. This paper reviews the initial outcomes of the program and discusses lessons learned and future directions in terms of training priorities.
Background: The Chornobyl accident in 1986 exposed thousands of people to radioactive iodine isotopes, particularly 131I; this exposure was followed by a large increase in thyroid cancer among those ...exposed as children and adolescents, particularly in Belarus, the Russian Federation, and Ukraine. Here we report the results of the first cohort study of thyroid cancer among those exposed as children and adolescents following the Chornobyl accident. Methods: A cohort of 32 385 individuals younger than 18 years of age and resident in the most heavily contaminated areas in Ukraine at the time of the accident was invited to be screened for any thyroid pathology by ultrasound and palpation between 1998 and 2000; 13 127 individuals (44%) were actually screened. Individual estimates of radiation dose to the thyroid were available for all screenees based on radioactivity measurements made shortly after the accident and on interview data. The excess relative risk per gray (Gy) was estimated using individual doses and a linear excess relative risk model. Results: Forty-five pathologically confirmed cases of thyroid cancer were found during the 1998–2000 screening. Thyroid cancer showed a strong, monotonic, and approximately linear relationship with individual thyroid dose estimate (P<.001), yielding an estimated excess relative risk of 5.25 per Gy (95% confidence interval CI = 1.70 to 27.5). Greater age at exposure was associated with decreased risk of radiation-related thyroid cancer, although this interaction effect was not statistically significant. Conclusion: Exposure to radioactive iodine was strongly associated with increased risk of thyroid cancer among those exposed as children and adolescents. In the absence of Chornobyl radiation, 11.2 thyroid cancer cases would have been expected compared with the 45 observed, i.e., a reduction of 75% (95% CI = 50% to 93%). The study also provides quantitative risk estimates minimally confounded by any screening effects. Caution should be exercised in generalizing these results to any future similar accidents because of the potential differences in the nature of the radioactive iodines involved, the duration and temporal patterns of exposures, and the susceptibility of the exposed population.
This paper presents several acceleration techniques for reduced-order models based on the proper orthogonal decomposition (POD) method. The techniques proposed herein are: (i) an algorithm for ...splitting the database of snapshots generated by the full-order model; (ii) a method for solving quasi-symmetrical matrices; (iii) a strategy for reducing the frequency of the projection. The acceleration techniques were applied to a POD-based reduced-order model of the two-phase flows in fluidized beds. This reduced-order model was developed using numerical results from a full-order computational fluid dynamics model of a two-dimensional fluidized bed. Using these acceleration techniques the computational time of the POD model was two orders of magnitude shorter than the full-order model.
Mitochondrial uncoupling protein 1 (UCP1) gives brown adipose tissue of mammals its specialized ability to burn calories as heat for thermoregulation. When activated by fatty acids, UCP1 catalyzes ...the leak of protons across the mitochondrial inner membrane, short-circuiting the mitochondrion to generate heat, bypassing ATP synthesis. In contrast, purine nucleotides bind and inhibit UCP1, regulating proton leak by a molecular mechanism that is unclear. We present the cryo-electron microscopy structure of the GTP-inhibited state of UCP1, which is consistent with its nonconducting state. The purine nucleotide cross-links the transmembrane helices of UCP1 with an extensive interaction network. Our results provide a structural basis for understanding the specificity and pH dependency of the regulatory mechanism. UCP1 has retained all of the key functional and structural features required for a mitochondrial carrier-like transport mechanism. The analysis shows that inhibitor binding prevents the conformational changes that UCP1 uses to facilitate proton leak.
Transgenic expression of antigen-specific T-cell receptor (TCR) genes is a promising approach for immunotherapy against infectious diseases and cancers. A key to the efficient application of this ...approach is the rapid and specific isolation and cloning of TCRs. Current methods are often labor-intensive, nonspecific, and/or relatively slow. Here, we describe an efficient system for antigen-specific αβTCR cloning and CDR3 substitution. We demonstrate the capability of cloning influenza-specific TCRs within 10 days using single-cell polymerase chain reaction (PCR) and Gibson Assembly techniques. This process can be accelerated to 5 days by generating receptor libraries, requiring only the exchange of the antigen-specific CDR3 region into an existing backbone. We describe the construction of this library for human γδ TCRs and report the cloning and expression of a TRGV9/TRDV2 receptor that is activated by zoledronic acid. The functional activity of these αβ and γδ TCRs can be characterized in a novel reporter cell line (Nur77-GFP Jurkat 76 TCRα(-)β(-)) for screening of TCR specificity and avidity. In summary, we provide a rapid method for the cloning, expression, and functional characterization of human and mouse TCRs that can assist in the development of TCR-mediated therapeutics.
Although differences in the rate of virus fusion and budding from the host cell membrane have been correlated with pathogenicity, no systematic study of the contribution of differences in viral ...envelope composition has previously been attempted. Using rigorous virus purification, marked differences between virions and host were observed. Over 125 phospholipid species have been quantitated for three strains of influenza (HKx31-H3N2, PR8-H1N1, and VN1203-H5N1) grown in eggs. The glycerophospholipid composition of purified virions differs from that of the host or that of typical mammalian cells. Phosphatidylcholine is the major component in most mammalian cell membranes, whereas in purified virions phosphatidylethanolamine dominates. Due to its effects on membrane curvature, it is likely that the variations in its content are important to viral processing during infection. This integrated method of virion isolation with systematic analysis of glycerophospholipids provides a tool for the assessment of species-specific biomarkers of viral pathogenicity.
This is a summary of a publication about Black participants of the GRIFFIN clinical study that was published in
in April 2022. The GRIFFIN clinical study looked at the treatment combination of ...daratumumab plus a standard therapy for multiple myeloma (called RVd therapy, which stands for lenalidomide, bortezomib, and dexamethasone) in adult patients who had not been treated before for multiple myeloma and so were considered to have newly diagnosed multiply myeloma. Multiple myeloma is a blood cancer of plasma cells. Based on the participants' age, medical history, and indicators of good general health, the participants in the GRIFFIN study were also eligible to receive autologous stem cell transplant as part of their therapy. This summary describes results for the Black participants of the GRIFFIN clinical study who received daratumumab plus RVd therapy (called D-RVd) to see if D-RVd therapy is better than RVd therapy at reducing the amount of multiple myeloma cancer cells in a patient's body.
Due to racial disparities leading to historically low representation of minority groups in clinical studies, optimal treatments are not defined for Black patients with newly diagnosed multiple myeloma. Since previously published results from the overall population in the GRIFFIN study indicated that D-RVd therapy was better than RVd therapy, the researchers wanted to determine if this was also the case among Black participants.
Out of 207 participants in the GRIFFIN study, 15% (32 participants) were Black and 78% (161 participants) were White. In both Black and White participants, D-RVd therapy reduced the amount of myeloma cancer cells more than RVd therapy. Additionally, D-RVd and RVd therapy had similar safety results for Black and White participants.
This analysis of GRIFFIN by race shows that Black people benefit from the daratumumab-containing D-RVd therapy as much as White people. Additionally, D-RVd therapy had similar safety results to RVd therapy for both Black and White people.
: NCT02874742 (ClinicalTrials.gov).
BACKGROUND
Non-verbal communication is an important aspect of the diagnostic and therapeutic process, especially with older patients. It is unknown how non-verbal communication varies with physician ...and patient race.
OBJECTIVE
To examine the joint influence of physician race and patient race on non-verbal communication displayed by primary care physicians during medical interviews with patients 65 years or older.
DESIGN, SETTING, AND PARTICIPANTS
Video-recordings of visits of 209 patients 65 years old or older to 30 primary care physicians at three clinics located in the Midwest and Southwest.
MAIN MEASURES
Duration of physicians’ open body position, eye contact, smile, and non-task touch, coded using an adaption of the Nonverbal Communication in Doctor–Elderly Patient Transactions form.
KEY RESULTS
African American physicians with African American patients used more open body position, smile, and touch, compared to the average across other dyads (adjusted mean difference for open body position = 16.55, p < 0.001; smile = 2.35, p = 0.048; touch = 1.33, p < 0.001). African American physicians with white patients spent less time in open body position compared to the average across other dyads, but they also used more smile and eye gaze (adjusted mean difference for open body position = 27.25, p < 0.001; smile = 3.16, p = 0.005; eye gaze = 17.05, p < 0.001). There were no differences between white physicians’ behavior toward African American vs. white patients.
CONCLUSION
Race plays a role in physicians’ non-verbal communication with older patients. Its influence is best understood when physician race and patient race are considered jointly.
A series of studies were conducted to explore the mechanism of the pharmacokinetic interaction between simvastatin (SV) and gemfibrozil (GFZ) reported recently in human subjects. After administration ...of a single dose of SV (4 mg/kg p.o.) to dogs pretreated with GFZ (75 mg/kg p.o., twice daily for 5 days), there was an increase (approximately 4-fold) in systemic exposure to simvastatin hydroxy acid (SVA), but not to SV, similar to the observation in humans. GFZ pretreatment did not increase the ex vivo hydrolysis of SV to SVA in dog plasma. In dog and human liver microsomes, GFZ exerted a minimal inhibitory effect on CYP3A-mediated SVA oxidation, but did inhibit SVA glucuronidation. After i.v. administration of (14)CSVA to dogs, GFZ treatment significantly reduced (2-3-fold) the plasma clearance of SVA and the biliary excretion of SVA glucuronide (together with its cyclization product SV), but not the excretion of a major oxidative metabolite of SVA, consistent with the in vitro findings in dogs. Among six human UGT isozymes tested, UGT1A1 and 1A3 were capable of catalyzing the glucuronidation of both GFZ and SVA. Further studies conducted in human liver microsomes with atorvastatin (AVA) showed that, as with SVA, GFZ was a less potent inhibitor of the CYP3A4-mediated oxidation of this drug than its glucuronidation. However, with cerivastatin (CVA), the glucuronidation as well as the CYP2C8- and CYP3A4-mediated oxidation pathways were much more susceptible to inhibition by GFZ than was observed with SVA or AVA. Collectively, the results of these studies provide metabolic insight into the nature of drug-drug interaction between GFZ and statins, and a possible explanation for the enhanced susceptibility of CVA to interactions with GFZ.
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