Faculty Bibliography

This study investigates associations between the strength of local Tobacco Retail Licensing (TRL) laws and adult tobacco use patterns (i.e., cigarette, e-cigarette, and dual use), and differences by sociodemographic characteristics, using California as a case study. We merged data from the American Lung Association's (ALA) State of Tobacco Control Reports and the California Health Interview Survey (CHIS) from 2016 to 2022. We recoded the ALA local policy grades as strongest (highest grade) versus weaker (all other grades). Using quantitative methods, we estimated multilevel multinomial logistic regression models to examine the relationship between the strength of local TRL laws and cigarette and e-cigarette single and dual use among adults aged 25 and older, nesting by city/town. We also examined the potential for effect modification by including interaction terms for race and ethnicity, income, and education in separate models. Our results showed that no associations existed between stronger TRL grades and exclusive cigarette, e-cigarette or dual use in any of the models. Neither were there statistically significant interactions by race and ethnicity, income, or education. These null findings suggest that while TRL laws may potentially be useful to restrict adolescent access, local TRL strength may have few impacts on adult nicotine consumption.

SHP2 is a phosphatase and a critical mediator of receptor tyrosine kinase (RTK)-driven RAS/mitogen-activated protein kinase (MAPK) signaling. Despite promising preclinical data, SHP2 inhibitors have shown minimal clinical efficacy, with no defined clinical mechanisms of primary resistance. Here, we elucidate phosphorylation of SHP2 at tyrosine 62 (pY62) as a hotspot phosphorylation site in the proteome and RTK-driven tumor types in patients. We demonstrate that SRC family kinases directly phosphorylate SHP2 at Y62, downstream of but not directly phosphorylated by RTKs. Using biochemical and biophysical analyses, we show that SHP2^Y62D enforces an open, active conformation, resulting in constitutive phosphatase activation that is sufficient to activate MAPK signaling and confer resistance to allosteric SHP2 inhibitors. These findings establish that SHP2 pY62 is a phosphorylation hotspot phenocopying mutational activation, a mechanism of primary resistance to SHP2 inhibitors, and a cancer drug target distinct from wildtype SHP2.

BACKGROUND:Tranexamic acid (TXA) has reduced, but not eliminated, blood transfusions surrounding total knee arthroplasty (TKA). Identifying risk factors for transfusion remains important for risk reduction and type and screen (T and S) optimization. METHODS:We retrospectively reviewed 7,254 patients who underwent primary, unilateral TKA and 307 patients who underwent primary bilateral TKA between January 2014 and January 2023, who received perioperative TXA and had preoperative hemoglobin (Hgb) values. We compared demographics, baseline Hgb levels, and surgical details between patients who were and were not transfused. Data were analyzed utilizing multivariate regressions and receiver operating characteristic (ROC) analyses. A total of 172 unilateral TKA patients (2.4%) received perioperative transfusions, with 170 (2.3%) receiving postoperative transfusions and two (0.03%) receiving intraoperative transfusions. There were 26 bilateral TKA patients (8.5%) who received postoperative transfusions with no documented intraoperative transfusions. RESULTS:For unilateral TKA, the risk of transfusion demonstrated an inverse correlation with preoperative Hgb levels, a bimodal association with body mass index (BMI), and a direct correlation with American Society of Anesthesiologists (ASA) class and estimated blood loss (EBL) on multivariate testing. The ROC analyses demonstrated an optimal Hgb cutoff of 12.1 g/dL for predicting transfusion. The transfusion rate below Hgb of 12.1 g/dL was 6.6%, compared to a rate of 1.4% above this Hgb threshold. Below Hgb of 11 g/dL, the transfusion rate was 11.1%, while for Hgb between 11 and 12 g/dL, the transfusion rate was 4.6%. CONCLUSION/CONCLUSIONS:Transfusion is rare in unilateral TKA when TXA is used and preoperative Hgb is ≥ 12.1 g/dL, challenging universal T and S. Patients who have Hgb less than 11.0 g/dL and bilateral TKA patients remain at higher risk. Risk factors such as Hgb between 11 and 12 g/dL, BMI, ASA and EBL may predict transfusion risk and need for T and S.

Knee injuries are one of the most common complaints in sports medicine. Magnetic resonance imaging is an essential adjunct to clinical evaluation for many traumatic injuries and overuse conditions. Given the heavy use of knee magnetic resonance imaging, developing faster magnetic resonance imaging acquisition methods and deployment in clinical practice would be valuable. In this article, we illustrate a spectrum of knee abnormalities from our clinical practice, utilizing a recently developed, publicly available sub-5-minute knee magnetic resonance imaging protocol with super-resolution image reconstruction based on deep learning. We review common traumatic injuries and overuse conditions of the knee and illustrate cases with this novel fast knee magnetic resonance imaging protocol.

Calcineurin inhibitors, particularly tacrolimus, have been a fundamental immunosuppressive treatment in solid organ transplantation for over four decades, helping prevent organ rejection in transplant recipients. Tacrolimus has also proven effective in treating several autoimmune diseases. Despite its effectiveness, the use of tacrolimus has been characterized by challenges related to its narrow therapeutic index-particularly in kidney transplantation-necessitating frequent blood monitoring and dose adjustments. In recent years, improved extended-release formulations have made strides in reducing toxic effects, such as neurotoxicity and nephrotoxicity, and enhancing medication adherence. However, there remains considerable room for improvement, which has the potential to ameliorate long-term graft outcomes and decrease the burden of pill intake, especially for vulnerable patient populations. Recent advances enabling very-extended oral drug delivery present potential opportunities to optimize the peak-trough effects of tacrolimus-based immunosuppression, while also benefitting from the synergy of drug compounding and minimizing pill burden. In this article, we review the history of tacrolimus as a cornerstone of immunosuppression in kidney transplantation, the iterative improvements in outcomes and patient quality-of-life enabled by increasingly extended-release formulations, and the potential outlook for very-extended release formulations in the future.

This case is a 37-year-old man with diffuse primary synovial chondromatosis of the elbow, with associated ulnar nerve compression and flexion contracture at the elbow. An open synovectomy with removal of loose bodies and an ulnar nerve decompression with anterior subcutaneous transposition were performed. Postoperatively, the patient's elbow mobility and nerve compression symptoms improved steadily, which significantly improved his function. Primary synovial chondromatosis of the elbow is a rare disease that can result in pain, swelling, decreased range of motion, and mechanical symptoms. Treatment usually involves synovectomy and removal of loose bodies to address patients' pain and joint motion.

PURPOSE/OBJECTIVE:Cannabidiol has well described drug interactions including inhibition of clobazam metabolism. Phenytoin is known to induce metabolism of cannabidiol. Cannabidiol inhibition of phenytoin metabolism is predicted but not well described. METHODS:We present the cases of two individuals with Lennox Gastaut Syndrome which demonstrate the clinical relevance of cannabidiol inhibition of phenytoin metabolism. RESULTS:In the first case, the addition of cannabidiol led to increased levels of phenytoin and clobazam which resulted in freedom from previously refractory tonic-clonic seizures. This was sustained for one year. The phenytoin dose was later lowered due to concern for liver function and this led to recurrent seizures despite continued elevation of N-desmethylclobazam levels, suggesting the higher phenytoin was responsible for the seizure control. In the second case, the addition of cannabidiol led to phenytoin toxicity with ataxia and falls. Lowering phenytoin dose led to resolution of these symptoms. CONCLUSION/CONCLUSIONS:Physicians should be aware of the interactions between phenytoin and cannabidiol in the management of epilepsy.

BACKGROUND AND AIMS/OBJECTIVE:The opioid crisis is still a public health emergency in the United States, despite recent declines in opioid overdose deaths (OODs) and increased availability of evidence-based practices (EBPs) for opioid use disorder (OUD). The geographic variability in OODs drives the need for localized decision-making, where interventions are tailored to the unique needs of communities. This study aimed to develop and calibrate a simulation model that evaluates the impact of enhanced implementation of EBP on OODs at the community-level. DESIGN/METHODS:We developed OPSiM (Opioid Policy Simulation Model), a community-level microsimulation model that simulates the course of opioid use, OUD, treatment, recovery and overdose-related events. The model was parameterized with data from the HEALing Communities Study and looked at six scenarios of EBPs implemented in 2025 with sustainment through 2030: (1) maintain 2024 EBP levels (status quo); (2) increase initiation of medications for opioid use disorder (MOUD); (3) increase MOUD retention; (4) increase MOUD initiation and retention; (5) increase distribution of naloxone; and (6) both scenarios 4 and 5. SETTING/METHODS:Twenty-nine communities in Massachusetts, New York, and Ohio, USA. PARTICIPANTS/METHODS:Simulated community residents with non-prescribed opioid use or OUD. MEASUREMENTS/METHODS:Estimated number of OODs per 100 000 individuals between 2025 and 2030 in each community, averaged across the 26 communities. FINDINGS/RESULTS:Under the status quo, the model projected 158 OODs (range across communities: 39-468) per 100 000 individuals between 2025 and 2030. Increasing medications for the treatment of OUD (MOUD) retention alone reduced OODs by 6% (range: 3-15%), while increasing MOUD initiation alone reduced OODs by 9% (range: 8-12%). Increasing both MOUD initiation and retention had a synergistic effect, reducing OODs by 21% (range: 15-31%). Reduction in OODs in response to increased MOUD initiation and/or retention was similar across urban and rural communities. The effect of increasing naloxone distribution varied substantially across communities due to differing saturation levels; in some communities, additional naloxone kits provided only marginal benefits. Rural communities were further from saturation whereas most urban communities were at or close to saturation. CONCLUSIONS:A tailored, multi-pronged approach that scales up medications for opioid use disorder alongside widespread naloxone distribution, and that addresses community-specific needs and capacities, will be most effective at reducing opioid overdose deaths in the United States.