Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Chronic pain affects nearly two billion people worldwide, surpassing heart disease, diabetes, and cancer in terms of economic costs. Lower back pain alone is the leading cause of years lived with disability worldwide. Despite limited treatment options, regenerative medicine, particularly extracellular vesicles (EVs) and exosomes, holds early promise for patients who have exhausted other treatment options. EVs, including exosomes, are nano-sized structures released by cells, facilitating cellular communication through bioactive molecule transfer, and offering potential regenerative properties to damaged tissues. Here, we review the potential of EVs and exosomes for the management of chronic pain. RECENT FINDINGS/RESULTS:In osteoarthritis, various exosomes, such as those derived from synovial mesenchymal stem cells, human placental cells, dental pulp stem cells, and bone marrow-derived mesenchymal stem cells (MSCs), demonstrate the ability to reduce inflammation, promote tissue repair, and alleviate pain in animal models. In intervertebral disc disease, Wharton's jelly MSC-derived EVs enhance cell viability and reduce inflammation. In addition, various forms of exosomes have been shown to reduce signs of inflammation in neurons and alleviate pain in neuropathic conditions in animal models. Although clinical applications of EVs and exosomes are still in the early clinical stages, they offer immense potential in the future management of chronic pain conditions. Clinical trials are ongoing to explore their therapeutic potential further, and with more research the potential applicability of EVs and exosomes will be fully understood.

KRAS is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with G12C mutation and advanced our understanding of its function. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V transgenic mouse model. We explore the therapeutic potential of KRASG12V degradation and characterize its impact on the tumor microenvironment (TME). Our study reveals that degrading KRASG12V abolishes lung and pancreatic tumors in mice and causes a robust inhibition of KRAS-regulated cancer intrinsic signaling. Importantly, targeted degradation of KRASG12V reprograms the TME towards a stimulatory milieu and drives antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides important insights into the impact of degrading KRASG12V on both tumor progression and immune response, highlighting degraders as a powerful strategy for targeting KRAS mutant cancers.

CYP1B1 is the most common gene implicated in primary congenital glaucoma (PCG) - the most common form of childhood glaucoma. How CYP1B1 mutations cause PCG is not known. Understanding the mechanism of PCG caused by CYP1B1 mutations is crucial for disease management, therapeutics development, and potential prevention. We performed a comprehensive metabolome/reactome analysis of CYP1B1 to enlist CYP1B1-mediated processes in eye development. The identified metabolic events were classified into major pathways. Functional analysis of these metabolic pathways was performed after cloning the CYP1B1 wild-type gene and expressing the wild-type and selected novel mutants (previously reported by our group L24R, F190L, H279D, and G329D) in heterologous hosts. Stability and enzymatic functions were investigated. Structural modeling of the wild-type and the variants was also performed. Reactome analysis revealed a total of 166 metabolic processes which could be classified into four major pathways including estradiol metabolism, retinoic acid metabolism, arachidonic acid metabolism, and melatonin metabolism. Stability assay revealed rapid denaturing of mutant proteins compared to wild-type. Enzymatic assays showed functional deficit in mutant proteins in metabolizing estradiol, retinoids, arachidonate, and melatonin. Modeling revealed that the examined mutations induced structural changes likely causative in functional loss in CYB1B1 as observed in enzymatic assays. Hence, mutations in the CYP1B1 gene are associated with a functional deficit in critical pathways of eye development. These findings implicate the potential contributions of altered metabolic regulations of estradiol, retinoids, arachidonate and melatonin to the pathogenesis of PCG during the processes of the formation of ocular structures and function.

The surtvep package is an open-source software designed for estimating time-varying effects in survival analysis using the Cox non-proportional hazards model in R. With the rapid increase in large-scale time-to-event data from national disease registries, detecting and accounting for time-varying effects in medical studies have become crucial. Current software solutions often face computational issues such as memory limitations when handling large datasets. Furthermore, modeling time-varying effects for time-to-event data can be challenging due to small at-risk sets and numerical instability near the end of the follow-up period. surtvep addresses these challenges by implementing a computationally efficient Kronecker product-based proximal algorithm, supporting both unstratified and stratified models. The package also incorporates P-spline and smoothing spline penalties to improve estimation (Eilers & Marx, 1996). Cross-validation and information criteria are available to determine the optimal tuning parameters. Parallel computation is enabled to further enhance computational efficiency. A variety of operating characteristics are provided, including estimated time-varying effects, confidence intervals, hypothesis testing, and estimated hazard functions and survival probabilities. The surtvep package thus offers a comprehensive and flexible solution to analyzing large-scale time-to-event data with dynamic effect trajectories.

BACKGROUND:Clinical guidelines have concluded that there are insufficient data to provide recommendations for the hemoglobin threshold for the use of red cell transfusion in patients with acute myocardial infarction (MI) and anemia. After the recent publication of the Myocardial Infarction and Transfusion (MINT) trial, we performed an individual patient-level data meta-analysis to evaluate the effect of restrictive versus liberal blood transfusion strategies. METHODS:We conducted searches in major databases. Eligible trials randomly assigned patients with MI and anemia to either a restrictive (i.e., transfusion threshold of 7-8 g/dl) or liberal (i.e., transfusion threshold of 10 g/dl) red cell transfusion strategy. We used individual patient data from each trial. The primary outcome was a composite of 30-day mortality or MI. RESULTS:We included 4311 patients from four trials. The primary outcome occurred in 334 patients (15.4%) in the restrictive strategy and 296 patients (13.8%) in the liberal strategy (relative risk [RR] 1.13, 95% confidence interval [CI], 0.97 to 1.30). Death at 30 days occurred in 9.3% of patients in the restrictive strategy and in 8.1% of patients in the liberal strategy (RR 1.15, 95% CI, 0.95 to 1.39). Cardiac death at 30 days occurred in 5.5% of patients in the restrictive strategy and in 3.7% of patients in the liberal strategy (RR 1.47, 95% CI, 1.11 to 1.94). Heart failure (RR 0.89, 95% CI, 0.70 to 1.13) was similar in the transfusion strategies. All-cause mortality at 6 months occurred in 20.5% of patients in the restrictive strategy compared with 19.1% of patients in the liberal strategy (hazard ratio 1.08, 95% CI, 1.05 to 1.11). CONCLUSIONS:Pooling individual patient data from four trials did not find a definitive difference in our primary composite outcome of MI or death at 30 days. At 6 months, a restrictive transfusion strategy was associated with increased all-cause mortality. (Partially funded by a grant from the U.S. National Heart, Lung, and Blood Institute [R01HL171977].).

Multiple open and endoscopic techniques have been described for recalcitrant cases of plantar fasciitis. Compared with open techniques, endoscopic plantar fasciotomy has been shown to be safe and effective with decreased postoperative pain and quicker recovery, as well as decreased risk of soft tissue and neurovascular injury, while retaining the ability to provide direct visualization of the plantar fascia to facilitate proper release. Single-portal endoscopic techniques may offer additional advantages including less portal site and postoperative pain, earlier return to activities, and cost-effectiveness and higher patient satisfaction when performed in the office setting. This Technical Note describes the authors' technique for nanoscopic plantar fasciotomy using a single-portal needle arthroscopy system, as well as advantages and limitations of this technique.

Despite the rise in chronic, untreated opioid use among pregnant women, their rate of receiving medications for opioid use disorder (MOUD) has remained stagnant since the mid-1990s. Using retrospective cross-sectional substance use treatment admissions data from 2015 to 2019, we examined access to treatment for opioid use by pregnant adults across 48 U.S. states. We found that younger adults, Black women, those referred to treatment by a criminal justice agency (e.g., judge, probation officer), those reporting polysubstance use, and those receiving treatment in residential settings were far less likely to receive MOUD (i.e., methadone, buprenorphine, naltrexone). We used multilevel analysis to examine the structural influence of state-level reproductive rights policies on pregnant women's access to MOUD. Adjusted counterfactual predictions reveal being admitted to treatment in a severely restrictive state context results in a significant decline in the likelihood of receiving MOUD, from 67% to 29%. We estimate 12,609 additional pregnant women seeking treatment for opioid use would have accessed first-line opioid pharmacotherapy if individuals in restrictive states had accessed medication at the same rate as those in more supportive states. Taken together, these findings offer insights into how reproductive rights serve as a structural determinant of health and safeguard for opioid medication treatment. We discuss the consequences of reversing reproductive rights policies amidst rising rates of drug overdose deaths among pregnant women along with the growing availability of illegally manufactured opioid analogs, as well as psychostimulant co-use, re-shaping overdose risk patterns in the U.S.

Methamphetamine (MA) dependence leads to severe physical and psychological issues. Current treatments, including psychosocial therapies and residential rehabilitation, face limitations such as high relapse rates, cost, and accessibility issues. As a result, there is an urgent need for novel approaches to treat MA dependence that are effective, affordable, and accessible to patients. Psilocybin, the active component in numerous mushrooms of the Psilocybe genus, has shown potential for enhancing psychotherapy for various addiction and mental health issues due to its effects on perception, cognition, and affect. Psilocybin-assisted psychotherapy (PAT) has demonstrated initial safety and efficacy in treating alcohol, cocaine, and nicotine dependence. The case presented here describes a 36-year-old transwoman and daily MA user, who participated in a single-arm open-label clinical trial assessing feasibility and safety of PAT for MA dependence at St. Vincent's Hospital, Sydney. Following inpatient withdrawal management and one session of psilocybin-assisted therapy, she experienced significant cognitive and emotional shifts and sustained MA abstinence. She reported improved mental health over 3 months following treatment completion. She also noted increased self-esteem, mindfulness, and distress tolerance. This study suggests that PAT (following inpatient MA withdrawal management) may offer a scalable, safe, and effective approach for treating MA dependence. However, further research is required to confirm the generalisability and efficacy of PAT for broader populations of people using MA. It is encouraging that this participant, a daily MA user, showed improvements in mood and cognition, in addition to abstinence from MA.

Mounier-Kuhn syndrome (MKS) or tracheobronchomegaly is an uncommon disease of the central airways. It is characterized by pathological dilatation of the trachea and main bronchi and inevitably leads to recurrent respiratory infections, bronchiectasis, hospitalizations, and results in considerable morbidity and mortality. Despite numerous case reports, there is a shortage of evidence on clinical outcomes and limited data on interventions, thus presenting a significant gap in the literature. Fortunately, new strategies and increasing clinical experience have improved the clinical approach, diagnostic workup, classification, and management of MKS. Articles in English, Spanish, and French were searched from databases, including Pubmed, Google Scholar, Medline, and SCOPUS, using the terms "Mounier-Kuhn syndrome," "Tracheomegaly," "Tracheobronchomegaly," and "Bronchomegaly," without date restrictions. A total of 360 articles with the aforementioned syntax were indexed on Pubmed. This state-of-the-art review attempts to fill a void in the current literature by summarize the current scientific knowledge and highlighting novel interventional strategies in the management of Mounier Kuhn Syndrome.

The Youth Risk Behavior Survey (YRBS) Data Summary & Trends Report for 2011-2021 released in February 2023 showed higher rates among female high school students relative to their male peers in endorsements of experiencing poor mental health. This review provides a developmental orientation to promote a biopsychosocial conceptualization of these recent national findings. Young women have higher rates of depressed mood, suicidal ideation, and suicidal plans relative to men, and this gender discrepancy is widening. Higher rates of endorsed school and electronic bullying, social media use, substance use, sexual victimization, and school safety concerns among young women are considered in relation to their sex-specific impact. Recommendations for clinicians are offered to improve the awareness of these important factors and to guide tailored interventions.