Faculty Bibliography

Psychedelics, substances with a long history of cultural and medicinal use, are experiencing a resurgence in clinical research, particularly in psychiatry. Despite their classification as Schedule I drugs, recent studies suggest therapeutic potential, particularly in treating refractory depression. With chronic pain representing a major health concern and with few non-opioid treatment options available, psychedelics are being explored as alternative treatment modalities. The National Institutes of Health (NIH) now funds psychedelic research, marking a shift from previous decades of limited funding. However, ethical considerations loom large. Vulnerable populations, such as those with chronic pain that impairs their autonomy, require careful consideration by researchers of risks and benefits. Additionally, researchers and interested entities must navigate complex regulatory landscapes involving the United States Food and Drug Administration (FDA) and Drug Enforcement Administration (DEA) when considering pursuing possible research. Furthermore, transparent collaboration among stakeholders-patients, researchers, and regulatory bodies-is crucial for participant safety and successful research. Although a number of ethical approaches can be taken, we posit that stakeholders consider utilizing principal-based research ethics, comprised of the principles of autonomy, beneficence, justice, and nonmaleficence, to guide the process. Ultimately, balancing therapeutic promise with ethical integrity is paramount. Careful planning, collaboration, and adherence to ethical principles can increase the likelihood that psychedelic research in chronic pain management progresses responsibly, offering hope for patients while safeguarding their well-being.

Anxiety disorders are highly comorbid with sleep disturbance and have also been associated with deficits in emotion regulation, the ability to control and express emotions. However, the extent to which specific dimensions of sleep disturbance and emotion regulation are associated with anxiety diagnosis is not well-explored. This study examined dimensions of emotion regulation and sleep disturbance that may predict greater likelihood of anxiety diagnosis using novel machine learning techniques. Participants (Mean(SD) age= 28.6(11.3) years, 62.7% female) with primary anxiety disorders (n = 257), including generalized anxiety disorder (n = 122) and social anxiety disorder (n = 135), and healthy controls (n = 89) completed the Difficulties in Emotion Regulation Scale and Pittsburgh Sleep Quality Index. A conditional inference tree was fit to classify likelihood of current anxiety diagnosis based on predictors. The best model fit included 4 split nodes and 5 terminal nodes. Worse scores on two emotion regulation subscales, strategies directed to manage negative emotions and nonacceptance of negative emotions, were the best predictors of current anxiety diagnosis (99.3% probability of diagnosis). For those with better emotion regulation, poor sleep quality and worse daytime functioning due to sleep were important predictors of anxiety diagnosis. Good emotion regulation and non-disturbed sleep predicted high likelihood of being a non-psychiatric control (88.2%). Limitations include cross-sectional design precluding designating directionality of effects of sleep and emotion regulation on anxiety onset; limited sample size; and self-reported sleep. Facets of emotion regulation and sleep disturbance may be important early targets for brief intervention for anxiety disorders.

PURPOSE/UNASSIGNED:Multiparametric magnetic resonance imaging (MRI) is known to provide predictors for malignancy and treatment outcome. The inclusion of these datasets in workflows for online adaptive planning remains under investigation. We demonstrate the feasibility of longitudinal relaxometry in online MR-guided adaptive stereotactic body radiotherapy (SBRT) to the prostate and dominant intra-prostatic lesion (DIL). METHODS/UNASSIGNED:Fifty patients with intermediate-risk prostate cancer were included in the study. The clinical target volume (CTV) was defined as the prostate gland plus 1 cm of seminal vesicles. The gross tumor volume (GTV) was defined as the DIL identified on multiparametric MRI. Online adaptive radiotherapy was delivered in a 1.5 T MR-Linac using a prescription of 800 cGy/900 cGy × 5 fractions to the CTV + 3 mm/GTV + 2 mm. Relaxometry and diffusion-weighted imaging were implemented using clinically available sequences. Test-retest measurements were performed in eight patients, at each treatment fraction. Bias and uncertainty in relaxometry measurements were also assessed using a reference phantom. RESULTS/UNASSIGNED:The bias in longitudinal/transverse relaxation times was negligible while uncertainty was within 3 %. Test-retest measurements demonstrate that bias/uncertainty in patient T1 and T2 were comparable to bias/uncertainty estimated in the phantom. Mean T1 and T2 relaxation were significantly different between the prostate and DIL. The correlation between T1, T2, and diffusion was significant in the DIL, but not in the prostate. During treatment, mean T1 in the DIL approaches mean T1 in the prostate. CONCLUSIONS/UNASSIGNED:Longitudinal relaxometry for online MR-guided adaptive SBRT is feasible in a high-field MR-Linac and may provide complementary information for target delineation and response assessment.

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.

The degree of immunological compatibility between donors and recipients greatly impacts allograft survival. In the United States kidney allocation system, HLA antigen-level matching has been shown to cause ethnic disparities and thus, has been de-emphasised. However, priority points are still awarded for antigen-level zero-ABDR matching, zero-DR matching and one-DR matching. Recently, the degree of HLA molecular (eplet) mismatch has emerged as a more accurate measure of immunological risk, and eplet mismatch load has gained attention as a possible biomarker to improve HLA compatibility. However, little is known about the frequency of eplets in population groups, which is a necessary step to ensure that candidates from any ethnical background can have similar chances at a well-matched organ. Eplet frequencies were estimated using HLA alleles in the Common, Intermediate and Well-Documented (CIWD) 3.0.0 catalogue for six population groups: African-American (AFA), Asian-Pacific Islander (API), European/European descent (EURO), Middle East/North Coast of Africa (MENA), Hispanic/Latino (HIS) and Native-American (NAM). We determined that 98.6% (484 out of 491) of HLA eplets are expressed by the common HLA alleles in all population groups. Of the seven eplets that were expressed by less common HLA alleles, six were Class I eplets and one was expressed by HLA-DQB1 alleles and most were expressed by HLA alleles that were more commonly observed in European/European descent populations. Our observations indicate that HLA eplets will not cause any significant disparity if applied to HLA molecular compatibility, regardless of the ethnic origin of both recipients and donors.

Mirror-image proteins, composed of D-amino acids, are an attractive therapeutic modality, as they exhibit high metabolic stability and lack immunogenicity. Development of mirror-image binding proteins is achieved through chemical synthesis of D-target proteins, phage display library selection of L-binders and chemical synthesis of (mirror-image) D-binders that consequently bind the physiological L-targets. Monobodies are well-established synthetic (L-)binding proteins and their small size (~90 residues) and lack of endogenous cysteine residues make them particularly accessible to chemical synthesis. Here, we develop monobodies with nanomolar binding affinities against the D-SH2 domain of the leukemic tyrosine kinase BCR::ABL1. Two crystal structures of heterochiral monobody-SH2 complexes reveal targeting of the pY binding pocket by an unconventional binding mode. We then prepare potent D-monobodies by either ligating two chemically synthesized D-peptides or by self-assembly without ligation. Their proper folding and stability are determined and high-affinity binding to the L-target is shown. D-monobodies are protease-resistant, show long-term plasma stability, inhibit BCR::ABL1 kinase activity and bind BCR::ABL1 in cell lysates and permeabilized cells. Hence, we demonstrate that functional D-monobodies can be developed readily. Our work represents an important step towards possible future therapeutic use of D-monobodies when combined with emerging methods to enable cytoplasmic delivery of monobodies.

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.

UNLABELLED: TRIAL REGISTRATION/UNASSIGNED:clinicaltrials.gov Identifier: NCT01179568.

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].).