Histone deacetylase 6 (HDAC6) represents a compelling target in major depressive disorder (MDD) pathophysiology, yet in vivo investigation has been constrained by inadequate imaging capabilities. Here, we report the development and validation of [18F]PB200, a novel positron emission tomography (PET) radiotracer specifically targeting brain HDAC6. PB200 was engineered with nanomolar affinity, high HDAC6 selectivity, and excellent blood-brain barrier permeability. [18F]PB200 was successfully synthesized in a radiochemical yield of 13 ± 4 % and validated through in vitro autoradiography and in vivo PET imaging across rodent and non-human primate models. We subsequently employed [18F]PB200 alongside TSPO-targeted [18F]FEPPA PET imaging in a chronic unpredictable mild stress (CUMS) mouse model of depression. This dual-tracer approach, complemented by in vitro experiments, revealed significant HDAC6 upregulation occurring concurrently with enhanced neuroinflammatory markers, including microglial activation and elevated pro-inflammatory cytokines. Our findings provide the first in vivo molecular imaging evidence directly linking HDAC6 upregulation to depressive pathophysiology and associated neuroinflammation. This work illuminates the molecular relationship between depression and neuroinflammation while establishing [18F]PB200 as a valuable tool for evaluating HDAC6-targeted therapeutic interventions, potentially advancing precision diagnosis and treatment approaches for depression.
Publications by Year: 2026
2026
BACKGROUND: Low left ventricular ejection fraction (LEF) can progress undiagnosed. Artificial intelligence-based electrocardiogram (ECG-AI) screening may provide a scalable means to detect LEF.
OBJECTIVES: The purpose of this study was to validate a complete ECG-AI software as a medical device for LEF detection.
METHODS: Four geographically diverse sites in the United States identified patients with both ECGs and transthoracic echocardiograms performed within 30 days of each other in clinical practice. Data were electronically extracted to specific guidelines and transmitted to the coordinating center for analysis.
RESULTS: Records of 16,000 subjects were extracted, resulting in an evaluable set of 13,960 subjects (mean age 66 years; 52% male). The device demonstrated excellent discrimination (AUROC: 0.92 [95% CI: 0.91-0.93]) and was 84.5% (95% CI: 82.2%-86.6%) sensitive and 83.6% (95% CI: 82.9%-84.2%) specific for LEF. The overall prevalence of LEF in the study data set was 7.9%, with LEF among 1.6% of the ECG-AI negative and 30.5% of ECG-AI positive subjects, contributing to positive and negative predictive values of 30.5% (95% CI: 28.8%-32.1%) and 98.4% (95% CI: 98.2%-98.7%), respectively.
CONCLUSIONS: External validation studies such as this one provide a rigorous framework to validate an algorithm's performance. This study demonstrated the algorithm's strong diagnostic accuracy over a geographically diverse, independent set of patients. In this generally unselected population, the algorithm produced a test negative result in 78% of the cases, suggesting potential utility as a rule-out strategy to defer echocardiography when other clinical findings are absent.
BACKGROUND: A label of betalactam (BL) allergy is estimated in around 10% of the population in their medical records. Second-line choices carry significant negative consequences, including reduced efficacy, effectiveness, and safety. This study aimed to develop a new highly specific score constructed by selecting variables assisted by artificial intelligence to identify low-risk BL-allergic patients.
METHODS: In this study, derivation and validation of the BL-predictor score were performed on a retrospective cohort of 2207 patients who underwent penicillin allergy testing at Málaga University Hospital (Spain). The development of the BL-predictor encompassed expert drafting and a two-step variable selection process consisting of univariate analysis and variable filtering, followed by stepwise logistic regression with resampling. To assess the efficiency, a multicentric retrospective external validation was performed in 4261 patients from six populations: Salamanca and Madrid, Spain; Nashville, United States of America; Verona, Italy; Paris, France; and Copenhagen, Denmark.
RESULTS: The definitive questionnaire consisted of eight items and risk points were computed from the logistic regression model as follows: +1 for reactions after first dose or in less than 1 h (ITEM-1), +2 for anaphylaxis (ITEM-2); +1 for previous reaction with the culprit (ITEM-3); -1 for resolution in > 24 h (ITEM-4); +2 for spontaneous resolution (ITEM-5); -2 for unknown symptoms (ITEM-6); -2 for reaction occurred > 5 years (ITEM-7), and -1 for another reported drug allergy (ITEM-8). After establishing a threshold of ≤ 0 points to classify individuals with low risk, internal validation showed a specificity of 86% and a negative predictive value (NPV) of 83%. Overall multicenter external validation showed a specificity of 93%, which implies a 25% increase in specificity compared to the previously published BL decision tool.
CONCLUSION: This score would simplify diagnostic procedures in low-risk patients, enabling rapid delabeling, potentially in non-specialty settings, and reducing diagnostic costs and the negative consequences associated with incorrect antibiotic allergy labels.
Amidst the opioid crisis, understanding the genetic basis of opioid use disorder (OUD) is crucial for identifying biological mechanisms and intervention points. However, genome-wide association studies (GWASs) have been hampered by inadequate sample sizes and often the use of control populations not assessed for prior opioid exposure. Because opioid exposure is a prerequisite for the development of OUD, consideration of exposure history in controls is important. Electronic health record data (EHR) paired with genomic information allow a broader sampling of patients with OUD and exposed controls. We leveraged data across two healthcare systems to evaluate the impact of using controls not screened for opioid exposure ('generic') versus minimally opioid-exposed control ('exposed'). First, at the phenotypic level, we conducted phenome-wide association studies (PheWAS) to compare the medical comorbidity profiles of OUD cases when using generic versus exposed controls. While PheWAS results for OUD-related comorbidities were more pronounced when using the generic group, 83% of the disease associations were overlapping and of similar effect sizes. Second, at the genetic level, we conducted GWAS (cases vs. generic; cases vs. exposed) and assessed differences in genetic correlations and degrees of phenotypic misclassification. Genetic results were concordant across control groups based on heritability (generic: 0.16 ± 0.07 vs. 0.10 ± 0.07), associations with the coding OPRM1 variant rs1799971 (pgeneric = 8.83E-03 vs. pexposed = 1.83E-02) and genetic correlations with prior OUD GWAS (rg-generic = 0.83 ± 0.26 vs. rg-exposed = 0.78 ± 0.27). Although GWASs were limited by sample size (Ngeneric = 6269, Nexposed = 6365), compared to an independent OUD GWAS (N = 425 944), the dilution value for the two GWAS was not different from 1, suggesting no major impact of phenotypic misclassification. This study represents the first effort to enhance OUD genetic research through optimization of control definitions using EHR data. Generic controls ascertained within the US health systems, where exposure to prescription opioids is high, offer a practical alternative for genetic studies of OUD.
INTRODUCTION: Long-acting injectable cabotegravir (CAB-LA) is superior to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis (PrEP) and could expand PrEP usage. Given price differentials between CAB-LA and TDF/FTC, evaluating the cost-effectiveness of potential PrEP coverage scenarios is warranted.
METHODS: We simulated PrEP coverage expansion among men who have sex with men (MSM) via introducing CAB-LA using two age- and risk-stratified HIV transmission models separately calibrated to local data from a high-incidence (Atlanta, USA) and a low-incidence (Montréal, Canada) North American setting. PrEP coverage of HIV-negative MSM was simulated to increase from 6% to 15%, 30%, 40% or 50% (Montréal) or from 29% to 40% or 50% (Atlanta), within 5 or 10 years, with 0%, 15%, 30%, 50% or 100% of current TDF/FTC users switching to CAB-LA. Costing took a healthcare payer perspective and included PrEP pharmaceuticals, PrEP programmatic costs and HIV-related care. Atlanta scenarios considered oral PrEP acquired at average recent market prices (primary analysis), and both settings modelled universal acquisition at the lowest available generic price (LAGP). Simulations were compared to baseline projections without CAB-LA-based expansions over 20 years, with costs and disability-adjusted life years (DALYs) discounted 3% annually. Incremental cost-effectiveness ratios (ICERs) of expansions were assessed against a $100,000 per DALY averted threshold.
RESULTS: In Atlanta, scenario median ICERs at recent prices ranged from $141,600 (90% CI $60,100-$256,000) to $203,800 ($99,300-$359,200) per DALY averted. All uncertainty intervals covered $100,000. Under universal LAGP TDF-FTC, median ICERs ranged from $255,800 ($112,900-$452,30) to $370,700 ($172,200-$669,100). The strongest expansion scenarios were expected to remain cost-effective until approximately $2800/dose, or approximately $1350 with universal LAGP TDF/FTC. In Montréal, scenarios had median ICERs from $920,000 to $2,540,000, excluding dominated runs.
CONCLUSIONS: In a high-incidence Atlanta MSM population, CAB-LA-based PrEP expansions are not projected to be cost-effective, though a minority of simulations achieved cost-effectiveness. However, lower prices could achieve cost-effectiveness. In a low-incidence Montréal MSM population, broad expansions are not expected to be cost-effective at modelled prices. Prioritizing CAB-LA to Montréal MSM facing access, adherence or persistence barriers to oral PrEP warrants a cost-effectiveness assessment.
OBJECTIVES: The impact of the genetic risk for RA on resultant disease phenotype in RA is incompletely understood. Using individual genetic variants associated with RA and a polygenic score (PGS), we hypothesized that those with higher genetic risk for RA would demonstrate a more severe disease course.
METHODS: We genotyped participants from the Veterans Affairs RA registry (VARA), a prospective cohort of RA. We evaluated associations between PTPN22 R620W genotype, HLA-DRB1 shared epitope (SE; 0, 1, or 2 copies of a high-risk HLA allele), and a non-HLA PGS with RA disease activity scores and disease characteristics using linear and logistic regression, adjusted for sex, age, and principal components of population structure.
RESULTS: Among 2557 VARA participants, 50 (2%) were homozygous for PTPN22 R620W, and 1603 (62%) had a PGS greater than the 50th percentile when compared with a reference population. PTPN22 R620W, SE, and the PGS were strongly associated with seropositivity (PGS OR = 1.41, 95% CI 1.26-1.58, P < 0.001). At enrolment, compared with those with no R620W alleles, those with two alleles had higher disease activity [CDAI β = 6.10, 95% CI 1.23-10.97, P = 0.014]; no difference was observed for those with one R620W allele or SE. PGS was not significantly associated with disease activity.
CONCLUSION: Genetic variation renders heterogeneous associations with disease activity and phenotype in RA. Individual genetic variants and pathway-specific genetic risk associated with RA may be more informative than the pooled genetic risk in understanding disease phenotype and disease activity.
This study builds on a growing body of research seeking to define multidimensional loss chasing. Analyzing data from 36,325 online sports bettors, the focus was to identify which loss accumulation period (loss period; i.e., immediate losses vs. daily, weekly, monthly, and total cumulative losses) maximizes the predictive relationship between loss chasing and diverse potential harm outcomes. We found that the daily loss period yielded the best predictive efficacy for two harm outcomes (loss trajectory and voluntary self-exclusion [VSE]). Loss chasing was not associated with a third harm outcome (percent change in net loss) for any loss period. Overall, the findings suggest that the loss accumulation period for loss chasing matters for predicting harms, with daily losses presenting the most potential importance and relevance to potential gambling harm. These findings can be used to inform new predictive models for identifying risk for gambling harm from betting records.
STUDY DESIGN: Retrospective cohort study.
OBJECTIVE: To characterize the success rate of anti-osteoporosis treatment for patients with spine fracture that otherwise confers eligibility for treatment. We also evaluated factors associated with successful initiation of treatment.
SUMMARY OF BACKGROUND DATA: Thoracic and lumbar spine fractures in patients ≥50 years of age after low energy injuries confer a diagnosis of osteoporosis and indicate eligibility for bone health treatment. Despite this, there is little information available regarding the extent to which these patients receive appropriate treatment and underlying factors that influence this decision.
METHODS: We included patients ≥50 years of age treated at one of four medical centers within a single system for Type A thoracic or lumbar spine fractures from low energy trauma between 2015- 2021. Clinical, radiographic, sociodemographic, and medication data were abstracted from the medical record. Patients were noted to have successful treatment if they had de novo initiation of bone health treatment, addition of a new bone health agent to a prior osteoporosis regimen, or switched between anti-osteoporosis agents within 90 days (90d) of injury. Bivariate statistics and logistic multivariable regression were utilized to identify factors associated with successful osteoporosis treatment while adjusting for potential confounders.
RESULTS: In total, 409 patients with complete data and 90d of follow-up were included. Only 41 (10%) patients had successful treatment initiation of bone health medications. In both bivariate and multivariable analyses, surgical intervention was the only factor significantly associated with bone health treatment. Patients treated with surgery demonstrated a more than 3-fold increase in the odds of receiving osteoporosis treatment (OR 3.35, 95%CI 1.42-7.58, P =0.003).
CONCLUSION: Appropriate osteoporosis treatment after low energy spine fracture was uncommon in our cohort, occurring in just 10% of patients. Active engagement on the part of spine surgeons increased the likelihood of receipt of bone health medications. This may represent a scalable intervention that can improve patient care.
LEVEL OF EVIDENCE: Level III.
The goal of the American Association of Bronchology and Interventional Pulmonology Essential Knowledge in Interventional Pulmonology Series is to provide clinicians with concise, up-to-date reviews of important topics in the field of interventional pulmonology. This 3-year alternating rotation of primary topics continues with the current discussion of selected concepts in bronchoscopic airway stenting. In this article, we update the reader on modern airway stenting practice in 3 parts: part 1- a data review of the therapeutic benefit of stenting in different clinical scenarios; part 2- an overview of stent-associated complications and initial postinsertion stent management; and part 3- new and evolving approaches to airway stenting. This review complements the Essential Knowledge in Interventional Pulmonology Lecture Series presented at the 2024 AABIP Annual Conference, available for viewing on the AABIP website (https://aabip.memberclicks.net/essential-knowledge-in-interventional-pu…).