Search

Simple Summary: Brachytherapy is a key component of radiation treatment in the curative treatment of locally advanced cervical cancer. To improve the delivery of brachytherapy, recent studies have explored the use of imaging, such as magnetic resonance imaging (MRI), in treatment planning. In this review, we reviewed the current evidence for image-guided brachytherapy and discussed future directions for research. Purpose: The standard of care for patients with locally advanced cervical cancer is definitive chemoradiation followed by a brachytherapy boost. This review describes the current status and future directions of image-guided adaptive brachytherapy for locally advanced cervical cancer. Methods: A systematic search of the PubMed and Clinicaltrials.gov databases was performed, focusing on studies published within the last 10 years. The search queried "cervical cancer [AND] image-guided brachytherapy [OR] magnetic resonance imaging (MRI) [OR] adaptive brachytherapy". Discussion: The retroEMBRACE and EMBRACE-I trials have established the use of MRI as the standard imaging modality for brachytherapy application and planning. Quantitative imaging and radiomics have the potential to improve outcomes, with three ongoing prospective studies examining the use of radiomics to further risk-stratify patients and personalize brachytherapy. Another active area of investigation includes utilizing the superior soft tissue contrast provided by MRI to increase the dose per fraction and decrease the number of fractions needed for brachytherapy, with several retrospective studies demonstrating the safety and feasibility of three-fraction courses. For developing countries with limited access to MRI, trans-rectal ultrasound (TRUS) appears to be an effective alternative, with several retrospective studies demonstrating improved target delineation with the use of TRUS in conjunction with CT guidance. Conclusions: Further investigation is needed to continue improving outcomes for patients with locally advanced cervical cancer treated with image-guided brachytherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancers are highly aggressive tumors that carry a poor prognosis. With recent advances in radiation therapy techniques and systemic therapy, there is hope that the treatment landscape for pancreatic cancers will improve in the near future. This review summarizes radiation dose escalation strategies to improve outcomes in locally advanced pancreatic cancer as well as novel neoadjuvant therapy strategies to improve outcomes in resectable and borderline resectable pancreatic cancers. This review aims to summarize the recent advances in radiation oncology for pancreatic cancer. A systematic search of the MEDLINE/PubMed database and Clinicaltrials.gov was performed, focusing on studies published within the last 10 years. Our search queried "locally advanced pancreatic cancer [AND] stereotactic body radiation therapy (SBRT) [OR] hypofractionation [OR] magnetic resonance guidance radiation therapy (MRgRT) [OR] proton" and "borderline resectable pancreatic cancer [AND] neoadjuvant radiation" and was limited only to prospective and retrospective studies and metanalyses. For locally advanced pancreatic cancers (LAPC), retrospective evidence supports the notion of radiation dose escalation to improve overall survival (OS). Novel methods for increasing the dose to high risk areas while avoiding dose to organs at risk (OARs) include SBRT or ablative hypofractionation using a simultaneous integrated boost (SIB) technique, MRgRT, or charged particle therapy. The use of molecularly targeted agents with radiation to improve radiosensitization has also shown promise in several prospective studies. For resectable and borderline resectable pancreatic cancers (RPC and BRPC), several randomized trials are currently underway to study whether current neoadjuvant regimens using radiation may be improved with the use of the multi-drug regimen FOLFIRINOX or immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Robotic-assisted pancreatectomy continues to proliferate despite limited evidence supporting its benefits from the patient's perspective. We compared patient-reported outcomes (PROs) between patients undergoing robotic and open pancreatectomies. PROs, measured with the FACT-Hep, FACT-G, and HCS, were assessed in the immediate postoperative (i.e., preoperative to discharge) and recovery (i.e., discharge to three months postoperative) periods. Linear mixed models estimated the association of operative approach on PROs. Minimally important differences (MIDs) were also considered. Among 139 patients, 105 (75.5%) underwent robotic pancreatectomies. Compared to those who underwent open operations, those who underwent robotic operations experienced worse FACT-Hep scores that were both statistically and clinically significant (mean difference [MD] 8.6 points, 95% CI 1.0–16.3). Declines in FACT-G (MD 4.3, 95% CI −1.0 to 9.6) and HCS (MD 4.3, 95% CI 0.8–7.9) scores appeared to contribute equally in both operative approaches to the decline in total FACT-Hep score. Patients who underwent robotic versus open operations both statistically and clinically significantly improved due to improvements in HCS (MD 6.1, 95% CI 2.3–9.9) but not in FACT-G (MD 1.2, 95% CI − 5.1-7.4). The robotic approach to pancreas surgery might offer, from the patient's perspective, greater improvement in symptoms over the open approach by three months postoperatively. [ABSTRACT FROM AUTHOR]

Background: Internal mammary artery pseudoaneurysms most commonly develop from thoracic penetrating trauma or procedures. However, other important etiologies should not be overlooked. Case Report: A 27-year-old female presentedwith antiphospholipid antibody syndrome, thrombotic microangiopathy, end-stage renal disease on hemodialysis, and epilepsy. On admission, the patient had pulseless electrical activity and hypertensive emergency. After the patientwas successfully resuscitated, she developed status epilepticus. Laboratoryworkup on admission revealed a subtherapeutic international normalized ratio, elevated C-reactive protein and sedimentation rate, and acute anemia. Imaging showed a right-sided subdural hematoma with amidline shift and likely internal mammary artery pseudoaneurysm. Angiography demonstrated aneurysmal dilation, segmental narrowing, and a string of beads appearance. Because of our patient's demographics, string of beads appearance on diagnostic angiography, history of renal disease, and negative hepatitis serology, fibromuscular dysplasia was considered the etiology of the internal mammary artery pseudoaneurysm. The family opted for 2 burr holes and a subdural drain but declined further diagnostic and therapeutic interventions because of anoxic brain injury and poor prognosis. Conclusion: In this patient, the etiology of the internal mammary artery pseudoaneurysm was attributed to fibromuscular dysplasia. Although this patient's family chose comfortmeasures, treatmentmethods are available for internal mammary artery pseudoaneurysms. [ABSTRACT FROM AUTHOR]

This article considers the problem of designing lead, lag, and lead-lag compensators for multi-input–multi-output (MIMO) linear systems under the $H_{\infty }$ performance measure. This is the first time that the lead, lag and lead-lag compensators are generalized to the MIMO cases by preserving their classical compensator structures. Theoretical results on the stability analysis and synthesis of MIMO systems under the $H_{\infty }$ control performance with the proposed lead, lag, and lead-lag compensators are obtained. Then relevant algorithms for designing lead, lag, and lead-lag compensators are provided to determine the compensator parameters. Differing from traditional design methods, which mostly rely on some trial-and-error procedures, the proposed methods are algorithmic and the compensators can be synthesized systematically. Illustrative examples are used to demonstrate the effectiveness and advantages of the proposed methods. [ABSTRACT FROM AUTHOR]

The development of mobile-health technology has the potential to revolutionize personalized medicine. Biomedical sensors (e.g. wearables) can assist with determining treatment plans for individuals, provide quantitative information to healthcare providers, and give objective measurements of health, leading to the goal of precise phenotypic correlates for genotypes. Even though treatments and interventions are becoming more specific and datasets more abundant, measuring the causal impact of health interventions requires careful considerations of complex covariate structures, as well as knowledge of the temporal and spatial properties of the data. Thus, interpreting biomedical sensor data needs to make use of specialized statistical models. Here, we show how the Bayesian structural time series framework, widely used in economics, can be applied to these data. This framework corrects for covariates to provide accurate assessments of the significance of interventions. Furthermore, it allows for a time-dependent confidence interval of impact, which is useful for considering individualized assessments of intervention efficacy. We provide a customized biomedical adaptor tool, MhealthCI, around a specific implementation of the Bayesian structural time series framework that uniformly processes, prepares, and registers diverse biomedical data. We apply the software implementation of MhealthCI to a structured set of examples in biomedicine to showcase the ability of the framework to evaluate interventions with varying levels of data richness and covariate complexity and also compare the performance to other models. Specifically, we show how the framework is able to evaluate an exercise intervention's effect on stabilizing blood glucose in a diabetes dataset. We also provide a future-anticipating illustration from a behavioral dataset showcasing how the framework integrates complex spatial covariates. Overall, we show the robustness of the Bayesian structural time series framework when applied to biomedical sensor data, highlighting its increasing value for current and future datasets. Author summary: In this paper, we propose and describe a robust and flexible modelling framework called MhealthCI based on the Bayesian structural time series, for which we have found to excel at analyzing diverse biosensor data. While Bayesian modelling is often employed in various fields such as finance, marketing, and weather forecasting, it is rarely used in biomedicine, specifically for biosensor and wearable data relating to human health and behavior. We use and apply this framework with the goal of interpreting and quantifying the causal impact of an intervention, a widespread goal of biomedicine. We describe the diversity of data types to which it could apply, provide intuition to its mechanics, collect relevant data in various fields, provide a wrapper tool around well-known R packages that prepares and registers diverse biosensor data to be analyzed, and finally apply the method to showcase its strength in quantifying the impact of interventions. [ABSTRACT FROM AUTHOR]

With the recent success of immunotherapy, there is a growing interest in combining radiation with immunotherapy to boost abscopal response rates. Several challenges exist in determining how to synergize these two modalities in the treatment of metastatic NSCLC. References for this review were identified through searches of MEDLINE/PubMed and Clinicaltrials.gov databases with the search terms "abscopal", "radiation OR radiotherapy," "NSCLC", and "lung" on the index date of July 2022 from 2000-2022. This systematic review focuses primarily on clinical papers. Early work combining radiotherapy with immunotherapy show promise in unlocking the abscopal effect. Preliminary evidence suggests that radiotherapy regimens with <5 fractions and smaller fields may be superior to regimens with 15 fractions and larger fields. There does not appear to be enough evidence to draw conclusions about the optimal timing of radiotherapy in relation to immunotherapy or the optimal anatomical location of radiation to induce the abscopal effect. Several studies suggest selecting patients with a higher absolute lymphocyte count (ALC) and lower neutrophil-to-lymphocyte ratio (NLR) may help to further boost abscopal response rates. Furthermore, selecting tumors with programmed death ligand-1 (PD-L1) expression, mismatch repair deficiency, and higher tumor mutational burden may similarly achieve this goal. Lastly, additional work is needed to minimize and predict for severe toxicity associated with combination therapy. [ABSTRACT FROM AUTHOR]

Background: Unbalanced translocations can cause developmental delay (DD), intellectual disability (ID), growth problems, dysmorphic features, and congenital anomalies. They may arise de novo or may be inherited from a parent carrying a balanced rearrangement. It is estimated that 1/500 people is a balanced translocation carrier. The outcomes of different chromosomal rearrangements have the potential to reveal the functional consequences of partial trisomy or partial monosomy and can help guide genetic counseling for balanced carriers, and other young patients diagnosed with similar imbalances. Methods: We performed clinical phenotyping and cytogenetic analyses of two siblings with a history of developmental delay (DD), intellectual disability (ID) and dysmorphic features. Results: The proband, a 38-year-old female, has a history of short stature, dysmorphic features and aortic coarctation. She underwent chromosomal microarray analysis, which identified partial monosomy of 4q and partial trisomy of 10p. Her brother, a 37-year-old male, has a history of more severe DD, behavioral problems, dysmorphic features, and congenital anomalies. Subsequently, karyotype confirmed two different unbalanced translocations in the siblings: 46,XX,der(4)t(4;10)(q33;p15.1) and 46,XY,der(10)t(4;10)(q33;p15.1), respectively. These chromosomal rearrangements represent two possible outcomes from a parent who is a carrier for a balanced translocation 46,XX,t(4;10)(q33;p15.1). Conclusion: To our knowledge, this 4q and 10p translocation has not been described in literature. In this report we compare clinical features due to the composite effects of partial monosomy 4q with partial trisomy 10p and partial trisomy 4q with partial monosomy 10p. These findings speak to the relevance of old and new genomic testing, the viability of these segregation outcomes, and need for genetic counseling. [ABSTRACT FROM AUTHOR]

Given the increased use of air cleaners as a prevention measure in classrooms during the COVID-19 pandemic, this study aimed to investigate the effects of portable air cleaners with HEPA filters and window A/C fans on real-time (1 minute) concentrations of PM less than 2.5 microns (PM2.5) or less than 1 microns (PM1.0) in two classrooms in a non-urban elementary school in Rhode Island. For half of each school day, settings were randomized to "high" or "low" for the air cleaner and "on" or "off" for the fan. Descriptive statistics and linear mixed models were used to evaluate the impacts of each set of conditions on PM2.5 and PM1.0 concentrations. The mean half-day concentrations ranged from 3.4–4.1 μg/m3 for PM2.5 and 3.4–3.9 μg/m3 for PM1.0. On average, use of the fan when the air cleaner was on the low setting decreased PM2.5 by 0.53 μg/m3 [95% CI: -0.64, -0.42] and use of the filter on high (compared to low) when the fan was off decreased PM2.5 by 0.10 μg/m3 [95% CI: -0.20, 0.005]. For PM1.0, use of the fan when the air cleaner was on low decreased concentrations by 0.18 μg/m3 [95% CI: -0.36, -0.01] and use of the filter on high (compared to low) when the fan was off decreased concentrations by 0.38 μg/m3 [95% CI: -0.55, -0.21]. In general, simultaneous use of the fan and filter on high did not result in additional decreases in PM concentrations compared to the simple addition of each appliance's individual effect estimates. Our study suggests that concurrent or separate use of an A/C fan and air cleaner in non-urban classrooms with low background PM may reduce classroom PM concentrations. [ABSTRACT FROM AUTHOR]

Background: The quality of patient-reported outcome measures (PROMs) used to assess the outcomes of primary hyperparathyroidism (PHPT), a common endocrine disorder that can negatively affect patients' health-related quality of life due to chronic symptoms, has not been rigorously examined. This systematic review aimed to summarize and evaluate evidence on the measurement properties of PROMs used in adult patients with PHPT, and to provide recommendations for appropriate measure selection. Methods: After PROSPERO registration (CRD42023438287), Medline, EMBASE, CINAHL Complete, Web of Science, PsycINFO, and Cochrane Trials were searched for full-text articles in English investigating PROM development, pilot studies, or evaluation of at least one PROM measurement property in adult patients with any clinical form of PHPT. Two reviewers independently identified studies for inclusion and conducted the review following the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) Methodology to assess risk of bias, evaluate the quality of measurement properties, and grade the certainty of evidence. Results: From 4989 records, nine PROM development or validation studies were identified for three PROMs: the SF-36, PAS, and PHPQoL. Though the PAS demonstrated sufficient test-retest reliability and convergent validity, and the PHPQoL sufficient test-retest reliability, convergent validity, and responsiveness, the certainty of evidence was low-to-very low due to risk of bias. All three PROMs lacked sufficient evidence for content validity in patients with PHPT. Conclusions: Based upon the available evidence, the SF-36, PAS, and PHPQoL cannot currently be recommended for use in research or clinical care, raising important questions about the conclusions of studies using these PROMs. Further validation studies or the development of more relevant PROMs with strong measurement properties for this patient population are needed. [ABSTRACT FROM AUTHOR]

Motivation Mapping distal regulatory elements, such as enhancers, is a cornerstone for elucidating how genetic variations may influence diseases. Previous enhancer-prediction methods have used either unsupervised approaches or supervised methods with limited training data. Moreover, past approaches have implemented enhancer discovery as a binary classification problem without accurate boundary detection, producing low-resolution annotations with superfluous regions and reducing the statistical power for downstream analyses (e.g. causal variant mapping and functional validations). Here, we addressed these challenges via a two-step model called De ep-learning framework for Co n de nsing enhancers and refining boundaries with large-scale functional assays (DECODE). First, we employed direct enhancer-activity readouts from novel functional characterization assays, such as STARR-seq, to train a deep neural network for accurate cell-type-specific enhancer prediction. Second, to improve the annotation resolution, we implemented a weakly supervised object detection framework for enhancer localization with precise boundary detection (to a 10 bp resolution) using Gradient-weighted Class Activation Mapping. Results Our DECODE binary classifier outperformed a state-of-the-art enhancer prediction method by 24% in transgenic mouse validation. Furthermore, the object detection framework can condense enhancer annotations to only 13% of their original size, and these compact annotations have significantly higher conservation scores and genome-wide association study variant enrichments than the original predictions. Overall, DECODE is an effective tool for enhancer classification and precise localization. Availability and implementation DECODE source code and pre-processing scripts are available at decode.gersteinlab.org. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Background: Use of combinations of long-acting β2 agonists/long-acting muscarinic antagonists (LABA/LAMA) in patients with chronic obstructive pulmonary disease (COPD) is increasing. Nevertheless, existing evidence on cardiovascular risk associated with LABA/LAMA versus another dual combination, LABA/inhaled corticosteroids (ICS), was limited and discrepant. Aim: The present cohort study aimed to examine comparative cardiovascular safety of LABA/LAMA and LABA/ICS with a target trial emulation framework, focusing on dual fixed-dose combination (FDC) therapies. Methods: We identified patients with COPD who initiated LABA/LAMA FDC or LABA/ICS FDC from a nationwide Taiwanese database during 2017–2020. The outcome of interest was a hospitalized composite cardiovascular events of acute myocardial infarction, unstable angina, heart failure, cardiac dysrhythmia, and ischemic stroke. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for composite and individual cardiovascular events after matching up to five LABA/LAMA FDC initiators to one LABA/ICS FDC initiator using propensity scores (PS). Results: Among 75,926 PS-matched patients, use of LABA/LAMA FDC did not show a higher cardiovascular risk compared to use of LABA/ICS FDC, with a HR of 0.89 (95% CI, 0.78–1.01) for the composite events, 0.80 (95% CI, 0.61–1.05) for acute myocardial infarction, 1.48 (95% CI, 0.68–3.25) for unstable angina, 1.00 (95% CI, 0.80–1.24) for congestive heart failure, 0.62 (95% CI, 0.37–1.05) for cardiac dysrhythmia, and 0.82 (95% CI, 0.66–1.02) for ischemic stroke. The results did not vary substantially in several pre-specified sensitivity and subgroup analyses. Conclusion: Our findings provide important reassurance about comparative cardiovascular safety of LABA/LAMA FDC treatment among patients with COPD. [ABSTRACT FROM AUTHOR]

Motivation Traditionally, an individual can only query and retrieve information from a genome browser by using accessories such as a mouse and keyboard. However, technology has changed the way that people interact with their screens. We hypothesized that we could leverage technological advances to use voice recognition as an interactive input to query and visualize genomic information. Results We developed an Amazon Alexa skill called Gene Tracer that allows users to use their voice to find disease-associated gene information, deleterious mutations and gene networks, while simultaneously enjoy a genome browser-like visualization experience on their screen. As the voice can be well recognized and understood, Gene Tracer provides users with more flexibility to acquire knowledge and is broadly applicable to other scenarios. Availabilityand implementation Alexa skill store (https://www.amazon.com/LT-Gene-tracer/dp/B08HCL1V68/) and a demonstration video (https://youtu.be/XbDbx7JDKmI). Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

The article provides information on the link between aging and cancer, specifically focusing on replication-driven changes to the epigenome. The study reveals a common epigenetic replication signature, termed CellDRIFT, which increases with age and is associated with an increased risk of cancer. The findings suggest that age-related replication may drive epigenetic changes in cells, potentially pushing them towards a more tumorigenic state.

Simple Summary: Based on recent clinical trials, radiation is a standard treatment option for limited metastatic sites in metastatic breast cancer, with the potential to improve survival. This is typically given in the form of high-dose radiation called stereotactic body radiotherapy (SBRT). However, SBRT is a newer technology that is not on option for all patients and does not have long-term follow-up. Prior to the widespread implementation of SBRT, we performed a clinical trial utilizing high-dose chemotherapy and standard radiation for metastases in patients with limited metastatic breast cancer. In this research, we analyzed the long-term outcomes of these patients. We found that, despite not using SBRT, radiation provided promising long-term disease control and survival. Therefore, conventional radiation might still be considered if SBRT in not an option for a patient, and our results also help suggest what long-term outcomes of SBRT treatment might look like. Background: Patients with oligometastatic breast cancer (oMBC) may benefit from aggressive local therapy. We sought to assess the effects of consolidative radiation therapy (RT) on outcomes in oMBC patients treated on a prospective phase II trial of high-dose chemotherapy (HDCT). Methods: Between 2005 and 2009, 12 patients with oMBC (≤3 metastatic sites) cancer were treated on protocol. Patients were to receive tandem HDCT supported by hematopoietic cell rescue (HCR). All radiographically identifiable oligometastatic sites received targeted radiation. Results: HDCT was initiated at a median of 6.7 (3.5–12.7) months after diagnosis of oMBC. Hormone receptors (HR) were positive in 91.6% of patients, and HER2 was overexpressed in 25% of patients. Median radiation dose (EQD2) was 41.2 (37.9–48.7) Gy. Median follow-up was 13.1 (6.8–15.1) years for living patients. Ten-year PFS and OS were 33% (95%CI, 10–59%) and 55% (95%CI, 22–79%), respectively. Durable local control of treated lesions was 87.5%. At the last follow up, two patients remained progression free and two more were without evidence of disease following additional salvage treatment. Conclusions: Although modern systemic therapies have obviated the use of HDC, aggressive local therapy warrants further evaluation and fractionated radiotherapy is a viable alternative if SBRT is not available. [ABSTRACT FROM AUTHOR]

Insulin therapy often increases body weight and leads to visceral fat accumulation. Progression in diabetes is also associated with accelerated loss of muscle mass. Little is known about body composition changes in type 2 diabetes mellitus (T2DM) patients on insulin therapy who use sodium–glucose cotransporter-2 (SGLT2) inhibitors versus dipeptidyl peptidase-4 (DPP4) inhibitors. This study examined the effect of 25 mg of empagliflozin compared with 5 mg of linagliptin for 24 weeks on body weight and body composition in patients with T2DM on premixed insulin. Body composition was assessed with bioelectrical impedance analysis. The mean difference between the linagliptin and empagliflozin groups in terms of mean body weight change from baseline to 24 weeks was − 1.80 kg (95% CI − 2.57, − 1.03). Empagliflozin also significantly reduced muscle mass (− 1.39 kg, 95% CI − 2.49, − 0.29) and total body water (− 1.07 kg, 95% CI − 1.88, − 0.27) compared with linagliptin. Compared to linagliptin, empagliflozin decreased body fat mass more from baseline to week 24, but this was not significant (− 0.31 kg, 95% CI − 1.51, 0.90). Further research on insulin-treated T2DM patients is necessary to investigate the long-term effects of SGLT2 and DPP4 inhibitors on body composition, as well as their effects on muscle strength and physical function. Trial registration: ClinicalTrials.gov no. NCT03458715, registration date: March 8, 2018. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Relapsing COVID-19 infections have been reported, but their etiology and severity are still unknown. In addition, there have been no cases in the literature that associate relapsing infection with immunosuppression, either from a disease course or medications. CASE PRESENTATION: This case series illustrates two patients who developed a relapsed infection, likely from recent rituximab infusions. In addition, both cases depicted a severe form of infection than the initial one. Laboratory investigations revealed these patients were unable to produce COVID-19 antibodies, even though one of the patients received convalescent plasma. CONCLUSION: Clinicians should be aware of the possibility of relapsing COVID-19, especially in immunosuppressed patients. Because rituximab induces B-cell depletion, it can also decrease the effectiveness of the COVID-19 vaccine. Therefore, these patients should receive the vaccine before their scheduled rituximab infusion. [ABSTRACT FROM AUTHOR]

RNA-seq has matured and become an important tool for studying RNA biology. Here we compared two RNA-seq (MGI DNBSEQ and Illumina NextSeq 500) and two microarray platforms (GeneChip Human Transcriptome Array 2.0 and Illumina Expression BeadChip) in healthy individuals administered recombinant human erythropoietin for transcriptome-wide quantification of differential gene expression. The results show that total RNA DNB-seq generated a multitude of target genes compared to other platforms. Pathway enrichment analyses revealed genes correlate to not only erythropoiesis and oxygen transport but also a wide range of other functions, such as tissue protection and immune regulation. This study provides a knowledge base of genes relevant to EPO biology through cross-platform comparisons and validation. [ABSTRACT FROM AUTHOR]

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × ∼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics. [Display omitted] • EN-TEx includes 1,635 datasets mapped to 4 personal genomes, ∼30 tissues × ∼15 assays • Comprehensive catalog of allele-specific activity, decorating regulatory elements • Model to transfer known eQTLs to difficult-to-profile tissues (e.g., skin→heart) • Transformer model for predicting allelic activity based on local sequence context Understanding the impact of genetic variants is important to functional genomics. EN-TEx provides epigenomes across tissues, coupled with long-read genome assemblies, to build generalizable models of variant impact. [ABSTRACT FROM AUTHOR]

High-density lipoprotein cholesterol (HDL-C) is thought to be atheroprotective yet some patients with elevated HDL-C levels develop cardiovascular disease, possibly due to the presence of dysfunctional HDL. We aimed to assess the metabolic fate of circulating HDL particles in patients with high HDL-C with and without coronary artery disease (CAD) using in vivo dual labeling of its cholesterol and protein moieties. We measured HDL apolipoprotein (apo) A-I, apoA-II, free cholesterol (FC), and cholesteryl ester (CE) kinetics using stable isotope-labeled tracers (D3-leucine and 13C2-acetate) as well as ex vivo cholesterol efflux to HDL in subjects with (n = 6) and without (n = 6) CAD that had HDL-C levels >90th percentile. Healthy controls with HDL-C within the normal range (n = 6) who underwent the same procedures were used as the reference. Subjects with high HDL-C with and without CAD had similar plasma lipid levels and similar apoA-I, apoA-II, HDL FC, and CE pool sizes with no significant differences in fractional clearance rates (FCRs) or production rates (PRs) of these components between groups. Subjects with high HDL-C with and without CAD also had similar basal and cAMP-stimulated ex vivo cholesterol efflux to HDL. When all subjects were considered (n = 18), unstimulated non-ABCA1-mediated efflux (but not ABCA1-specific efflux) was correlated positively with apoA-I production (r = 0.552, p = 0.017) and HDL FC and CE pool sizes, and negatively with the fractional clearance rate of FC (r = −0.759, p = 4.1 × 10−4) and CE (r = −0.652, p = 4.57 × 10−3). Our data are consistent with the concept that ex vivo non-ABCA1 efflux capacity may correlate with slower in vivo turnover of HDL cholesterol moieties. The use of a dual labeling protocol provided for the first time the opportunity to assess the association of ex vivo cholesterol efflux capacity with in vivo HDL cholesterol metabolic parameters. [ABSTRACT FROM AUTHOR]