Endogenous mitochondrial NAD(P)H fluorescence can predict lifespan.

Many aging clocks have recently been developed to predict health outcomes and deconvolve heterogeneity in aging. However, existing clocks are limited by technical constraints, such as low spatial resolution, long processing time, sample destruction, and a bias towards specific aging phenotypes. Therefore, here we present a non-destructive, label-free and subcellular resolution approach for quantifying aging through optically resolving age-dependent changes to the biophysical properties of NAD(P)H in mitochondria through fluorescence lifetime imaging (FLIM) of endogenous NAD(P)H fluorescence.

ROBUST DISCOVERY OF MUTATIONAL SIGNATURES USING POWER POSTERIORS.

Mutational processes, such as the molecular effects of carcinogenic agents or defective DNA repair mechanisms, are known to produce different mutation types with characteristic frequency profiles, referred to as mutational signatures. Non-negative matrix factorization (NMF) has successfully been used to discover many mutational signatures, yielding novel insights into cancer etiology and targeted therapies. However, the NMF model is only a rough approximation to reality, and even small departures from this assumed model can have large negative effects on the accuracy and reliability of the results.

Cost-effectiveness of screening with transcriptional signatures for incipient TB among U.S. migrants.

Introduction: Host-response-based transcriptional signatures (HrTS) have been developed to identify "incipient tuberculosis (TB)". No study has reported the cost-effectiveness of HrTS for post-arrival migrant screening programs in low-incidence countries.

Objectives: To assess the potential health impact and cost-effectiveness of HrTS for post-arrival TB infection screening among new migrants in the United States.

The long-term effects of domestic and international tuberculosis service improvements on tuberculosis trends within the USA: a mathematical modelling study.

Background: For settings with low tuberculosis incidence, disease elimination is a long-term goal. We investigated pathways to tuberculosis pre-elimination (incidence <1·0 cases per 100 000 people) and elimination (incidence <0·1 cases per 100 000 people) in the USA, where incidence was estimated at 2·9 per 100 000 people in 2023.

Methods: Using a mathematical modelling framework, we simulated how US tuberculosis incidence could be affected by changes in tuberculosis services in the countries of origin for future migrants to the USA, as well as changes in tuberculosis services inside the USA.

Estimated rates of progression to tuberculosis disease for persons infected with Mycobacterium tuberculosis in the United States.

Background: In the United States, over 80% of tuberculosis (TB) disease cases are estimated to result from reactivation of latent TB infection (LTBI) acquired more than 2 years previously ("reactivation TB"). We estimated reactivation TB rates for the US population with LTBI, overall, by age, sex, race-ethnicity, and US-born status, and for selected comorbidities (diabetes, end-stage renal disease, and HIV).

Methods: We collated nationally representative data for 2011-2012.

Radiotherapy-Induced Neurocognitive Impairment Is Driven by Heightened Apoptotic Priming in Early Life and Prevented by Blocking BAX.

Unlabelled: Although external beam radiotherapy (xRT) is commonly used to treat central nervous system (CNS) tumors in patients of all ages, young children treated with xRT frequently experience life-altering and dose-limiting neurocognitive impairment (NI) while adults do not. The lack of understanding of mechanisms responsible for these differences has impeded the development of neuroprotective treatments. Using a newly developed mouse model of xRT-induced NI, we found that neurocognitive function is impaired by ionizing radiation in a dose- and age-dependent manner, with the youngest animals being most affected.

Establishing a natural history of X-linked dystonia parkinsonism.

X-linked dystonia parkinsonism is a neurodegenerative movement disorder that affects men whose mothers originate from the island of Panay, Philippines. Current evidence indicates that the most likely cause is an expansion in the gene that may be amenable to treatment. To prepare for clinical trials of therapeutic candidates for X-linked dystonia parkinsonism, we focused on the identification of quantitative phenotypic measures that are most strongly associated with disease progression.

Bayesian Data Selection.

Insights into complex, high-dimensional data can be obtained by discovering features of the data that match or do not match a model of interest. To formalize this task, we introduce the "data selection" problem: finding a lower-dimensional statistic-such as a subset of variables-that is well fit by a given parametric model of interest. A fully Bayesian approach to data selection would be to parametrically model the value of the statistic, nonparametrically model the remaining "background" components of the data, and perform standard Bayesian model selection for the choice of statistic.

Model-based dimensionality reduction for single-cell RNA-seq using generalized bilinear models.

Dimensionality reduction is a critical step in the analysis of single-cell RNA-seq (scRNA-seq) data. The standard approach is to apply a transformation to the count matrix followed by principal components analysis (PCA). However, this approach can induce spurious heterogeneity and mask true biological variability.

Reproducible Model Selection Using Bagged Posteriors.

Bayesian model selection is premised on the assumption that the data are generated from one of the postulated models. However, in many applications, all of these models are incorrect (that is, there is misspecification). When the models are misspecified, two or more models can provide a nearly equally good fit to the data, in which case Bayesian model selection can be highly unstable, potentially leading to self-contradictory findings.

Exploiting endogenous and therapy-induced apoptotic vulnerabilities in immunoglobulin light chain amyloidosis with BH3 mimetics.

Immunoglobulin light chain (AL) amyloidosis is an incurable hematologic disorder typically characterized by the production of amyloidogenic light chains by clonal plasma cells. These light chains misfold and aggregate in healthy tissues as amyloid fibrils, leading to life-threatening multi-organ dysfunction. Here we show that the clonal plasma cells in AL amyloidosis are highly primed to undergo apoptosis and dependent on pro-survival proteins MCL-1 and BCL-2.

Realistic biomarkers from plasma extracellular vesicles for detection of beryllium exposure.

Purpose: Exposures related to beryllium (Be) are an enduring concern among workers in the nuclear weapons and other high-tech industries, calling for regular and rigorous biological monitoring. Conventional biomonitoring of Be in urine is not informative of cumulative exposure nor health outcomes. Biomarkers of exposure to Be based on non-invasive biomonitoring could help refine disease risk assessment.

Trends, Mechanisms, and Racial/Ethnic Differences of Tuberculosis Incidence in the US-Born Population Aged 50 Years or Older in the United States.

Background: Older age is a risk factor for tuberculosis (TB) in low incidence settings. Using data from the US National TB Surveillance System and American Community Survey, we estimated trends and racial/ethnic differences in TB incidence among US-born cohorts aged ≥50 years.

Methods: In total, 42 000 TB cases among US-born persons ≥50 years were reported during 2001-2019.

Identifying longevity associated genes by integrating gene expression and curated annotations.

Aging is a complex process with poorly understood genetic mechanisms. Recent studies have sought to classify genes as pro-longevity or anti-longevity using a variety of machine learning algorithms. However, it is not clear which types of features are best for optimizing classification performance and which algorithms are best suited to this task.

Robust Bayesian inference via coarsening.

The standard approach to Bayesian inference is based on the assumption that the distribution of the data belongs to the chosen model class. However, even a small violation of this assumption can have a large impact on the outcome of a Bayesian procedure. We introduce a novel approach to Bayesian inference that improves robustness to small departures from the model: rather than conditioning on the event that the observed data are generated by the model, one conditions on the event that the model generates data close to the observed data, in a distributional sense.

Intranasal Dexmedetomidine for Sedation During Magnetoencephalography.

Purpose: Magnetoencephalography (MEG) is a noninvasive tool used clinically for presurgical evaluation of patients with medically intractable epilepsy. These recordings require patients to lie still for prolonged periods of time in a magnetically shielded room. Children or uncooperative adults with epilepsy may require sedation to reduce movement artefact and obtain high-quality recordings.

Mixture models with a prior on the number of components.

A natural Bayesian approach for mixture models with an unknown number of components is to take the usual finite mixture model with symmetric Dirichlet weights, and put a prior on the number of components-that is, to use a mixture of finite mixtures (MFM). The most commonly-used method of inference for MFMs is reversible jump Markov chain Monte Carlo, but it can be nontrivial to design good reversible jump moves, especially in high-dimensional spaces. Meanwhile, there are samplers for Dirichlet process mixture (DPM) models that are relatively simple and are easily adapted to new applications.

Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine.

Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients.

Balloon Occlusion Testing to Assess Retinal Collateral and Predict Visual Outcomes in the Management of a Fusiform Intraorbital Ophthalmic Artery Aneurysm: Technical Note and Literature Review.

Background And Importance: Aneurysms of the ophthalmic artery (OA) within the orbit and optic canal are extremely rare. Given the peripheral location of these aneurysms and the fact that most are fusiform, parent artery occlusion is preferred for symptomatic aneurysms. However, the impact of OA occlusion on vision is not always innocuous.

Comparison of Intranasal Dexmedetomidine and Oral Pentobarbital Sedation for Transthoracic Echocardiography in Infants and Toddlers: A Prospective, Randomized, Double-Blind Trial.

Background: Acquisition of transthoracic echocardiographic (TTEcho) images in children often requires sedation. The optimal sedative for TTEcho has not been determined. Children with congenital heart disease are repeatedly exposed to sedatives and anesthetics that may affect brain development.

Angiographic and clinical outcomes of balloon remodeling versus unassisted coil embolization in the ruptured aneurysm cohort of the GEL THE NEC study.

Background And Purpose: GEL THE NEC (GTN) was a multicenter prospective registry developed to assess the safety and efficacy of HydroSoft coils in treating intracranial aneurysms. We compared the angiographic and clinical outcomes of aneurysms treated with balloon assisted coil embolization (BACE) versus unassisted coil embolization (CE) in the ruptured aneurysm cohort.

Materials And Methods: GTN was performed at 27 centers in five countries.