Publications by Year: 2026

Repeated concussion traumatic brain injury (TBI) results in long-term brain damage and cognitive dysfunctions, leading to neurodegenerative diseases. The brain clearance system plays a crucial role in TBI recovery and neurodegenerative disease amelioration by draining waste macromolecules from the brain. Pharmacological therapeutics have failed to demonstrate benefits in human TBI. Photobiomodulation (PBM) has gained interest in neuroscience and has been shown to improve brain drainage. Here, we evaluated the efficiency of PBM in the treatment of multiple concussions in mice and the augmentation of the brain clearance system. Three consecutive closed-head concussive TBIs were induced with a 1-h interval to the left hemisphere in C57BL/6 male mice. A near-infrared irradiation (1270 nm, 10 mW/cm2) was used for PBM 4 h after the last TBI and the following 3 days twice a day. Laser speckle contrast imaging was used to assess cerebral blood flow (rCBF). In vivo 2-photon laser scanning microscopy assessed PBM effects on cerebral microcirculation, tissue oxygen supply (NADH), and meningeal lymphatics clearance. Brain compliance was evaluated by intracranial pressure waveform analysis. Neurological severity scores were obtained at 0-3 days after TBI. Two-way ANOVA for multiple comparisons was used to test intergroup differences, with the statistical significance set at p < 0.05. Multiple concussions progressively impaired rCBF, cortical microcirculation, tissue oxygen supply, and brain drainage function (p < 0.05). Compared to the sham-treated group, PBM improved rCBF, microcirculation, tissue oxygenation, and the brain drainage system (p < 0.05). Neurological function was more preserved in the PBMT group than in sham-treated mice (p < 0.05). Our study demonstrated that PBMT can be used as an adjunct therapy even in the acute period of TBI.

The planning of sample size for research studies often focuses on obtaining a significant result given a specified level of power, significance, and an anticipated effect size. This planning requires prior knowledge of the study design and a statistical analysis to calculate the proposed sample size. However, there may not be one specific testable analysis from which to derive power (Silberzahn et al., Advances in Methods and Practices in Psychological Science, 1(3), 337356, 2018) or a hypothesis to test for the project (e.g., creation of a stimuli database). Modern power and sample size planning suggestions include accuracy in parameter estimation (AIPE, Kelley, Behavior Research Methods, 39(4), 755-766, 2007; Maxell et al., Annual Review of Psychology, 59, 537-563, 2008) and simulation of proposed analyses (Chalmers & Adkins, The Quantitative Methods for Psychology, 16(4), 248-280, 2020). These toolkits offer flexibility in traditional power analyses that focus on the if-this, then-that approach. However, both AIPE and simulation require either a specific parameter (e.g., mean, effect size, etc.) or a statistical test for planning sample size. In this tutorial, we explore how AIPE and simulation approaches can be combined to accommodate studies that may not have a specific hypothesis test or wish to account for the potential of a multiverse of analyses. Specifically, we focus on studies that use multiple items and suggest that sample sizes can be planned to measure those items adequately and precisely, regardless of the statistical test. This tutorial also provides multiple code vignettes and package functionality that researchers can adapt and apply to their own measures.

Despite substantial advances in the secondary prevention of cardiovascular disease, atherosclerosis of the coronary arteries and its consequences remain the leading cause of death worldwide. Residual cardiovascular risk refers to the ongoing risk of recurrent cardiovascular events that persists in patients with coronary artery disease despite receiving optimal secondary prevention treatment and effective control of conventional risk factors. Lifestyle modification and therapies modulating thrombosis, blood pressure and LDL-cholesterol levels represent the standard approach for the prevention of recurrent cardiovascular events in patients with coronary artery disease. However, current evidence-based therapies and lifestyle modification strategies only partially modulate the pathophysiological pathways involved in the progression and destabilization of atherosclerotic disease, and other mechanisms might have an important role, accounting, at least in part, for the residual cardiovascular risk in these patients. In this Review, we appraise the available evidence and latest insights into the mechanisms and associated biomarkers of recurrent adverse cardiovascular events and provide perspectives on strategies to reduce residual cardiovascular risk in patients with coronary artery disease.

Whole-body regeneration requires adult stem cells with high plasticity to differentiate into missing cell types. Planarians possess a unique configuration of organs embedded in a vast pool of pluripotent stem cells. How stem cells integrate positional information with discrete fates remains unknown. Here, we use the planarian pharynx to define the cell fates that depend on the pioneer transcription factor FoxA. We find that Roundabout receptor RoboA suppresses aberrant pharynx cell fates by altering foxA expression, independent of the canonical ligand Slit. An RNAi screen for extracellular proteins identifies Anosmin1a as a potential partner of RoboA. Perturbing global patterning demonstrates that roboA/anosmin1a functions locally in the brain. By contrast, altering pharynx fate with foxA knockdown induces head-specific neurons in the pharynx, indicating a latent plasticity of stem cells. Our data links critical extracellular cues with cell fate decisions of highly plastic stem cells, ensuring the fidelity of organ regeneration.

According to the excitation-inhibition imbalance theory, GABAergic and glutamatergic systems influence the clinical symptoms, particularly cognitive deficits in schizophrenia spectrum disorders (SSD). These systems have been found disrupted in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) in SSD, and may contribute to P300 abnormalities in electroencephalography recordings. Therefore, we explored the relationships among MRS-derived GABA and Glx levels in the ACC and left DLPFC (lDLPFC), auditory P3b subcomponent amplitudes and latencies, cognition, and symptom severity in SSD. In total, 107 patients and 107 healthy controls (HC) were included in the study, with the exact numbers varying across specific analyses. We grouped patients into higher (SSD+, N = 41) and lower (SSD-, N = 65) symptom severity clusters based on PANSS total scores. P3b amplitudes were lower in SSD patients than HC at central and parietal sites. SSD+ exhibited widespread P3b amplitude reductions, significant at parietal and trend-level at central and frontal regions, while SSD- showed a trend-level amplitude reduction limited to the parietal region. GABA levels in the lDLPFC were higher in SSD- compared to controls and were positively associated with P3b amplitudes at central and parietal sites within SSD- and overall SSD group. Although P3b amplitudes positively correlated with the BACS composite scores and behavioral performance, lDLPFC GABA levels showed no direct association with cognitive or behavioral performance. ACC GABA, ACC Glx, and lDLPFC Glx levels showed no group differences or P3b associations. Our findings suggest P3b amplitude reductions as a marker of cognitive dysfunction in SSD, more pronounced in patients with higher illness severity, and that enhanced lDLPFC GABA may contribute to offsetting these reductions. Our work provides the first empirical evidence of the interplay between the GABAergic system and cortical electrophysiological signal patterns associated with cognitive dysfunction in SSD.

Microbiological tests for tuberculosis (TB) disease in children have suboptimal accuracy and respiratory samples are often challenging to obtain. Using liquid chromatography/mass spectrometry, we performed plasma high-resolution metabolomics (HRM) to identify blood-based biomarkers associated with TB disease in children. We analyzed plasma samples from 438 children 0-14 years being evaluated for TB disease in India, Peru, Uganda, The Gambia, and South Africa. All children underwent a standard clinical evaluation and were followed up after 3 months. Children were classified as Confirmed (n = 104), Unconfirmed (n = 108), or Unlikely TB (n = 226) as per NIH consensus definitions. Controlling for age and study site, we found creatine, alanine, retinol, citrulline, fumarate, and tryptophan to be significantly decreased in children with Confirmed TB disease versus those with Unlikely TB, while cortisol, nicotinamide, and butyrylcarnitine were increased (FDR-corrected p-value < 0.2). Using logistic regression, we found this nine-metabolite signature had an area under the receiver operator characteristic curve (AUC) of 0.72 (95% CI (0.67 - 0.82) in the test set of participants with Confirmed and Unlikely TB and an AUC of 0.49 (95% CI 0.42 - 0.55) in the Unconfirmed TB group. These results show a nine-metabolite plasma signature has moderate accuracy for identification of Confirmed TB disease in children.

Real-world evidence (RWE) is increasingly used to complement findings from randomized controlled trials (RCTs), contextualizing the effectiveness and safety of medical interventions as delivered in routine clinical practice. Advances in the curation and accessibility of electronic health record (EHR) data present the opportunity to utilize real-world data (RWD) to investigate therapeutic areas including oncology, where administrative healthcare claims databases alone are often not fit-for-purpose. The RCT DUPLICATE initiative has previously evaluated when RWE can most appropriately draw causal conclusions by emulating trials for nononcology indications. Here, we present the design and trial selection for the emulation of comparative oncology trials with real-world evidence (ENCORE) project, which extends this work to oncology. ENCORE is designed to emulate 12 RCTs in four oncology-specialized EHR databases across four different cancer indications, specifically non-small-cell lung cancer, breast cancer, colorectal cancer, and multiple myeloma. It will place special emphasis on systematic evaluation of fitness of data in relation to the study design and statistical analysis for a particular research question and preregistration of study protocols prior to initiation and analysis. Prespecified criteria will assess agreement of treatment effect estimates between RCTs and their respective emulations. Through extensive sensitivity analyses benchmarked against RCT results, the ENCORE project aims to inform understanding of how measurement, design, and analytic decisions influence the interpretation of results from emulated oncology trials using RWD.

BACKGROUND: Females have a higher risk of incident knee osteoarthritis (KOA) than males, particularly in the lateral compartment; however, the underlying mechanisms remain unclear. We investigated whether knee flexor and extensor strength mediate the association between sex and lateral radiographic and symptomatic KOA risk.

METHODS: This cohort study utilized data from the Osteoarthritis Initiative, a longitudinal prospective study of participants aged 45–79 years. We included knees without radiographic or symptomatic KOA at baseline. Knee extensor and flexor strength were measured isometrically using a validated device (Good Strength Chair) and normalized to body mass index. Mediation analyses were performed using marginal structural models to assess the contribution of knee flexor and extensor strength to the relationship between sex and the risk of lateral radiographic and symptomatic KOA, adjusting for age, race, knee injury history, physical activity, knee alignment, cartilage volume, and hormone therapy.

RESULTS: A total of 5,126 eligible knees from 3,056 participants without radiographic KOA and 6,773 from 3,720 participants without symptomatic KOA were identified at baseline. Among 5,126 knees without radiographic KOA, the 8-year risks of lateral radiographic KOA were 5.9% in females and 3.4% in males, with an odds ratio (OR) of 1.72 (95% confidence interval [CI]: 1.28 to 2.31). The indirect effects of female sex on lateral radiographic KOA via flexors and extensor strength were OR = 1.14 (95% CI: 1.04 to 1.26) and 1.16 (95% CI: 1.05 to 1.27), respectively. The direct effects (not mediated through flexor/extensor strength) were OR = 1.48 (95% CI: 1.01 to 1.95) and 1.46 (95% CI: 1.01 to 1.92). Knee flexor and extensor strength mediated 31.1% and 33.9% of the total effect of sex on lateral radiographic KOA risk, respectively. Similar results were also observed for incident lateral symptomatic KOA.

CONCLUSION: The lateral radiographic and symptomatic KOA risk is higher in females than males, partly mediated by lower flexor and extensor strength. These findings suggest that enhancing knee flexor and extensor strength in females may help reduce their risk of developing lateral radiographic and symptomatic KOA.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-026-03745-6.

BACKGROUND: Histone deacetylases (HDACs) are epigenetic molecules responsible for regulation of gene transcription. Dysregulation of HDACs has been linked to neurodegenerative disease. Here, we used the class I HDAC PET radioligand [11C]Martinostat to quantify and map changes in the distribution of these molecules in the brain in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In this exploratory cross-sectional study, we acquired brain PET-MR with [11C]Martinostat in 14 DLB (median age 70 years (IQR 14), 21% female), 10 PD (median age 70 (8), 20% female) including four with cognitive impairment and six without, and 17 healthy control (HC) participants (median age 62 (14), 47% female). [11C]Martinostat uptake was compared amongst groups using whole brain voxel-wise analysis and targeted region of interest (ROI)-based approaches, adjusted for age and sex. Regional levels were also quantified in postmortem brain bank samples.

RESULTS: Compared to HC, [11C]Martinostat uptake in DLB was increased in precentral gyrus (ROI p = 0.044) and putamen (p < 0.001), as well as in cognitive and limbic circuitry including anterior cingulate (p = 0.042) and entorhinal cortex (p = 0.023). [11C]Martinostat uptake in DLB was decreased in inferior parietal cortex p < 0.001) compared to HC, consistent with prior observations in Alzheimer's disease. In PD, [11C]Martinostat uptake was also increased in precentral gyrus (p = 0.013), correlating with both disease duration and Hoehn and Yahr motor stage. In postmortem DLB tissue, class I HDAC levels were elevated in anterior cingulate cortex (isoform 1 p = 0.041, isoform 3 p = 0.024) and were reduced in inferior parietal cortex (isoform 1 p < 0.001).

CONCLUSIONS: The findings of this exploratory study reveal elevated levels of class I HDACs in motor cortex in PD and bidirectional changes in their regional density in the Lewy body dementias.