Integrated multi-omics analysis identifies features that predict human pluripotent stem cell-derived progenitor differentiation to cardiomyocytes.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are advancing cardiovascular development and disease modeling, drug testing, and regenerative therapies. However, hPSC-CM production is hindered by significant variability in the differentiation process. Establishment of early quality markers to monitor lineage progression and predict terminal differentiation outcomes would address this robustness and reproducibility roadblock in hPSC-CM production. An integrated transcriptomic and epigenomic analysis assesses how attributes of the cardiac progenitor cell (CPC) affect CM differentiation outcome. Resulting analysis identifies predictive markers of CPCs that give rise to high purity CM batches, including TTN, TRIM55, DGKI, MEF2C, MAB21L2, MYL7, LDB3, SLC7A11, MAB21L2, and CALD1. Predictive models developed from these genes provide high accuracy in determining terminal CM purities at the CPC stage. Further, insights into mechanisms of batch failure and dominant non-CM cell types generated in failed batches are elucidated. Namely EMT, MAPK, and WNT signaling emerge as significant drivers of batch divergence, giving rise to off-target populations of fibroblasts/mural cells, skeletal myocytes, epicardial cells, and a non-CPC SLC7A11+ subpopulation. This study demonstrates how integrated multi-omic analysis of progenitor cells can identify quality attributes of that progenitor and predict differentiation outcomes, thereby improving differentiation protocols and increasing process robustness.

Histone deacetylase inhibition expands cellular proteostasis repertoires to enhance neuronal stress resilience.

Neurons are long-lived, terminally differentiated cells with limited regenerative capacity. Cellular stressors such as endoplasmic reticulum (ER) protein folding stress and membrane trafficking stress accumulate as neurons age and accompany age-dependent neurodegeneration. Current strategies to improve neuronal resilience are focused on using factors to reprogram neurons or targeting specific proteostasis pathways. We discovered a different approach. In an unbiased screen for modifiers of neuronal membrane trafficking defects, we unexpectedly identified a role for histone deacetylases (HDACs) in limiting cellular flexibility in choosing cellular pathways to respond to diverse types of stress. We show that genetic or pharmacological inactivation of HDACs results in improved neuronal health in response to ER protein folding stress and endosomal membrane trafficking stress in C. elegans and mammalian neurons. Surprisingly, HDAC inhibition enabled neurons to activate latent proteostasis pathways tailored to the nature of the individual stress, instead of generalized transcriptional upregulation. These findings shape our understanding of neuronal stress responses and suggest new therapeutic strategies to enhance neuronal resilience.

Neoadjuvant therapy for melanoma: past, present, and future.

Modern systemic therapy has dramatically improved outcomes for many patients with advanced metastatic melanoma. The success of these therapies has attracted much scientific interest while these therapies have made their way into the treatment of earlier stages of disease. Randomized trials have led to the approval of adjuvant immunotherapy and targeted therapy for resected stage III melanoma. However, most recently, these therapies have gained traction in the neoadjuvant setting. Promising early results led to randomized controlled trials that have now established neoadjuvant therapy as standard of care in advanced melanoma patients. Questions remain regarding the optimal choice of therapy, duration and timing of neoadjuvant therapy, extent of surgery, and the need for additional adjuvant therapy for patients who received neoadjuvant therapy. Herein we provide an overview of neoadjuvant therapy for melanoma and dilemmas to its broader applications.

Conformal printed electronics on flexible substrates and inflatable catheters using lathe-based aerosol jet printing.

With the growth of additive manufacturing (AM), there has been increasing demand for fabricating conformal electronics that directly integrate with larger components to enable unique functionality. However, fabrication of conformal electronics is challenging because devices must merge with host substrates regardless of curvilinearity, topography, or substrate material. In this work, we employ aerosol jet (AJ) printing, an AM method for jet printing electronics using ink-based materials, and a custom-made lathe mechanism for mounting flexible substrates and 3D objects on a rotating axis. Using this method of lathe-based AJ printing, conformal electronics are printed around the circumference of rotational bodies with 3D curvilinear surfaces through cylindrical-coordinate motion. We characterize the diverse capabilities of lathe AJ (LAJ) printing and demonstrate flexible conformal electronics including multilayer carbon nanotube transistors. Lastly, a graphene sensor is conformally printed on an inflated catheter balloon for temperature and inflation monitoring, thus highlighting the versatilities of LAJ printing.

Risk of Incident Melanoma Among Individuals With Low-Count Monoclonal B-Cell Lymphocytosis.

PURPOSE: Chronic lymphocytic leukemia (CLL)-phenotype monoclonal B-cell lymphocytosis (MBL) is a premalignant condition that is roughly 500-fold more common than CLL. It is unknown whether the two-fold increased risk of developing melanoma associated with CLL extends to individuals with MBL. METHODS: Using the Mayo Clinic Biobank, we identified participants who were 40 years or older with no previous hematological malignancies, who resided in the 27 counties around Mayo Clinic, and who had available biospecimens for screening. Eight-color flow cytometry was used to screen for MBL. Individuals with MBL were classified as low-count MBL (LC-MBL) or high-count MBL on the basis of clonal B-cell percent. Incident melanomas were identified using International Classification of Diseases codes and confirmed via medical records review. Cox regression models were used to estimate hazard ratios (HRs) and 95% CI. RESULTS: Of the 7,334 participants screened, 1,151 were identified with a CD5-positive MBL, of whom 1,098 had LC-MBL. After a median follow-up of 3.2 years (range, 0-13.5), 131 participants developed melanoma, of whom 36 individuals were positive for MBL. The estimated 5-year cumulative incidence of melanoma was 3.4% and 2.0% among those with and without MBL, respectively. After adjusting for age, sex, and history of previous melanoma, individuals with MBL exhibited a 1.86-fold (95% CI, 1.25 to 2.78) risk of melanoma. This elevated risk persisted when analysis was restricted to those without a history of melanoma (HR, 2.05 [95% CI, 1.30 to 3.23]). Individuals with LC-MBL had a 1.92-fold (95% CI, 1.29 to 2.87) increased risk of developing melanoma overall and a 2.74-fold increased risk (95% CI, 1.50 to 5.03) of melanoma in situ compared with those without MBL. CONCLUSION: LC-MBL is associated with an approximately two-fold increased risk of melanoma overall and a 2.74-fold increased risk of melanoma in situ.

Temporal trends of adolescents and young adults (AYA) with gynecologic malignancy in the United States.

In this retrospective cohort study examining 13,763,447 patients with 16 different malignancies, including 1,232,841 patients with five gynecologic malignancies (uterus [n = 690,590], ovary [n = 276,812], cervix [n = 166,779], vulva [n = 81,575], and vagina [n = 17,085]), identified in the Commission-on-Cancer's National Cancer Database from 2004 to 2020, cervical cancer (25.3 %) had the highest rate of adolescent and young adult (AYA) patients among 27 gender-stratified cancer groups (25.3%). There were 8 groups that the annual rates of AYA patients statistically increased during the study period at a P < .05 level, of which 7 (87.5 %) groups were for female malignancies. Among these 7 female malignancies, the annual percentage rate increase in AYA patients was largest for colorectal cancer (4.1 %, 95 % confidence interval 3.6-4.6), followed by malignancies in the ovary (3.1 %, 95 % confidence interval 1.6-4.5 in 2014-2020), pancreas (2.1 %, 95 % confidence interval 1.0-3.2), uterus (1.2 %, 95 % confidence interval 0.3-2.0 in 2013-2020), breast (0.8 %, 95 % confidence interval 0.2-1.4 in 2012-2020), cervix (0.8 %, 95 % confidence interval 0.2-1.5 in 2011-2020), and kidney (0.4 %, 95 % confidence interval 0.1-0.9). In conclusion, these data suggested that proportion of cancers attributable to AYA patients is increasing in several obesity-related female malignancies and in the three most common gynecologic malignancies.

Neuromodulation modifies α-synuclein spreading dynamics in vivo and the pattern is predicted by changes in whole-brain function.

BACKGROUND: Many neurodegenerative disease treatments, such as deep brain stimulation for Parkinson's Disease, can alleviate symptoms by primarily compensating for circuit dysfunctions. However, the stimulation's effect on the underlying disease progression remains relatively unknown. Here, we report that neuromodulation can not only modulate circuit function but also modulate the in vivo spreading dynamics of α-synuclein pathology, the primary pathological hallmark observed in Parkinson's Disease. METHODS: In a mouse model, pre-formed fibrils were injected into the striatum to induce widespread α-synuclein pathology. Two days after fibril injection, mice were treated for two weeks with daily optogenetic stimulation of the Secondary Motor Area, Layer V. Whole brains were then extracted, immunolabeled, cleared, and imaged with light-sheet fluorescent microscopy. RESULTS: Repeated optogenetic stimulation led to a decrease in pathology at the site of stimulation and at various cortical and subcortical regions, while the contralateral cortex saw a consistent increase. Aligning the pathology changes with optogenetic-fMRI measured brain activity, we found that the changes in pathology and brain function had similar spatial locations but opposite polarity. CONCLUSION: These results demonstrate the ability to modulate and predict whole brain pathology changes using neuromodulation, opening a new horizon for investigating optimized neuromodulation therapies.

Data-driven biomarkers better associate with stroke motor outcomes than theory-based biomarkers.

Chronic motor impairments are a leading cause of disability after stroke. Previous studies have associated motor outcomes with the degree of damage to predefined structures in the motor system, such as the corticospinal tract. However, such theory-based approaches may not take full advantage of the information contained in clinical imaging data. The present study uses data-driven approaches to model chronic motor outcomes after stroke and compares the accuracy of these associations to previously-identified theory-based biomarkers. Using a cross-validation framework, regression models were trained using lesion masks and motor outcomes data from 789 stroke patients from the Enhancing NeuroImaging Genetics through Meta Analysis (ENIGMA) Stroke Recovery Working Group. Using the explained variance metric to measure the strength of the association between chronic motor outcomes and imaging biomarkers, we compared theory-based biomarkers, like lesion load to known motor tracts, to three data-driven biomarkers: lesion load of lesion-behaviour maps, lesion load of structural networks associated with lesion-behaviour maps, and measures of regional structural disconnection. In general, data-driven biomarkers had stronger associations with chronic motor outcomes accuracy than theory-based biomarkers. Data-driven models of regional structural disconnection performed the best of all models tested (R 2 = 0.210, P < 0.001), performing significantly better than the theory-based biomarkers of lesion load of the corticospinal tract (R 2 = 0.132, P < 0.001) and of multiple descending motor tracts (R 2 = 0.180, P < 0.001). They also performed slightly, but significantly, better than other data-driven biomarkers including lesion load of lesion-behaviour maps (R 2 = 0.200, P < 0.001) and lesion load of structural networks associated with lesion-behaviour maps (R 2 = 0.167, P < 0.001). Ensemble models - combining basic demographic variables like age, sex, and time since stroke - improved the strength of associations for theory-based and data-driven biomarkers. Combining both theory-based and data-driven biomarkers with demographic variables improved predictions, and the best ensemble model achieved R 2 = 0.241, P < 0.001. Overall, these results demonstrate that out-of-sample associations between chronic motor outcomes and data-driven imaging features, particularly when lesion data is represented in terms of structural disconnection, are stronger than associations between chronic motor outcomes and theory-based biomarkers. However, combining both theory-based and data-driven models provides the most robust associations.

Nail Bed Regeneration by Excision of Distal Scarred Matrix in a Patient with Porphyria Cutanea Tarda.

Onycholysis secondary to nail bed scarring can be a challenging problem for hand surgeons, given the relatively few techniques available for nail bed lengthening. Here, we present the case of a patient with upper extremity onycholysis, secondary to porphyria cutanea tarda. We used a technique first described by Lemperle et al in 2003 to successfully lengthen the nail bed and improve the appearance of the nail plate. This involved full-thickness excision of a crescent-shaped wedge of the distal nail bed in all five right sided digits in a single operation. We found this technique to be simple and effective, meeting our patient's goals after just one excision.

Iowa Brain-Behavior Modeling Toolkit: An Open-Source MATLAB Tool for Inferential and Predictive Modeling of Imaging-Behavior and Lesion-Deficit Relationships.

The traditional analytical framework taken by neuroimaging studies in general, and lesion-behavior studies in particular, has been inferential in nature and has focused on identifying and interpreting statistically significant effects within the sample under study. While this framework is well-suited for hypothesis testing approaches, achieving the modern goal of precision medicine requires a different framework that is predictive in nature and that focuses on maximizing the predictive power of models and evaluating their ability to generalize beyond the data that were used to train them. However, few tools exist to support the development and evaluation of predictive models in the context of neuroimaging or lesion-behavior research, creating an obstacle to the widespread adoption of predictive modeling approaches in the field. Further, existing tools for lesion-behavior analysis are often unable to accommodate categorical outcome variables and often impose restrictions on the predictor data. Researchers therefore often must use different software packages and analytical approaches depending on whether they are addressing a classification vs. regression problem and on whether their predictor data correspond to binary lesion images, continuous lesion-network images, connectivity matrices, or other data modalities. To address these limitations, we have developed a MATLAB software toolkit that supports both inferential and predictive modeling frameworks, accommodates both classification and regression problems, and does not impose restrictions on the modality of the predictor data. The toolkit features both a graphical user interface and scripting interface, includes implementations of multiple mass-univariate, multivariate, and machine learning models, features built-in and customizable routines for hyper-parameter optimization, cross-validation, model stacking, and significance testing, and automatically generates text-based descriptions of key methodological details and modeling results to improve reproducibility and minimize errors in the reporting of methods and results. Here, we provide an overview and discussion of the toolkit's features and demonstrate its functionality by applying it to the question of how expressive and receptive language impairments relate to lesion location, structural disconnection, and functional network disruption in a large sample of patients with left hemispheric brain lesions. We find that impairments in expressive vs. receptive language are most strongly associated with left lateral prefrontal and left posterior temporal/parietal damage, respectively. We also find that impairments in expressive vs. receptive language are associated with partially overlapping patterns of fronto-temporal structural disconnection, and that the associated functional networks are also similar. Importantly, we find that lesion location and lesion-derived network measures are highly predictive of both types of impairment, with predictions from models trained on these measures explaining ~30-40% of the variance on average when applied to data from patients not used to train the models. We have made the toolkit publicly available, and we have included a comprehensive set of tutorial notebooks to support new users in applying the toolkit in their studies.

A neural network for religious fundamentalism derived from patients with brain lesions.

Religious fundamentalism, characterized by rigid adherence to a set of beliefs putatively revealing inerrant truths, is ubiquitous across cultures and has a global impact on society. Understanding the psychological and neurobiological processes producing religious fundamentalism may inform a variety of scientific, sociological, and cultural questions. Research indicates that brain damage can alter religious fundamentalism. However, the precise brain regions involved with these changes remain unknown. Here, we analyzed brain lesions associated with varying levels of religious fundamentalism in two large datasets from independent laboratories. Lesions associated with greater fundamentalism were connected to a specific brain network with nodes in the right orbitofrontal, dorsolateral prefrontal, and inferior parietal lobe. This fundamentalism network was strongly right hemisphere lateralized and highly reproducible across the independent datasets (r = 0.82) with cross-validations between datasets. To explore the relationship of this network to lesions previously studied by our group, we tested for similarities to twenty-one lesion-associated conditions. Lesions associated with confabulation and criminal behavior showed a similar connectivity pattern as lesions associated with greater fundamentalism. Moreover, lesions associated with poststroke pain showed a similar connectivity pattern as lesions associated with lower fundamentalism. These findings are consistent with the current understanding of hemispheric specializations for reasoning and lend insight into previously observed epidemiological associations with fundamentalism, such as cognitive rigidity and outgroup hostility.

Assessing hip joint-related structure and patient-reported outcomes in people with Marfan syndrome.

OBJECTIVE: People with Marfan syndrome (MFS) have clinical symptoms of hip pain, but to date, there is limited knowledge about hip-related structural abnormalities in these patients. Therefore, the purpose of this cross-sectional study was to assess hip-related structural abnormalities and patient-reported outcomes (PRO) in a cohort of patients with MFS compared to healthy controls. METHODS: Nineteen individuals with MFS (17 females, 39.8±11.5 years) and 19 age, sex, and body mass index-matched healthy, asymptomatic individuals (17 females, 36.2±12.5 years) underwent radiographic imaging and unilateral hip MRI. The Scoring Osteoarthritis with MRI (SHOMRI) technique was used to assess hip-related morphological abnormalities between the MFS and control groups. All participants completed the Hip disability and Osteoarthritis Outcome Score (HOOS) to assess hip-related symptoms, pain, and function during activities of daily living (ADL) and quality of life (QOL). RESULTS: The MFS group exhibited higher lateral center edge angles (p < .001). Despite similar severity of femoral cartilage damage (p = 1.0), the MFS group exhibited a higher severity (p = 0.046) of acetabular cartilage degeneration (1.21±1.08) compared to the controls (0.53±1.02). There were no between-group differences in severity of labral pathology, subchondral cysts, or edema. Individuals with MFS also self-reported significantly lower HOOS symptoms (p = 0.003), pain (p = 0.014), ADL (p = 0.028), and QOL (p = 0.014) sub-scores, indicating worse hip-related PRO in MFS. CONCLUSION: Our study results suggest that individuals with MFS exhibit early signs of acetabular cartilage degeneration and poor hip-related clinical outcomes compared to healthy individuals. Future work should investigate the underlying biomechanical mechanisms associated with hip joint degeneration in the MFS population.

Novel Identification of Ankyrin-R in Cardiac Fibroblasts and a Potential Role in Heart Failure.

Altered ankyrin-R (AnkR; encoded by ANK1) expression is associated with diastolic function, left ventricular remodeling, and heart failure with preserved ejection fraction (HFpEF). First identified in erythrocytes, the role of AnkR in other tissues, particularly the heart, is less studied. Here, we identified the expression of both canonical and small isoforms of AnkR in the mouse myocardium. We demonstrate that cardiac myocytes primarily express small AnkR (sAnkR), whereas cardiac fibroblasts predominantly express canonical AnkR. As canonical AnkR expression in cardiac fibroblasts is unstudied, we focused on expression and localization in these cells. AnkR is expressed in both the perinuclear and cytoplasmic regions of fibroblasts with considerable overlap with the trans-Golgi network protein 38, TGN38, suggesting a potential role in trafficking. To study the role of AnkR in fibroblasts, we generated mice lacking AnkR in activated fibroblasts (Ank1-ifKO mice). Notably, Ank1-ifKO mice fibroblasts displayed reduced collagen compaction, supportive of a novel role of AnkR in normal fibroblast function. At the whole animal level, in response to a heart failure model, Ank1-ifKO mice displayed an increase in fibrosis and T-wave inversion compared with littermate controls, while preserving cardiac ejection fraction. Collagen type I fibers were decreased in the Ank1-ifKO mice, suggesting a novel function of AnkR in the maturation of collagen fibers. In summary, our findings illustrate the novel expression of AnkR in cardiac fibroblasts and a potential role in cardiac function in response to stress.

Distinct active zone protein machineries mediate Ca2+ channel clustering and vesicle priming at hippocampal synapses.

Action potentials trigger neurotransmitter release at the presynaptic active zone with spatiotemporal precision. This is supported by protein machinery that mediates synaptic vesicle priming and clustering of CaV2 Ca2+ channels nearby. One model posits that scaffolding proteins directly tether vesicles to CaV2s; however, here we find that at mouse hippocampal synapses, CaV2 clustering and vesicle priming are executed by separate machineries. CaV2 nanoclusters are positioned at variable distances from those of the priming protein Munc13. The active zone organizer RIM anchors both proteins but distinct interaction motifs independently execute these functions. In transfected cells, Liprin-α and RIM form co-assemblies that are separate from CaV2-organizing complexes. At synapses, Liprin-α1-Liprin-α4 knockout impairs vesicle priming but not CaV2 clustering. The cell adhesion protein PTPσ recruits Liprin-α, RIM and Munc13 into priming complexes without co-clustering CaV2s. We conclude that active zones consist of distinct machineries to organize CaV2s and prime vesicles, and Liprin-α and PTPσ specifically support priming site assembly.

The evolution and ongoing challenge of unproven cell-based interventions.

Unproven cell-based interventions (CBIs) emerged early in the 2000s as a particularly problematic form of unproven therapy and remain a vexing policy problem to this day. These unproven interventions can harm patients both physically and financially and can complicate the process of developing a rigorous evidence base to support the translation of novel stem cell or other cell therapies. In this concise review, we examine the emergence of unproven CBIs and the various policy approaches that have been pursued or proposed to address this problem. We review the evolution of this field over the last 2 decades and explore why these policy efforts have proven challenging. We conclude by highlighting potential directions that the field could evolve and urging continued attention to both current and future forms of unproven CBIs to minimize future risks to patients and the field and to promote the development of evidence-based cell therapies.

Tracheal Anastomosis Leaks Across Suture Techniques and Tensions: A Biomechanical Ex Vivo Study.

BACKGROUND: Anastomotic leak after tracheal resection may occur while coughing in the early postoperative period. We investigated the varying effects of suturing technique, stretch, and tension on anastomotic leaks during simulated coughs. METHODS: End-to-end anastomoses were performed using continuous or interrupted sutures on excised porcine larynges. Tracheas were secured to a pressurized system simulating cough forces, submerged in a water bath, and stretched to 1, 2, and 3 cm above baseline. Peak pressure, incomplete cough generation, and observed leakages were recorded. Parameters were analyzed using Analysis of Variance (ANOVA), multiple linear regression, and logistic regression modeling. RESULTS: Peak tension (B = -0.660, p < 0.001) and stretch lengths (B = -0.329, p = 0.006) were associated with variance in peak pressure (R2 = 0.77, F(3,294) = 8.182, p < 0.001). Incomplete coughs increased with higher peak tension (odds ratio [OR] = 15.627, p < 0.001) and stretching to 3 cm above baseline (OR = 4.335, p < 0.007). Similarly, leak occurrences, primarily from the posterior tracheal wall, increased with higher peak tension (OR = 1.787, p < 0.001) and stretching to 3 cm (OR = 2.613, p = 0.017). No significance was identified with suturing technique. CONCLUSION: Interrupted and continuous suture techniques do not differ in anastomotic strength during simulated coughs. Increased peak tracheal tension is associated with a weaker anastomosis, and tracheal stretch to 3 cm was associated with a weaker anastomosis. Our study supports the commonly held clinical belief that, to create a stronger anastomosis, tension should be minimized, and particular attention should be placed at the posterior tracheal wall during closure. LEVEL OF EVIDENCE: N/A, Benchtop study Laryngoscope, 2024.

Neuroanatomy of cerebellar mutism syndrome: the role of lesion location.

Approximately 25% of paediatric patients who undergo cerebellar tumour resection develop cerebellar mutism syndrome. Our group recently showed that damage to the cerebellar deep nuclei and superior cerebellar peduncles, which we refer to as the cerebellar outflow pathway, is associated with an increased risk of cerebellar mutism syndrome. Here, we tested whether these findings replicate in an independent cohort. We evaluated the relationship between lesion location and the development of cerebellar mutism syndrome in an observational study of 56 paediatric patients ranging from five months to 14 years of age who underwent cerebellar tumour resection. We hypothesized that individuals who developed cerebellar mutism syndrome after surgery, relative to those who did not, would have lesions that preferentially intersect with: (i) the cerebellar outflow pathway and (ii) a previously generated 'lesion-symptom map' of cerebellar mutism syndrome. Analyses were conducted in accordance with pre-registered hypotheses and analytic methods (https://osf.io/r8yjv/). We found supporting evidence for both hypotheses. Compared to patients who did not develop cerebellar mutism syndrome, patients with cerebellar mutism syndrome (n = 10) had lesions with greater overlap with the cerebellar outflow pathway (Cohen's d = 0.73, P = 0.05), and the cerebellar mutism syndrome lesion-symptom map (Cohen's d = 1.1, P = 0.004). These results strengthen the association of lesion location with the risk of developing cerebellar mutism syndrome and demonstrate generalizability across cohorts. These findings may help to inform the optimal surgical approach to paediatric cerebellar tumours.

Neuromodulation with Ultrasound: Hypotheses on the Directionality of Effects and a Community Resource.

Low-intensity Transcranial Ultrasound Stimulation (TUS) is a promising non-invasive technique for deep-brain stimulation and focal neuromodulation. Research with animal models and computational modelling has raised the possibility that TUS can be biased towards enhancing or suppressing neural function. Here, we first conduct a systematic review of human TUS studies for perturbing neural function and alleviating brain disorders. We then collate a set of hypotheses on the directionality of TUS effects and conduct an initial meta-analysis on the human TUS study reported outcomes to date (n = 32 studies, 37 experiments). We find that parameters such as the duty cycle show some predictability regarding whether the targeted area's function is likely to be enhanced or suppressed. Given that human TUS sample sizes are exponentially increasing, we recognize that results can stabilize or change as further studies are reported. Therefore, we conclude by establishing an Iowa-Newcastle (inTUS) resource for the systematic reporting of TUS parameters and outcomes to support further hypothesis testing for greater precision in brain stimulation and neuromodulation with TUS.