275 results on '"M., Ford"'
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2. Spatial transcriptome-guided multi-scale framework connects P. aeruginosa metabolic states to oxidative stress biofilm microenvironment.
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Tracy J Kuper, Mohammad Mazharul Islam, Shayn M Peirce-Cottler, Jason A Papin, and Roseanne M Ford
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Biology (General) ,QH301-705.5 - Abstract
With the generation of spatially resolved transcriptomics of microbial biofilms, computational tools can be used to integrate this data to elucidate the multi-scale mechanisms controlling heterogeneous biofilm metabolism. This work presents a Multi-scale model of Metabolism In Cellular Systems (MiMICS) which is a computational framework that couples a genome-scale metabolic network reconstruction (GENRE) with Hybrid Automata Library (HAL), an existing agent-based model and reaction-diffusion model platform. A key feature of MiMICS is the ability to incorporate multiple -omics-guided metabolic models, which can represent unique metabolic states that yield different metabolic parameter values passed to the extracellular models. We used MiMICS to simulate Pseudomonas aeruginosa regulation of denitrification and oxidative stress metabolism in hypoxic and nitric oxide (NO) biofilm microenvironments. Integration of P. aeruginosa PA14 biofilm spatial transcriptomic data into a P. aeruginosa PA14 GENRE generated four PA14 metabolic model states that were input into MiMICS. Characteristic of aerobic, denitrification, and oxidative stress metabolism, the four metabolic model states predicted different oxygen, nitrate, and NO exchange fluxes that were passed as inputs to update the agent's local metabolite concentrations in the extracellular reaction-diffusion model. Individual bacterial agents chose a PA14 metabolic model state based on a combination of stochastic rules, and agents sensing local oxygen and NO. Transcriptome-guided MiMICS predictions suggested microscale denitrification and oxidative stress metabolic heterogeneity emerged due to local variability in the NO biofilm microenvironment. MiMICS accurately predicted the biofilm's spatial relationships between denitrification, oxidative stress, and central carbon metabolism. As simulated cells responded to extracellular NO, MiMICS revealed dynamics of cell populations heterogeneously upregulating reactions in the denitrification pathway, which may function to maintain NO levels within non-toxic ranges. We demonstrated that MiMICS is a valuable computational tool to incorporate multiple -omics-guided metabolic models to mechanistically map heterogeneous microbial metabolic states to the biofilm microenvironment.
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- 2024
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3. Editorial: Emerging aspects of ketone metabolism in health & disease
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Brianna Jane Stubbs, Kenneth M. Ford, and Jeff Volek
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ketosis ,ketogenic diet ,ketone ester ,exogenous ketone ,ketone infusion ,butanediol ,Physiology ,QP1-981 - Published
- 2024
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4. An answered call for aid? Cannabinoid clinical framework for the opioid epidemic
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Krista Hammaker, Nathaniel Weathington, Joseph Maroon, Lawton W. Tang, Brian Donohue, Rachel Yehuda, Kenneth M. Ford, Myro Figura, Ben Kelmendi, Belinda Tan, Matthew W. Cook, Steven D. Factor, Laura Lagano, Henry Patrick Driscoll, Adam S. Howe, EunBit G. Cho, and David M. Rabin
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Cannabinoids ,Chronic pain ,Opioids ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background The opioid crisis continues in full force, as physicians and caregivers are desperate for resources to help patients with opioid use and chronic pain disorders find safer and more accessible non-opioid tools. Main body The purpose of this article is to review the current state of the opioid epidemic; the shifting picture of cannabinoids; and the research, policy, and current events that make opioid risk reduction an urgent public health challenge. The provided table contains an evidence-based clinical framework for the utilization of cannabinoids to treat patients with chronic pain who are dependent on opioids, seeking alternatives to opioids, and tapering opioids. Conclusion Based on a comprehensive review of the literature and epidemiological evidence to date, cannabinoids stand to be one of the most interesting, safe, and accessible tools available to attenuate the devastation resulting from the misuse and abuse of opioid narcotics. Considering the urgency of the opioid epidemic and broadening of cannabinoid accessibility amidst absent prescribing guidelines, the authors recommend use of this clinical framework in the contexts of both clinical research continuity and patient care.
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- 2023
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5. Microfluidic Isolation of Neuronal-Enriched Extracellular Vesicles Shows Distinct and Common Neurological Proteins in Long COVID, HIV Infection and Alzheimer’s Disease
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Lynn Pulliam, Bing Sun, Erin McCafferty, Steven A. Soper, Malgorzata A. Witek, Mengjia Hu, Judith M. Ford, Sarah Song, Dimitrios Kapogiannis, Marshall J. Glesby, Daniel Merenstein, Phyllis C. Tien, Heather Freasier, Audrey French, Heather McKay, Monica M. Diaz, Igho Ofotokun, Jordan E. Lake, Joseph B. Margolick, Eun-Young Kim, Steven R. Levine, Margaret A. Fischl, Wei Li, Jeremy Martinson, and Norina Tang
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L1CAM ,extracellular vesicles ,OLINK ,long COVID ,HIV ,Alzheimer’s disease ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Long COVID (LongC) is associated with a myriad of symptoms including cognitive impairment. We reported at the beginning of the COVID-19 pandemic that neuronal-enriched or L1CAM+ extracellular vesicles (nEVs) from people with LongC contained proteins associated with Alzheimer’s disease (AD). Since that time, a subset of people with prior COVID infection continue to report neurological problems more than three months after infection. Blood markers to better characterize LongC are elusive. To further identify neuronal proteins associated with LongC, we maximized the number of nEVs isolated from plasma by developing a hybrid EV Microfluidic Affinity Purification (EV-MAP) technique. We isolated nEVs from people with LongC and neurological complaints, AD, and HIV infection with mild cognitive impairment. Using the OLINK platform that assesses 384 neurological proteins, we identified 11 significant proteins increased in LongC and 2 decreased (BST1, GGT1). Fourteen proteins were increased in AD and forty proteins associated with HIV cognitive impairment were elevated with one decreased (IVD). One common protein (BST1) was decreased in LongC and increased in HIV. Six proteins (MIF, ENO1, MESD, NUDT5, TNFSF14 and FYB1) were expressed in both LongC and AD and no proteins were common to HIV and AD. This study begins to identify differences and similarities in the neuronal response to LongC versus AD and HIV infection.
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- 2024
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6. Blood Markers Show Neural Consequences of LongCOVID-19
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Norina Tang, Tatsuo Kido, Jian Shi, Erin McCafferty, Judith M. Ford, Kaitlyn Dal Bon, and Lynn Pulliam
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LongCOVID-19 ,blood markers ,neuronal extracellular vesicles ,BDNF ,cortisol ,cognition ,Cytology ,QH573-671 - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system. To search for neurological markers of LongC, we investigated the soluble biomolecules present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC). COVID-19 positive participants were infected between 2020 and 2022, not hospitalized, and were vaccinated or unvaccinated before infection. IL-1β was significantly increased in both nLongC and Cov and IL-8 was elevated in only nLongC. Both brain-derived neurotrophic factor and cortisol were significantly elevated in nLongC and Cov compared to HC. nEVs from people with nLongC had significantly elevated protein markers of neuronal dysfunction, including amyloid beta 42, pTau181 and TDP-43. This study shows chronic peripheral inflammation with increased stress after COVID-19 infection. Additionally, differentially expressed nEV neurodegenerative proteins were identified in people recovering from COVID-19 regardless of persistent symptoms.
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- 2024
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7. Gender bias in autism screening: measurement invariance of different model frameworks of the Autism Spectrum Quotient
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Hannah L. Belcher, Nora Uglik-Marucha, Silia Vitoratou, Ruth M. Ford, and Sharon Morein-Zamir
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Autistic spectrum disorders ,neurodevelopmental disorders ,psychological testing ,statistical methodology ,community mental health teams ,Psychiatry ,RC435-571 - Abstract
Background The Autism Spectrum Quotient is a popular autism screening tool recommended for identifying potential cases of autism. However, many women with autism demonstrate a different presentation of traits to those currently captured by screening measures and assessment methods, such as the Autism Spectrum Quotient. Aims Different models of the Autism Spectrum Quotient have been proposed in the literature, utilising different items from the original 50-item scale. Within good-fitting models, the current study aimed to explore whether these items assess autistic traits similarly across men and women. Method Seventeen Autism Spectrum Quotient models were identified from the literature. Using the responses of a large sample of adults from the UK general population (5246 women, 1830 men), confirmatory factor analysis was used to evaluate the fit of each model. Measurement invariance with respect to gender, adjusting for age, was explored in the 11 model frameworks that were found to have satisfactory fit to our data. Results It emerged that only two items were gender invariant (non-biased), whereas for the remaining items, the probability of endorsement was influenced by gender. In particular, women had a higher probability of endorsing items relating to social skills and communication. Conclusions If the items of the Autism Spectrum Quotient indeed reflect autism-related traits, those items should be rephrased to ensure they do not present a gender-related bias. This is vital for ensuring more timely diagnoses and support for all people with autism.
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- 2023
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8. Antitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers
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James J. Harding, Sarina A. Piha-Paul, Ronak H. Shah, Jessica J. Murphy, James M. Cleary, Geoffrey I. Shapiro, David I. Quinn, Irene Braña, Victor Moreno, Mitesh Borad, Sherene Loi, Iben Spanggaard, Haeseong Park, James M. Ford, Mónica Arnedos, Salomon M. Stemmer, Christelle de la Fouchardiere, Christos Fountzilas, Jie Zhang, Daniel DiPrimeo, Casey Savin, S. Duygu Selcuklu, Michael F. Berger, Lisa D. Eli, Funda Meric-Bernstam, Komal Jhaveri, David B. Solit, and Ghassan K. Abou-Alfa
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Science - Abstract
In biliary tract cancer HER2 alterations correlate with poor prognosis. Here, the authors present the results of a phase II clinical trial reporting the efficacy and safety of the tyrosine kinase inhibitor neratinib in patients with HER2-mutation positive advanced biliary tract cancers.
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- 2023
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9. Formed in His Image: A Guide for Christian Formation
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Coleman M. Ford
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- 2023
10. Spectroscopic r-process Abundance Retrieval for Kilonovae. II. Lanthanides in the Inferred Abundance Patterns of Multicomponent Ejecta from the GW170817 Kilonova
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Nicholas Vieira, John J. Ruan, Daryl Haggard, Nicole M. Ford, Maria R. Drout, and Rodrigo Fernández
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Nuclear abundances ,R-process ,Radiative transfer simulations ,Spectral line identification ,Astrophysics ,QB460-466 - Abstract
In kilonovae, freshly synthesized r -process elements imprint features on optical spectra, as observed in AT2017gfo, the counterpart to the GW170817 binary neutron star merger. However, measuring the r -process compositions of the merger ejecta is computationally challenging. Vieira et al. introduced Spectroscopic r -process Abundance Retrieval for Kilonovae ( SPARK ), a software tool to infer elemental abundance patterns of the ejecta and associate spectral features with particular species. Previously, we applied SPARK to the 1.4-day spectrum of AT2017gfo and inferred its abundance pattern for the first time, characterized by electron fraction Y _e = 0.31, a substantial abundance of strontium, and a dearth of lanthanides and heavier elements. This ejecta is consistent with wind from a remnant hypermassive neutron star and/or accretion disk. We now extend our inference to spectra at 2.4 and 3.4 days and test the need for multicomponent ejecta, where we stratify the ejecta in composition. The ejecta at 1.4 and 2.4 days is described by the same single blue component. At 3.4 days, a new redder component with lower Y _e = 0.16 and a significant abundance of lanthanides emerges. This new redder component is consistent with dynamical ejecta and/or neutron-rich ejecta from a magnetized accretion disk. As expected from photometric modeling, this component emerges as the ejecta expands, the photosphere recedes, and the earlier bluer component dims. At 3.4 days, we find an ensemble of lanthanides, with the presence of cerium most concrete. This presence of lanthanides has important implications for the contribution of kilonovae to the r -process abundances observed in the Universe.
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- 2024
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11. KilonovAE: Exploring Kilonova Spectral Features with Autoencoders
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N. M. Ford, Nicholas Vieira, John J. Ruan, and Daryl Haggard
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Neutron stars ,R-process ,Radiative transfer simulations ,Spectral line identification ,Dimensionality reduction ,Astrophysics ,QB460-466 - Abstract
Kilonovae are likely a key site of heavy r -process element production in the Universe, and their optical/infrared spectra contain insights into both the properties of the ejecta and the conditions of the r -process. However, the event GW170817/AT2017gfo is the only kilonova so far with well-observed spectra. To understand the diversity of absorption features that might be observed in future kilonovae spectra, we use the TARDIS Monte Carlo radiative transfer code to simulate a suite of optical spectra spanning a wide range of kilonova ejecta properties and r -process abundance patterns. To identify the most common and prominent absorption lines, we perform dimensionality reduction using an autoencoder, and we find spectra clusters in the latent space representation using a Bayesian Gaussian Mixture model. Our synthetic kilonovae spectra commonly display strong absorption by strontium _38 Sr ii , yttrium _38 Y ii , and zirconium _40 Zr i–ii , with strong lanthanide contributions at low electron fractions ( Y _e ≲ 0.25). When a new kilonova is observed, our machine-learning framework will provide context on the dominant absorption lines and key ejecta properties, helping to determine where this event falls within the larger “zoo” of kilonovae spectra.
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- 2024
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12. Advances in cellular and molecular predatory biology of Bdellovibrio bacteriovorus six decades after discovery
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Ting F. Lai, Rhian M. Ford, and Simona G. Huwiler
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predatory bacteria ,Bdellovibrio bacteriovorus ,molecular mechanisms ,history ,methods ,antimicrobial resistance ,Microbiology ,QR1-502 - Abstract
Since its discovery six decades ago, the predatory bacterium Bdellovibrio bacteriovorus has sparked recent interest as a potential remedy to the antibiotic resistance crisis. Here we give a comprehensive historical overview from discovery to progressive developments in microscopy and molecular mechanisms. Research on B. bacteriovorus has moved from curiosity to a new model organism, revealing over time more details on its physiology and fascinating predatory life cycle with the help of a variety of methods. Based on recent findings in cryo-electron tomography, we recapitulate on the intricate molecular details known in the predatory life cycle including how this predator searches for its prey bacterium, to how it attaches, grows, and divides all from within the prey cell. Finally, the newly developed B. bacteriovorus progeny leave the prey cell remnants in the exit phase. While we end with some unanswered questions remaining in the field, new imaging technologies and quantitative, systematic advances will likely help to unravel them in the next decades.
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- 2023
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13. How does conservation land tenure affect economic impacts of wildlife: An analysis of subsistence farmers and herders in Bhutan
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Yeshey, Rodney J. Keenan, Rebecca M. Ford, and Craig R. Nitschke
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Wildlife conservation ,Livelihood ,Economic loss ,Crop depredation ,Livestock depredation ,Sustainable development ,Forestry ,SD1-669.5 ,Plant ecology ,QK900-989 - Abstract
Protected areas (PA) to conserve wildlife are the cornerstone of biodiversity conservation but they can also result in increased human-wildlife conflict (HWC), which poses a serious challenge to jointly achieving sustainable development goals of food security and biodiversity conservation, particular in regions with high conservation values and subsistence farmers. In the Himalayan Kingdom of Bhutan, expanding PAs and other conservation efforts have led to increased wildlife populations that are causing more damage to crop and livestock and impacting on the livelihoods of subsistence farmers and herders. In this study, we used a social-ecological systems framework to quantify the intensity this impact and associated economic losses with identified wildlife species and compared differences between livelihood types (crop farming versus livestock husbandry) and land tenure (inside versus outside protected areas). Results indicated that Meso-scale wildlife species that are not the focus of conservation caused higher economic losses. Approximately 43% of total economic loss through crop depredation was attributed to wild pig (Sus scrofa) and 56% of the total economic loss through livestock predation was caused by wild dogs (Cuon alpinus). Losses borne by respondents whose livelihoods depend mainly on livestock were significantly higher, with a mean loss equivalent to US$1328 per household per annum, than those depending on crop production (US$171 per household per annum). Economic losses incurred through crop and livestock depredation were significantly higher for the respondents residing inside PAs, which is attributed by those households to a perceived increase in wildlife populations because of conservation policies. Interventions for prevention and mitigation of these impacts should recognize these varying unintended effects of wildlife and be better targeted at groups living in different parts of the landscape. These include expanding compensation scheme to losses caused by wild dogs and pigs, supporting ecotourism ventures within PAs to diversify income options and introducing control measures for these animals.
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- 2023
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14. In-hospital stress and patient outcomes: A systematic review and meta-analysis
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Daniel M. Ford, Luke Budworth, Rebecca Lawton, Elizabeth A. Teale, and Daryl B. O’Connor
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Medicine ,Science - Abstract
Background Hospital inpatients are exposed to high levels of stress during hospitalisation that may increase susceptibility to major adverse health events post-hospitalisation (known as post-hospital syndrome). However, the existing evidence base has not been reviewed and the magnitude of this relationship remains unknown. Therefore, the aim of the current systematic review and meta-analysis was to: 1) synthesise existing evidence and to determine the strength of the relationship between in-hospital stress and patient outcomes, and 2) determine if this relationship differs between (i) in-hospital vs post-hospital outcomes, and (ii) subjective vs objective outcome measures. Methods A systematic search of MEDLINE, EMBASE, PsychINFO, CINAHL, and Web of Science from inception to February 2023 was conducted. Included studies reported a measure of perceived and appraised stress while in hospital, and at least one patient outcome. A random-effects model was generated to pool correlations (Pearson’s r), followed by sub-group and sensitivity analyses. The study protocol was preregistered on PROSPERO (CRD42021237017). Results A total of 10 studies, comprising 16 effects and 1,832 patients, satisfied the eligibility criteria and were included. A small-to-medium association was found: as in-hospital stress increased, patient outcomes deteriorated (r = 0.19; 95% CI: 0.12–0.26; I2 = 63.6; p < 0.001). This association was significantly stronger for (i) in-hospital versus post-hospital outcomes, and (ii) subjective versus objective outcome measures. Sensitivity analyses indicated that our findings were robust. Conclusions Higher levels of psychological stress experienced by hospital inpatients are associated with poorer patient outcomes. However, more high-quality, larger scale studies are required to better understand the association between in-hospital stressors and adverse outcomes.
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- 2023
15. Multi-model order spatially constrained ICA reveals highly replicable group differences and consistent predictive results from resting data: A large N fMRI schizophrenia study
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Xing Meng, Armin Iraji, Zening Fu, Peter Kochunov, Aysenil Belger, Judy M. Ford, Sara McEwen, Daniel H. Mathalon, Bryon A. Mueller, Godfrey Pearlson, Steven G. Potkin, Adrian Preda, Jessica Turner, Theo G.M. van Erp, Jing Sui, and Vince D. Calhoun
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Functional network connectivity(FNC) ,Component number ,Spatially constrained ICA ,Resting fMRI ,Machine learning ,Intrinsic connectivity networks ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Brain functional networks identified from resting functional magnetic resonance imaging (fMRI) data have the potential to reveal biomarkers for brain disorders, but studies of complex mental illnesses such as schizophrenia (SZ) often yield mixed results across replication studies. This is likely due in part to the complexity of the disorder, the short data acquisition time, and the limited ability of the approaches for brain imaging data mining. Therefore, the use of analytic approaches which can both capture individual variability while offering comparability across analyses is highly preferred. Fully blind data-driven approaches such as independent component analysis (ICA) are hard to compare across studies, and approaches that use fixed atlas-based regions can have limited sensitivity to individual sensitivity. By contrast, spatially constrained ICA (scICA) provides a hybrid, fully automated solution that can incorporate spatial network priors while also adapting to new subjects. However, scICA has thus far only been used with a single spatial scale (ICA dimensionality, i.e., ICA model order). In this work, we present an approach using multi-objective optimization scICA with reference algorithm (MOO-ICAR) to extract subject-specific intrinsic connectivity networks (ICNs) from fMRI data at multiple spatial scales, which also enables us to study interactions across spatial scales. We evaluate this approach using a large N (N > 1,600) study of schizophrenia divided into separate validation and replication sets. A multi-scale ICN template was estimated and labeled, then used as input into scICA which was computed on an individual subject level. We then performed a subsequent analysis of multiscale functional network connectivity (msFNC) to evaluate the patient data, including group differences and classification. Results showed highly consistent group differences in msFNC in regions including cerebellum, thalamus, and motor/auditory networks. Importantly, multiple msFNC pairs linking different spatial scales were implicated. The classification model built on the msFNC features obtained up to 85% F1 score, 83% precision, and 88% recall, indicating the strength of the proposed framework in detecting group differences between schizophrenia and the control group. Finally, we evaluated the relationship of the identified patterns to positive symptoms and found consistent results across datasets. The results verified the robustness of our framework in evaluating brain functional connectivity of schizophrenia at multiple spatial scales, implicated consistent and replicable brain networks, and highlighted a promising approach for leveraging resting fMRI data for brain biomarker development.
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- 2023
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16. Editorial: The toxicology of drugs of abuse
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Benjamin M. Ford, Tory R. Spindle, and Nicola Simola
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alcohol ,amphetamines ,cannabinoids ,cathinones ,central toxicity ,peripheral toxicity ,Psychiatry ,RC435-571 - Published
- 2023
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17. Advanced brain age correlates with greater rumination and less mindfulness in schizophrenia
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Samantha V. Abram, Brian J. Roach, Jessica P.Y. Hua, Laura K.M. Han, Daniel H. Mathalon, Judith M. Ford, and Susanna L. Fryer
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Aging ,Structural MRI ,Meditation ,Rumination ,Stress ,Psychosis ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Background: Individual variation in brain aging trajectories is linked with several physical and mental health outcomes. Greater stress levels, worry, and rumination correspond with advanced brain age, while other individual characteristics, like mindfulness, may be protective of brain health. Multiple lines of evidence point to advanced brain aging in schizophrenia (i.e., neural age estimate > chronological age). Whether psychological dimensions such as mindfulness, rumination, and perceived stress contribute to brain aging in schizophrenia is unknown. Methods: We estimated brain age from high-resolution anatomical scans in 54 healthy controls (HC) and 52 individuals with schizophrenia (SZ) and computed the brain predicted age difference (BrainAGE-diff), i.e., the delta between estimated brain age and chronological age. Emotional well-being summary scores were empirically derived to reflect individual differences in trait mindfulness, rumination, and perceived stress. Core analyses evaluated relationships between BrainAGE-diff and emotional well-being, testing for slopes differences across groups. Results: HC showed higher emotional well-being (greater mindfulness and less rumination/stress), relative to SZ. We observed a significant group difference in the relationship between BrainAge-diff and emotional well-being, explained by BrainAGE-diff negatively correlating with emotional well-being scores in SZ, and not in HC. That is, SZ with younger appearing brains (predicted age
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- 2023
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18. Cerebellar stimulation in schizophrenia: A systematic review of the evidence and an overview of the methods
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Jessica P. Y. Hua, Samantha V. Abram, and Judith M. Ford
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transcranial stimulation ,cerebellar vermis ,schizophrenia ,negative symptoms ,depression ,tDCS ,Psychiatry ,RC435-571 - Abstract
BackgroundCerebellar structural and functional abnormalities underlie widespread deficits in clinical, cognitive, and motor functioning that are observed in schizophrenia. Consequently, the cerebellum is a promising target for novel schizophrenia treatments. Here we conducted an updated systematic review examining the literature on cerebellar stimulation efficacy and tolerability for mitigating symptoms of schizophrenia. We discuss the purported mechanisms of cerebellar stimulation, current methods for implementing stimulation, and future directions of cerebellar stimulation for intervention development with this population.MethodsTwo independent authors identified 20 published studies (7 randomized controlled trials, 7 open-label studies, 1 pilot study, 4 case reports, 1 preclinical study) that describe the effects of cerebellar circuitry modulation in patients with schizophrenia or animal models of psychosis. Published studies up to October 11, 2022 were identified from a search within PubMed, Scopus, and PsycInfo.ResultsMost studies stimulating the cerebellum used transcranial magnetic stimulation or transcranial direct-current stimulation, specifically targeting the cerebellar vermis/midline. Accounting for levels of methodological rigor across studies, these studies detected post-cerebellar modulation in schizophrenia as indicated by the alleviation of certain clinical symptoms (mainly negative and depressive symptoms), as well as increased frontal-cerebellar connectivity and augmentation of canonical neuro-oscillations known to be abnormal in schizophrenia. In contrast to a prior review, we did not find consistent evidence for cognitive improvements following cerebellar modulation stimulation. Modern cerebellar stimulation methods appear tolerable for individuals with schizophrenia, with only mild and temporary side effects.ConclusionCerebellar stimulation is a promising intervention for individuals with schizophrenia that may be more relevant to some symptom domains than others. Initial results highlight the need for continued research using more methodologically rigorous designs, such as additional longitudinal and randomized controlled trials.Systematic review registration[https://www.crd.york.ac.uk/prospero/], identifier [CRD42022346667].
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- 2022
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19. Fever of Unknown Origin: A True Tale of Medicine, Mystery, and Magic
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Judith M. Ford
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- 2022
20. Federally Qualified Health Center Penetration Associated With Reduced Community COVID-19 Mortality in Four United States Cities
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Mary M. Ford, Angela Allard, Jordan Goldberg, and Cynthia Summers
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Computer applications to medicine. Medical informatics ,R858-859.7 ,Public aspects of medicine ,RA1-1270 - Abstract
Background: The COVID-19 pandemic has had significant impacts on health care access and delivery, with disparate effects across social and racial lines. Federally Qualified Health Centers (FQHCs) provide critical primary care services to the nation’s most underserved populations, including many communities hardest hit by COVID-19. Methods: We conducted an ecological analysis that aimed to examine FQHC penetration, COVID-19 mortality, and socio-demographic factors in 4 major United States cities: New York, New York; Chicago, Illinois; Detroit, Michigan; and Seattle, Washington. Results: We found the distribution of COVID-19 cases and mortality varied spatially and in magnitude by city. COVID-19 mortality was significantly higher in communities with higher percentages of low-income residents and higher percentages of racial/ethnic minority residents. FQHC penetration was protective against increased COVID-19 mortality, after model adjustment. Conclusions: Our study underpins the critical role of safety-net health care and policymakers must ensure investment in long-term sustainability of FQHCs, through strategic deployment of capital, workforce development, and reimbursement reform.
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- 2022
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21. Generalization of Runoff Risk Prediction at Field Scales to a Continental‐Scale Region Using Cluster Analysis and Hybrid Modeling
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Chanse M. Ford, Yao Hu, Chirantan Ghosh, Lauren M. Fry, Siamak Malakpour‐Estalaki, Lacey Mason, Lindsay Fitzpatrick, Amir Mazrooei, and Dustin C. Goering
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runoff potential ,clustering ,XGBoost ,National Water Model ,hybrid modeling ,generalization ,Geophysics. Cosmic physics ,QC801-809 - Abstract
Abstract As surface water resources in the U.S. continue to be pressured by excess nutrients carried by agricultural runoff, the need to assess runoff risk at the field scale continues to grow in importance. Most landscape hydrologic models developed at regional scales have limited applicability at finer spatial scales. Hybrid models can be used to address the scale mismatch between model simulation and applicability, but could be limited by their ability to generalize over a large domain with heterogeneous hydrologic characteristics. To assist the generalization, we develop a regionalization approach based on the principal component analysis and K‐means clustering to identify the clusters with similar runoff potential over the Great Lakes region. For each cluster, hybrid models are developed by combining National Oceanic and Atmospheric Administration's National Water Model and a data‐driven model, eXtreme gradient boosting with field‐scale measurements, enabling prediction of daily runoff risk level at the field scale over the entire region.
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- 2022
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22. Statistical assessment on determining local presence of rare bat species
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Kathryn M. Irvine, Katharine M. Banner, Christian Stratton, William M. Ford, and Brian E. Reichert
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acoustic survey ,autonomous recording units ,Bayesian hierarchical model ,count detection model ,false positives ,imperfect detection ,Ecology ,QH540-549.5 - Abstract
Abstract Surveying cryptic, sparsely distributed taxa using autonomous recording units, although cost‐effective, provides imperfect knowledge about species presence. Summertime bat acoustic surveys in North America exemplify the challenges with characterizing sources of uncertainty: observation error, inability to census populations, and natural stochastic variation. Statistical uncertainty, if not considered thoroughly, hampers determining rare species presence accurately and/or estimating rangewide status and trends with suitable precision. Bat acoustic data are processed using an automated workflow in which proprietary or open‐source algorithms assign a species label to each recorded high‐frequency echolocation sequence. A false‐negative occurs, if a species is actually present but not recorded and/or all recordings from the species are of such poor quality that a correct species identity cannot be assigned to any observation. False positives for a focal species are a direct result of the presence and incorrect identification of a recording from another species. We compare four analytical approaches in terms of parameter estimation and their resulting (in)correct decisions regarding species presence or absence using realistic data‐generating scenarios for bat acoustic data within a simulation study. The current standard for deciding species presence or absence uses a multinomial likelihood‐ratio test p value (maximum likelihood estimate [MLE]‐metric) that accounts for known species misidentifications, but not imperfect detection and only returns a binary outcome (evidence of presence or not). We found that the MLE‐metric had estimated median correct decisions less than 60% for presence and greater than 85% for absence. Alternatively, a multispecies count detection model was equivalent to or better than the MLE‐metric for correct claims of rare species presence or absence using the posterior probability a species was present at a site and, importantly, provided unbiased estimates of relative activity and probability of occurrence, creating opportunities for reducing posterior uncertainty through the inclusion of meaningful covariates. Single‐species occupancy models with and without false‐positive detections removed were insufficient for determining local presence because of substantially biased occurrence and detection probabilities. We propose solutions to potential barriers for integrating local, short‐term and rangewide, long‐term acoustic surveys within a cohesive statistical framework that facilitates determining local species presence with uncertainty concurrent with estimating species–environment relationships.
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- 2022
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23. 270 Development of a Predictive Nomogram for Circumferential Resection Margin in Rectal Cancer Surgery
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Megan Shroder, Molly M Ford, Fei Ye, Zhiguo Zhao, Aimal Khan, Shannon McChesney, M. Benjamin Hopkins, and Alexander T. Hawkins
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Medicine - Abstract
OBJECTIVES/GOALS: A negative circumferential resection margin (CRM) after surgical resection of rectal cancer decreases local recurrence and increases overall survival. While MRI is used to predict this risk, there is no predictive model that incorporates clinical factors to predict the risk of CRM positivity. METHODS/STUDY POPULATION: Utilizing the National Cancer Database from 2010-2014, we performed a retrospective study evaluating factors predictive for positive CRM after surgical resection of rectal cancer. The primary outcome was positive CRM (tumor≤1 mm from the surgical margin). Our population included patients with clinical stage I-III rectal cancer who underwent total mesorectal excision. For the primary outcome, multivariable logistic models were used to estimate the probability of a positive CRM. Model performance was evaluated by using the area under the receiver operating characteristic curve (AUC). Model calibration was assessed by examining the calibration plot. Bootstrapping method (300-iteration) was used to internally validate and estimate optimism-adjusted measures of discrimination and overall model fit. RESULTS/ANTICIPATED RESULTS: There were 28,790 patients included. 2,245 (7.8%) had positive CRM. Older age, race, larger tumor size, higher tumor grade, mucinous and signet tumor histology, APR, open operative approach, facility location, higher T stage, lymphovascular invasion, lack of neoadjuvant chemotherapy/radiation, and perineural invasion were all significantly associated with positive CRM (p DISCUSSION/SIGNIFICANCE: An objective model that predicts positive CRM and associated poor clinical outcomes is possible to be used in conjunction with MRI. Positive CRM is associated with specific patient demographics, tumor characteristics, and operative approach. These factors can be used to predict CRM positivity in the preoperative period and plan accordingly.
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- 2023
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- View/download PDF
24. Psychological Dimensions Relevant to Motivation and Pleasure in Schizophrenia
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Samantha V. Abram, Lauren P. Weittenhiller, Claire E. Bertrand, John R. McQuaid, Daniel H. Mathalon, Judith M. Ford, and Susanna L. Fryer
- Subjects
optimism ,cognitive behavioral theory ,reappraisal ,mindfulness ,rumination ,social reward sensitivity ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Motivation and pleasure deficits are common in schizophrenia, strongly linked with poorer functioning, and may reflect underlying alterations in brain functions governing reward processing and goal pursuit. While there is extensive research examining cognitive and reward mechanisms related to these deficits in schizophrenia, less attention has been paid to psychological characteristics that contribute to resilience against, or risk for, motivation and pleasure impairment. For example, psychological tendencies involving positive future expectancies (e.g., optimism) and effective affect management (e.g., reappraisal, mindfulness) are associated with aspects of reward anticipation and evaluation that optimally guide goal-directed behavior. Conversely, maladaptive thinking patterns (e.g., defeatist performance beliefs, asocial beliefs) and tendencies that amplify negative cognitions (e.g., rumination), may divert cognitive resources away from goal pursuit or reduce willingness to exert effort. Additionally, aspects of sociality, including the propensity to experience social connection as positive reinforcement may be particularly relevant for pursuing social goals. In the current review, we discuss the roles of several psychological characteristics with respect to motivation and pleasure in schizophrenia. We argue that individual variation in these psychological dimensions is relevant to the study of motivation and reward processing in schizophrenia, including interactions between these psychological dimensions and more well-characterized cognitive and reward processing contributors to motivation. We close by emphasizing the value of considering a broad set of modulating factors when studying motivation and pleasure functions in schizophrenia.
- Published
- 2022
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- View/download PDF
25. From Sound Perception to Automatic Detection of Schizophrenia: An EEG-Based Deep Learning Approach
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Carla Barros, Brian Roach, Judith M. Ford, Ana P. Pinheiro, and Carlos A. Silva
- Subjects
auditory processing ,convolutional neural network ,deep learning ,EEG ,schizophrenia ,Psychiatry ,RC435-571 - Abstract
Deep learning techniques have been applied to electroencephalogram (EEG) signals, with promising applications in the field of psychiatry. Schizophrenia is one of the most disabling neuropsychiatric disorders, often characterized by the presence of auditory hallucinations. Auditory processing impairments have been studied using EEG-derived event-related potentials and have been associated with clinical symptoms and cognitive dysfunction in schizophrenia. Due to consistent changes in the amplitude of ERP components, such as the auditory N100, some have been proposed as biomarkers of schizophrenia. In this paper, we examine altered patterns in electrical brain activity during auditory processing and their potential to discriminate schizophrenia and healthy subjects. Using deep convolutional neural networks, we propose an architecture to perform the classification based on multi-channels auditory-related EEG single-trials, recorded during a passive listening task. We analyzed the effect of the number of electrodes used, as well as the laterality and distribution of the electrical activity over the scalp. Results show that the proposed model is able to classify schizophrenia and healthy subjects with an average accuracy of 78% using only 5 midline channels (Fz, FCz, Cz, CPz, and Pz). The present study shows the potential of deep learning methods in the study of impaired auditory processing in schizophrenia with implications for diagnosis. The proposed design can provide a base model for future developments in schizophrenia research.
- Published
- 2022
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- View/download PDF
26. Aperiodic measures of neural excitability are associated with anticorrelated hemodynamic networks at rest: A combined EEG-fMRI study
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Michael S. Jacob, Brian J. Roach, Kaia S. Sargent, Daniel H. Mathalon, and Judith M. Ford
- Subjects
Scale-free ,Aperiodic ,Resting-state ,EEG-fMRI ,Neurometabolic coupling ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The hallmark of resting EEG spectra are distinct rhythms emerging from a broadband, aperiodic background. This aperiodic neural signature accounts for most of total EEG power, although its significance and relation to functional neuroanatomy remains obscure. We hypothesized that aperiodic EEG reflects a significant metabolic expenditure and therefore might be associated with the default mode network while at rest. During eyes-open, resting-state recordings of simultaneous EEG-fMRI, we find that aperiodic and periodic components of EEG power are only minimally associated with activity in the default mode network. However, a whole-brain analysis identifies increases in aperiodic power correlated with hemodynamic activity in an auditory-salience-cerebellar network, and decreases in aperiodic power are correlated with hemodynamic activity in prefrontal regions. Desynchronization in residual alpha and beta power is associated with visual and sensorimotor hemodynamic activity, respectively. These findings suggest that resting-state EEG signals acquired in an fMRI scanner reflect a balance of top-down and bottom-up stimulus processing, even in the absence of an explicit task.
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- 2021
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- View/download PDF
27. Fashion versus fitspo: The effect of viewing images of contemporary Barbie® dolls in passive versus active poses on college women’s body image and affect
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Jennifer B. Webb, Nataya M. Ford, and Meagan P. Padro
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Social Psychology ,General Psychology ,Applied Psychology - Published
- 2023
28. Systematic <scp>d</scp>-Amino Acid Substitutions to Control Peptide and Hydrogel Degradation in Cellular Microenvironments
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Kartik Bomb, Qi Zhang, Eden M. Ford, Catherine A. Fromen, and April M. Kloxin
- Subjects
Inorganic Chemistry ,Polymers and Plastics ,Organic Chemistry ,Materials Chemistry - Published
- 2023
29. Alpha Event-Related Desynchronization During Reward Processing in Schizophrenia
- Author
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Susanna L. Fryer, Tobias F. Marton, Brian J. Roach, Clay B. Holroyd, Samantha V. Abram, Ken J. Lau, Judith M. Ford, John R. McQuaid, and Daniel H. Mathalon
- Subjects
Cognitive Neuroscience ,Radiology, Nuclear Medicine and imaging ,Neurology (clinical) ,Biological Psychiatry - Published
- 2023
30. Rich-club connectivity and structural connectome organization in youth at clinical high-risk for psychosis and individuals with early illness schizophrenia
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Jessica P.Y. Hua, Jennifer Cummings, Brian J. Roach, Susanna L. Fryer, Rachel L. Loewy, Barbara K. Stuart, Judith M. Ford, Sophia Vinogradov, and Daniel H. Mathalon
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Psychiatry and Mental health ,Biological Psychiatry - Published
- 2023
31. A Case Report of Severe Factor XI Deficiency during Cardiac Surgery: Less Can Be More
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Toshinobu Kazui, Vance G. Nielsen, Spencer D. Audie, Rajagopalan M. Venkataramani, John T. Bryant, Kristin Swenson, and Paul M. Ford
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cardiopulmonary bypass ,severe factor XI deficiency ,perioperative outcomes ,rotational thromboelastimetry ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Severe congenital Factor XI (FXI) deficiency (
- Published
- 2022
- Full Text
- View/download PDF
32. Multimodel Order Independent Component Analysis: A Data-Driven Method for Evaluating Brain Functional Network Connectivity Within and Between Multiple Spatial Scales
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Theo G.M. van Erp, Jessica A. Turner, Bryon A. Mueller, Armin Iraji, Sara McEwen, Xing Meng, Vince D. Calhoun, Godfrey D. Pearlson, Peter Kochunov, Zening Fu, Steven G. Potkin, Jing Sui, Judith M. Ford, Adrian Preda, Aysenil Belger, and Daniel H. Mathalon
- Subjects
Brain Mapping ,Computer science ,General Neuroscience ,Functional connectivity ,Resting fmri ,Rest ,Work (physics) ,Brain ,computer.software_genre ,Independent component analysis ,Magnetic Resonance Imaging ,Data-driven ,Functional networks ,Order (biology) ,Schizophrenia ,Humans ,Data mining ,computer - Abstract
Background: While functional connectivity is widely studied, there has been little work studying functional connectivity at different spatial scales. Likewise, the relationship of functional connec...
- Published
- 2023
33. Reliability and clinical utility of spatially constrained estimates of intrinsic functional networks from very short <scp>fMRI</scp> scans
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Marlena Duda, Armin Iraji, Judith M. Ford, Kelvin O. Lim, Daniel H. Mathalon, Bryon A. Mueller, Steven G. Potkin, Adrian Preda, Theo G. M. Van Erp, and Vince D. Calhoun
- Subjects
Neurology ,Radiological and Ultrasound Technology ,Radiology, Nuclear Medicine and imaging ,Neurology (clinical) ,Anatomy - Published
- 2023
34. National Cancer Institute Combination Therapy Platform Trial with Molecular Analysis for Therapy Choice (ComboMATCH)
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Funda Meric-Bernstam, James M. Ford, Peter J. O'Dwyer, Geoffrey I. Shapiro, Lisa M. McShane, Boris Freidlin, Roisin E. O'Cearbhaill, Suzanne George, Julia Glade-Bender, Gary H. Lyman, James V. Tricoli, David Patton, Stanley R. Hamilton, Robert J. Gray, Douglas S. Hawkins, Bhanumati Ramineni, Keith T. Flaherty, Petros Grivas, Timothy A. Yap, Jordan Berlin, James H. Doroshow, Lyndsay N. Harris, and Jeffrey A. Moscow
- Subjects
Cancer Research ,Oncology - Abstract
Over the past decade, multiple trials, including the precision medicine trial National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH, EAY131, NCT02465060) have sought to determine if treating cancer based on specific genomic alterations is effective, irrespective of the cancer histology. Although many therapies are now approved for the treatment of cancers harboring specific genomic alterations, most patients do not respond to therapies targeting a single alteration. Further, when antitumor responses do occur, they are often not durable due to the development of drug resistance. Therefore, there is a great need to identify rational combination therapies that may be more effective. To address this need, the NCI and National Clinical Trials Network have developed NCI-ComboMATCH, the successor to NCI-MATCH. Like the original trial, NCI-ComboMATCH is a signal-seeking study. The goal of ComboMATCH is to overcome drug resistance to single-agent therapy and/or utilize novel synergies to increase efficacy by developing genomically-directed combination therapies, supported by strong preclinical in vivo evidence. Although NCI-MATCH was mainly comprised of multiple single-arm studies, NCI-ComboMATCH tests combination therapy, evaluating both combination of targeted agents as well as combinations of targeted therapy with chemotherapy. Although NCI-MATCH was histology agnostic with selected tumor exclusions, ComboMATCH has histology-specific and histology-agnostic arms. Although NCI-MATCH consisted of single-arm studies, ComboMATCH utilizes single-arm as well as randomized designs. NCI-MATCH had a separate, parallel Pediatric MATCH trial, whereas ComboMATCH will include children within the same trial. We present rationale, scientific principles, study design, and logistics supporting the ComboMATCH study.
- Published
- 2023
35. Covert pre-leukaemic clones in healthy co-twins of patients with childhood acute lymphoblastic leukaemia
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Anthony M. Ford, Susan Colman, and Mel Greaves
- Subjects
Cancer Research ,Oncology ,Hematology - Published
- 2022
36. Religious/spiritual abuse and trauma: A systematic review of the empirical literature
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Heidi M. Ellis, Joshua N. Hook, Sabrina Zuniga, Adam S. Hodge, Kristy M. Ford, Don E. Davis, and Daryl R. Van Tongeren
- Subjects
Complementary and Manual Therapy ,Psychiatry and Mental health ,Clinical Psychology ,Complementary and alternative medicine - Published
- 2022
37. The Low-redshift Lyman Continuum Survey. II. New Insights into LyC Diagnostics
- Author
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Sophia R. Flury, Anne E. Jaskot, Harry C. Ferguson, Gábor Worseck, Kirill Makan, John Chisholm, Alberto Saldana-Lopez, Daniel Schaerer, Stephan R. McCandliss, Xinfeng Xu, Bingjie Wang, M. S. Oey, N. M. Ford, Timothy Heckman, Zhiyuan Ji, Mauro Giavalisco, Ricardo Amorín, Hakim Atek, Jeremy Blaizot, Sanchayeeta Borthakur, Cody Carr, Marco Castellano, Stephane De Barros, Mark Dickinson, Steven L. Finkelstein, Brian Fleming, Fabio Fontanot, Thibault Garel, Andrea Grazian, Matthew Hayes, Alaina Henry, Valentin Mauerhofer, Genoveva Micheva, Goran Ostlin, Casey Papovich, Laura Pentericci, Swara Ravindranath, Joakim Rosdahl, Michael Rutkowski, Paola Santini, Claudia Scarlata, Harry Teplitz, Trinh Thuan, Maxime Trebitsch, Eros Vanzella, and Anne Verhamme
- Published
- 2022
- Full Text
- View/download PDF
38. The Low-redshift Lyman Continuum Survey. I. New, Diverse Local Lyman Continuum Emitters
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Sophia R. Flury, Anne E. Jaskot, Harry C. Ferguson, Gábor Worseck, Kirill Makan, John Chisholm, Alberto Saldana-Lopez, Daniel Schaerer, Stephan McCandliss, Bingjie Wang, N. M. Ford, Timothy Heckman, Zhiyuan Ji, Mauro Giavalisco, Ricardo Amorin, Hakim Atek, Jeremy Blaizot, Sanchayeeta Borthakur, Cody Carr, Marco Castellano, Stefano Cristiani, Stephane De Barros, Mark Dickinson, Steven L. Finkelstein, Brian Fleming, Fabio Fontanot, Thibault Garel, Andrea Grazian, Matthew Hayes, Alaina Henry, Valentin Mauerhofer, Genoveva Micheva, M. S. Oey, Goran Ostlin, Casey Papovich, Laura Pentericci, Swara Ravindranath, Joakim Rosdahl, Michael Rutkowski, Paola Santini, Claudia Scarlata, Harry Teplitz, Trinh Thuan, Maxime Trebitsch, Eros Vanzella, Anne Verhamme, and Xinfeng Xu
- Published
- 2022
- Full Text
- View/download PDF
39. Chemorepellent-Loaded Nanocarriers Promote Localized Interference of Escherichia coli Transport to Inhibit Biofilm Formation
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Tracy J. Kuper, Leon Z. Wang, Robert K. Prud’homme, Sujit S. Datta, and Roseanne M. Ford
- Subjects
Biomaterials ,Biochemistry (medical) ,Biomedical Engineering ,General Chemistry - Published
- 2022
40. Long-term bowel dysfunction and decision regret in diverticulitis: A mixed methods study
- Author
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Noah J. Harrison, Molly M. Ford, Erin M. Wolf Horrell, Michael Feng, Fei Ye, Kevin C. Zhang, and Alexander T. Hawkins
- Subjects
Intestinal Diseases ,Postoperative Complications ,Elective Surgical Procedures ,Rectal Neoplasms ,Emotions ,Quality of Life ,Humans ,Surgery ,Prospective Studies ,Syndrome ,Article ,Colectomy ,Diverticulitis - Abstract
BACKGROUND: This study had aimed to describe long-term decision regret, bowel dysfunction, and the overall quality of life in patients with diverticulitis, and to determine if elective colectomy was associated with these patient-reported outcome measures. METHODS: This mixed-methods, survey-based study was administered to a national cohort of patients in the United States with diverticulitis. We measured decision regret (Brehaut Decision Regret), bowel dysfunction (Low Anterior Resection Syndrome score), and the overall quality of life (EuroQol 5 Dimension) in this population. We asked open-ended questions to elucidate factors that influenced patients’ choices between elective colectomy and observation. RESULTS: Among the 614 respondents, 294 (48%) chose between colectomy and observational management, 94 (15%) had surgery, and 157 (26%) had major Low Anterior Resection Syndrome. Of the 294 that chose between colectomy and observational management, 51 (17%) experienced decision regret. Colectomy was associated with an average decrease in the Brehaut Decision Regret score by 6 points but was not associated with a categorical measure of decision regret (Brehaut Score ≥50). Bowel dysfunction and overall quality of life were not significantly associated with colectomy. Disease-related factors, psychosocial factors, and interactions with physicians were commonly cited as reasons for pursuing colectomy or observational management. CONCLUSION: Patients with self-reported diverticulitis describe high levels of decision regret and bowel dysfunction regardless of chosen management strategy. Physicians should be aware that psychosocial factors can strongly influence a patient’s choice between colectomy and observational management. We advocated for future prospective studies using patient reported outcome metrics to improve outcomes in diverticulitis.
- Published
- 2022
41. Clinical Trial Development in TP53-Mutated Locally Advanced and Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma
- Author
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Cristina P Rodriguez, Hyunseok Kang, Jessica L Geiger, Barbara Burtness, Christine H Chung, Curtis R Pickering, Carole Fakhry, Quynh Thu Le, Sue S Yom, Thomas J Galloway, Erica Golemis, Alice Li, Jeffrey Shoop, Stuart Wong, Ranee Mehra, Heath Skinner, Nabil F Saba, Elsa R Flores, Jeffrey N Myers, James M Ford, Rachel Karchin, Robert L Ferris, Charles Kunos, Jean M Lynn, and Shakun Malik
- Subjects
Cancer Research ,Oncology ,Squamous Cell Carcinoma of Head and Neck ,Head and Neck Neoplasms ,Papillomavirus Infections ,Mutation ,Humans ,Tumor Suppressor Protein p53 ,Genes, p53 - Abstract
TP53 mutation is the most frequent genetic event in head and neck squamous cell carcinoma (HNSCC), found in more than 80% of patients with human papillomavirus–negative disease. As mutations in the TP53 gene are associated with worse outcomes in HNSCC, novel therapeutic approaches are needed for patients with TP53-mutated tumors. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issues of identifying and developing clinical trials for patients with TP53 mutations. Subcommittees, or breakout groups, were tasked with developing clinical studies in both the locally advanced and recurrent and/or metastatic (R/M) disease settings as well as considering signal-seeking trial designs. A fourth breakout group was focused on identifying and standardizing biomarker integration into trial design; this information was provided to the other breakout groups prior to the meeting to aid in study development. A total of 4 concepts were prioritized to move forward for further development and implementation. This article summarizes the proceedings of the Clinical Trials Planning Meeting with the goal of developing clinical trials for patients with TP53-mutant HNSCC that can be conducted within the National Clinical Trials Network.
- Published
- 2022
42. Enhancing Repair of Oxidative DNA Damage with Small-Molecule Activators of MTH1
- Author
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Yujeong Lee, Yoshiyuki Onishi, Lisa McPherson, Anna M. Kietrys, Marian Hebenbrock, Yong Woong Jun, Ishani Das, Shanthi Adimoolam, Debin Ji, Michael G. Mohsen, James M. Ford, and Eric T. Kool
- Subjects
Oxidative Stress ,DNA Repair Enzymes ,8-Hydroxy-2'-Deoxyguanosine ,Carcinogenesis ,Nucleotides ,Neoplasms ,Humans ,Molecular Medicine ,DNA ,General Medicine ,Biochemistry ,Phosphoric Monoester Hydrolases ,DNA Damage - Abstract
Impaired DNA repair activity has been shown to greatly increase rates of cancer clinically. It has been hypothesized that upregulating repair activity in susceptible individuals may be a useful strategy for inhibiting tumorigenesis. Here, we report that selected tyrosine kinase (TK) inhibitors including nilotinib, employed clinically in the treatment of chronic myeloid leukemia, are activators of the repair enzyme Human MutT Homolog 1 (MTH1). MTH1 cleanses the oxidatively damaged cellular nucleotide pool by hydrolyzing the oxidized nucleotide 8-oxo-2'-deoxyguanosine (8-oxo-dG)TP, which is a highly mutagenic lesion when incorporated into DNA. Structural optimization of analogues of TK inhibitors resulted in compounds such as SU0448, which induces 1000 ± 100% activation of MTH1 at 10 μM and 410 ± 60% at 5 μM. The compounds are found to increase the activity of the endogenous enzyme, and at least one (SU0448) decreases levels of 8-oxo-dG in cellular DNA. The results suggest the possibility of using MTH1 activators to decrease the frequency of mutagenic nucleotides entering DNA, which may be a promising strategy to suppress tumorigenesis in individuals with elevated cancer risks.
- Published
- 2022
43. The Gastric Cancer Registry: A Genomic Translational Resource for Multidisciplinary Research in Gastric Cancer
- Author
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Alison F. Almeda, Susan M. Grimes, HoJoon Lee, Stephanie Greer, GiWon Shin, Madeline McNamara, Anna C. Hooker, Maya M. Arce, Matthew Kubit, Marie C. Schauer, Paul Van Hummelen, Cindy Ma, Meredith A. Mills, Robert J. Huang, Joo Ha Hwang, Manuel R. Amieva, Summer S. Han, James M. Ford, and Hanlee P. Ji
- Subjects
Oncology ,Stomach Neoplasms ,Epidemiology ,Interdisciplinary Research ,Humans ,Genomics ,Registries ,Germ-Line Mutation ,Information Systems - Abstract
Background: Gastric cancer is a leading cause of cancer morbidity and mortality. Developing information systems which integrate clinical and genomic data may accelerate discoveries to improve cancer prevention, detection, and treatment. To support translational research in gastric cancer, we developed the Gastric Cancer Registry (GCR), a North American repository of clinical and cancer genomics data. Methods: Participants self-enrolled online. Entry criteria into the GCR included the following: (i) diagnosis of gastric cancer, (ii) history of gastric cancer in a first- or second-degree relative, or (iii) known germline mutation in the gene CDH1. Participants provided demographic and clinical information through a detailed survey. Some participants provided specimens of saliva and tumor samples. Tumor samples underwent exome sequencing, whole-genome sequencing, and transcriptome sequencing. Results: From 2011 to 2021, 567 individuals registered and returned the clinical questionnaire. For this cohort 65% had a personal history of gastric cancer, 36% reported a family history of gastric cancer, and 14% had a germline CDH1 mutation. 89 patients with gastric cancer provided tumor samples. For the initial study, 41 tumors were sequenced using next-generation sequencing. The data was analyzed for cancer mutations, copy-number variations, gene expression, microbiome, neoantigens, immune infiltrates, and other features. We developed a searchable, web-based interface (the GCR Genome Explorer) to enable researchers’ access to these datasets. Conclusions: The GCR is a unique, North American gastric cancer registry which integrates clinical and genomic annotation. Impact: Available for researchers through an open access, web-based explorer, the GCR Genome Explorer will accelerate collaborative gastric cancer research across the United States and world.
- Published
- 2022
44. Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer
- Author
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Winston R. Becker, Stephanie A. Nevins, Derek C. Chen, Roxanne Chiu, Aaron M. Horning, Tuhin K. Guha, Rozelle Laquindanum, Meredith Mills, Hassan Chaib, Uri Ladabaum, Teri Longacre, Jeanne Shen, Edward D. Esplin, Anshul Kundaje, James M. Ford, Christina Curtis, Michael P. Snyder, and William J. Greenleaf
- Subjects
Genetics - Abstract
To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated single-cell chromatin accessibility profiles and single-cell transcriptomes from 1,000 to 10,000 cells per sample for 48 polyps, 27 normal tissues and 6 CRCs collected from patients with or without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from homeostasis to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T cells and a subtype of pre-cancer-associated fibroblasts. In the cancerous state, we observe T cell exhaustion, RUNX1-regulated cancer-associated fibroblasts and increasing accessibility associated with HNF4A motifs in epithelia. DNA methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.
- Published
- 2022
45. Somatic tumor testing implications for Lynch syndrome germline genetic testing
- Author
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Kathleen Barrus, Natasha Purington, Nicolette Chun, Uri Ladabaum, and James M. Ford
- Subjects
Cancer Research ,Germ Cells ,Genetics ,Humans ,Genetic Predisposition to Disease ,Microsatellite Instability ,Genetic Testing ,Colorectal Neoplasms, Hereditary Nonpolyposis ,DNA Mismatch Repair ,Molecular Biology ,Germ-Line Mutation ,Retrospective Studies - Abstract
Clinicians involved in cancer treatment often utilize somatic tumor sequencing to help tailor chemotherapy and immunotherapy. However, somatic tumor sequencing can also identify patients at risk for germline pathogenic variants causing cancer predisposition syndromes like Lynch syndrome. The extent to which clinicians realize this implication of tumor sequencing is currently unclear. We performed a retrospective chart review of Stanford Health Care patients who had somatic variant(s) in the Lynch syndrome genes or microsatellite instability identified on tumor sequencing to determine the proportion of patients who were referred to genetics. Among 6,556 patients who had tumor testing, 90 (1.37%) had findings compatible with Lynch syndrome. Of the 62 patients who had not already seen genetics, 47/62 (75.8%) were not referred to genetics for germline testing. Additionally, 26/47 (55.3%) of these individuals had a tumor type within the Lynch syndrome spectrum. Of the 10 patients who did elect germline testing after tumor sequencing, 3/10 were positive for Lynch syndrome. Our study highlights the need for specific guidelines to inform clinician referral practices on germline follow-up of somatic tumor testing and demonstrates the importance of continued research on the relationship between somatic tumor variants and germline variants to inform such guidelines.
- Published
- 2022
46. Oncogenic role of an uncharacterized cold‐induced zinc finger protein 726 in breast cancer
- Author
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Shreetama Bandyopadhayaya, Pooja Yadav, Ankit Sharma, Sanjay Kumar Dey, Alo Nag, Rekha Maheshwari, Bridget M. Ford, and Chandi C. Mandal
- Subjects
Cell Biology ,Molecular Biology ,Biochemistry - Published
- 2023
47. The Scanner as the Stimulus: Deficient Gamma-BOLD Coupling in Schizophrenia at Rest
- Author
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Michael S Jacob, Kaia Sargent, Brian J Roach, Elhum A Shamshiri, Daniel H Mathalon, and Judith M Ford
- Subjects
Psychiatry and Mental health - Abstract
Functional magnetic resonance imaging (fMRI) scanners are unavoidably loud and uncomfortable experimental tools that are necessary for schizophrenia (SZ) neuroscience research. The validity of fMRI paradigms might be undermined by well-known sensory processing abnormalities in SZ that could exert distinct effects on neural activity in the presence of scanner background sound. Given the ubiquity of resting-state fMRI (rs-fMRI) paradigms in SZ research, elucidating the relationship between neural, hemodynamic, and sensory processing deficits during scanning is necessary to refine the construct validity of the MR neuroimaging environment. We recorded simultaneous electroencephalography (EEG)-fMRI at rest in people with SZ (n = 57) and healthy control participants without a psychiatric diagnosis (n = 46) and identified gamma EEG activity in the same frequency range as the background sounds emitted from our scanner during a resting-state sequence. In participants with SZ, gamma coupling to the hemodynamic signal was reduced in bilateral auditory regions of the superior temporal gyri. Impaired gamma-hemodynamic coupling was associated with sensory gating deficits and worse symptom severity. Fundamental sensory-neural processing deficits in SZ are present at rest when considering scanner background sound as a “stimulus.” This finding may impact the interpretation of rs-fMRI activity in studies of people with SZ. Future neuroimaging research in SZ might consider background sound as a confounding variable, potentially related to fluctuations in neural excitability and arousal.
- Published
- 2023
48. supplementary table TS1 from National Cancer Institute Combination Therapy Platform Trial with Molecular Analysis for Therapy Choice (ComboMATCH)
- Author
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Jeffrey A. Moscow, Lyndsay N. Harris, James H. Doroshow, Jordan Berlin, Timothy A. Yap, Petros Grivas, Keith T. Flaherty, Bhanumati Ramineni, Douglas S. Hawkins, Robert J. Gray, Stanley R. Hamilton, David Patton, James V. Tricoli, Gary H. Lyman, Julia Glade-Bender, Suzanne George, Roisin E. O'Cearbhaill, Boris Freidlin, Lisa M. McShane, Geoffrey I. Shapiro, Peter J. O'Dwyer, James M. Ford, and Funda Meric-Bernstam
- Abstract
supplementary table TS1
- Published
- 2023
49. Data from National Cancer Institute Combination Therapy Platform Trial with Molecular Analysis for Therapy Choice (ComboMATCH)
- Author
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Jeffrey A. Moscow, Lyndsay N. Harris, James H. Doroshow, Jordan Berlin, Timothy A. Yap, Petros Grivas, Keith T. Flaherty, Bhanumati Ramineni, Douglas S. Hawkins, Robert J. Gray, Stanley R. Hamilton, David Patton, James V. Tricoli, Gary H. Lyman, Julia Glade-Bender, Suzanne George, Roisin E. O'Cearbhaill, Boris Freidlin, Lisa M. McShane, Geoffrey I. Shapiro, Peter J. O'Dwyer, James M. Ford, and Funda Meric-Bernstam
- Abstract
Over the past decade, multiple trials, including the precision medicine trial National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH, EAY131, NCT02465060) have sought to determine if treating cancer based on specific genomic alterations is effective, irrespective of the cancer histology. Although many therapies are now approved for the treatment of cancers harboring specific genomic alterations, most patients do not respond to therapies targeting a single alteration. Further, when antitumor responses do occur, they are often not durable due to the development of drug resistance. Therefore, there is a great need to identify rational combination therapies that may be more effective. To address this need, the NCI and National Clinical Trials Network have developed NCI-ComboMATCH, the successor to NCI-MATCH. Like the original trial, NCI-ComboMATCH is a signal-seeking study. The goal of ComboMATCH is to overcome drug resistance to single-agent therapy and/or utilize novel synergies to increase efficacy by developing genomically-directed combination therapies, supported by strong preclinical in vivo evidence. Although NCI-MATCH was mainly comprised of multiple single-arm studies, NCI-ComboMATCH tests combination therapy, evaluating both combination of targeted agents as well as combinations of targeted therapy with chemotherapy. Although NCI-MATCH was histology agnostic with selected tumor exclusions, ComboMATCH has histology-specific and histology-agnostic arms. Although NCI-MATCH consisted of single-arm studies, ComboMATCH utilizes single-arm as well as randomized designs. NCI-MATCH had a separate, parallel Pediatric MATCH trial, whereas ComboMATCH will include children within the same trial. We present rationale, scientific principles, study design, and logistics supporting the ComboMATCH study.
- Published
- 2023
50. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium
- Author
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Dick Schijven, Merel C. Postema, Masaki Fukunaga, Junya Matsumoto, Kenichiro Miura, Sonja M. C. de Zwarte, Neeltje E. M. van Haren, Wiepke Cahn, Hilleke E. Hulshoff Pol, René S. Kahn, Rosa Ayesa-Arriola, Víctor Ortiz-García de la Foz, Diana Tordesillas-Gutierrez, Javier Vázquez-Bourgon, Benedicto Crespo-Facorro, Dag Alnæs, Andreas Dahl, Lars T. Westlye, Ingrid Agartz, Ole A. Andreassen, Erik G. Jönsson, Peter Kochunov, Jason M. Bruggemann, Stanley V. Catts, Patricia T. Michie, Bryan J. Mowry, Yann Quidé, Paul E. Rasser, Ulrich Schall, Rodney J. Scott, Vaughan J. Carr, Melissa J. Green, Frans A. Henskens, Carmel M. Loughland, Christos Pantelis, Cynthia Shannon Weickert, Thomas W. Weickert, Lieuwe de Haan, Katharina Brosch, Julia-Katharina Pfarr, Kai G. Ringwald, Frederike Stein, Andreas Jansen, Tilo T. J. Kircher, Igor Nenadić, Bernd Krämer, Oliver Gruber, Theodore D. Satterthwaite, Juan Bustillo, Daniel H. Mathalon, Adrian Preda, Vince D. Calhoun, Judith M. Ford, Steven G. Potkin, Jingxu Chen, Yunlong Tan, Zhiren Wang, Hong Xiang, Fengmei Fan, Fabio Bernardoni, Stefan Ehrlich, Paola Fuentes-Claramonte, Maria Angeles Garcia-Leon, Amalia Guerrero-Pedraza, Raymond Salvador, Salvador Sarró, Edith Pomarol-Clotet, Valentina Ciullo, Fabrizio Piras, Daniela Vecchio, Nerisa Banaj, Gianfranco Spalletta, Stijn Michielse, Therese van Amelsvoort, Erin W. Dickie, Aristotle N. Voineskos, Kang Sim, Simone Ciufolini, Paola Dazzan, Robin M. Murray, Woo-Sung Kim, Young-Chul Chung, Christina Andreou, André Schmidt, Stefan Borgwardt, Andrew M. McIntosh, Heather C. Whalley, Stephen M. Lawrie, Stefan du Plessis, Hilmar K. Luckhoff, Freda Scheffler, Robin Emsley, Dominik Grotegerd, Rebekka Lencer, Udo Dannlowski, Jesse T. Edmond, Kelly Rootes-Murdy, Julia M. Stephen, Andrew R. Mayer, Linda A. Antonucci, Leonardo Fazio, Giulio Pergola, Alessandro Bertolino, Covadonga M. Díaz-Caneja, Joost Janssen, Noemi G. Lois, Celso Arango, Alexander S. Tomyshev, Irina Lebedeva, Simon Cervenka, Carl M. Sellgren, Foivos Georgiadis, Matthias Kirschner, Stefan Kaiser, Tomas Hajek, Antonin Skoch, Filip Spaniel, Minah Kim, Yoo Bin Kwak, Sanghoon Oh, Jun Soo Kwon, Anthony James, Geor Bakker, Christian Knöchel, Michael Stäblein, Viola Oertel, Anne Uhlmann, Fleur M. Howells, Dan J. Stein, Henk S. Temmingh, Ana M. Diaz-Zuluaga, Julian A. Pineda-Zapata, Carlos López-Jaramillo, Stephanie Homan, Ellen Ji, Werner Surbeck, Philipp Homan, Simon E. Fisher, Barbara Franke, David C. Glahn, Ruben C. Gur, Ryota Hashimoto, Neda Jahanshad, Eileen Luders, Sarah E. Medland, Paul M. Thompson, Jessica A. Turner, Theo G. M. van Erp, Clyde Francks, Neurology, and Child and Adolescent Psychiatry / Psychology
- Subjects
subcortical ,Neuroinformatics ,Multidisciplinary ,All institutes and research themes of the Radboud University Medical Center ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Schizophrenia ,brain imaging ,cortical ,asymmetry - Abstract
Contains fulltext : 291574.pdf (Publisher’s version ) (Open Access) Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
- Published
- 2023
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