Author: "Clifford S" - Searchworks@Jio Institute Digital Library Search Results

8,323 results on '"Clifford S"'

1. Insights from in vivo preclinical cancer studies with histotripsy

Author: Tejaswi Worlikar, Timothy Hall, Man Zhang, Mishal Mendiratta-Lala, Michael Green, Clifford S. Cho, and Zhen Xu
Subjects: Histotripsy, cancer, boiling histotripsy, preclinical, immune effects, in vivo, Medical technology, R855-855.5
Abstract: AbstractHistotripsy is the first noninvasive, non-ionizing, and non-thermal ablation technique that mechanically fractionates target tissue into acellular homogenate via controlled acoustic cavitation. Histotripsy has been evaluated for various preclinical applications requiring noninvasive tissue removal including cancer, brain surgery, blood clot and hematoma liquefaction, and correction of neonatal congenital heart defects. Promising preclinical results including local tumor suppression, improved survival outcomes, local and systemic anti-tumor immune responses, and histotripsy-induced abscopal effects have been reported in various animal tumor models. Histotripsy is also being investigated in veterinary patients with spontaneously arising tumors. Research is underway to combine histotripsy with immunotherapy and chemotherapy to improve therapeutic outcomes. In addition to preclinical cancer research, human clinical trials are ongoing for the treatment of liver tumors and renal tumors. Histotripsy has been recently approved by the FDA for noninvasive treatment of liver tumors. This review highlights key learnings from in vivo shock-scattering histotripsy, intrinsic threshold histotripsy, and boiling histotripsy cancer studies treating cancers of different anatomic locations and discusses the major considerations in planning in vivo histotripsy studies regarding instrumentation, tumor model, study design, treatment dose, and post-treatment tumor monitoring.
Published: 2024
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2. Kidney Blood Flow and Renin-Angiotensin-Aldosterone System Measurements Associated With Kidney and Cardiovascular Dysfunction in Pediatric Shock

Author: Grace Fisler, MD, Kristina Murphy, DO, Fiore Mastroianni, MD, James B. Schneider, MD, Clifford S. Deutschman, MD, MS, MCCM, Daniel E. Leisman, MD, MS, and Matthew D. Taylor, MD
Subjects: Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract: IMPORTANCE:. Pediatric acute kidney injury (AKI) is a prevalent and morbid complication of shock. Its pathogenesis and early identification remain elusive. OBJECTIVES:. We aim to determine whether renal blood flow (RBF) measurements by point-of-care ultrasound (POCUS) and renin-angiotensin-aldosterone system (RAAS) hormones in pediatric shock associate with vasoactive requirements and AKI. DESIGN, SETTING, AND PARTICIPANTS:. This is a single-center prospective, noninterventional observational cohort study in one tertiary PICU in North American from 2020 to 2022 that enrolled children younger than 18 years with shock without preexisting end-stage renal disease. MAIN OUTCOMES AND MEASURES:. RBF was measured by POCUS on hospital days 1 and 3 and plasma RAAS hormone levels were measured on day 1. The primary outcome was the presence of AKI by Kidney Disease Improving Global Outcomes criteria at first ultrasound with key secondary outcomes of creatinine, blood urea nitrogen (BUN), Vasoactive-Inotrope Score (VIS), and norepinephrine equivalent dosing (NED) 48 hours after first ultrasound. RESULTS:. Fifty patients were recruited (20 with AKI, mean age 10.5 yr, 48% female). POCUS RBF showed lower qualitative blood flow (power Doppler ultrasound [PDU] score) and higher regional vascular resistance (renal resistive index [RRI]) in children with AKI (p = 0.017 and p = 0.0007). Renin and aldosterone levels were higher in the AKI cohort (p = 0.003 and p = 0.007). Admission RRI and PDU associated with higher day 3 VIS and NED after adjusting for age, day 1 VIS, and RAAS hormones. Admission renin associated with higher day 3 creatinine and BUN after adjusting for age, day 1 VIS, and the ultrasound parameters. CONCLUSIONS AND RELEVANCE:. In pediatric shock, kidney blood flow was abnormal and renin and aldosterone were elevated in those with AKI. Kidney blood flow abnormalities are independently associated with future cardiovascular dysfunction; renin elevations are independently associated with future kidney dysfunction. Kidney blood flow by POCUS may identify children who will have persistent as opposed to resolving AKI. RAAS perturbations may drive AKI in pediatric shock.
Published: 2024
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3. Automatic detection of ALS from single-trial MEG signals during speech tasks: a pilot study

Author: Debadatta Dash, Kristin Teplansky, Paul Ferrari, Abbas Babajani-Feremi, Clifford S. Calley, Daragh Heitzman, Sara G. Austin, and Jun Wang
Subjects: amyotrophic lateral sclerosis, beta oscillation, functional connectivity, magnetoencephalography, speech, Psychology, BF1-990
Abstract: Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, and fast-progressive neurodegenerative disease characterized by the degeneration of motor neurons. ALS patients often experience an initial misdiagnosis or a diagnostic delay due to the current unavailability of an efficient biomarker. Since impaired speech is typical in ALS, we hypothesized that functional differences between healthy and ALS participants during speech tasks can be explained by cortical pattern changes, thereby leading to the identification of a neural biomarker for ALS. In this pilot study, we collected magnetoencephalography (MEG) recordings from three early-diagnosed patients with ALS and three healthy controls during imagined (covert) and overt speech tasks. First, we computed sensor correlations, which showed greater correlations for speakers with ALS than healthy controls. Second, we compared the power of the MEG signals in canonical bands between the two groups, which showed greater dissimilarity in the beta band for ALS participants. Third, we assessed differences in functional connectivity, which showed greater beta band connectivity for ALS than healthy controls. Finally, we performed single-trial classification, which resulted in highest performance with beta band features (∼ 98%). These findings were consistent across trials, phrases, and participants for both imagined and overt speech tasks. Our preliminary results indicate that speech-evoked beta oscillations could be a potential neural biomarker for diagnosing ALS. To our knowledge, this is the first demonstration of the detection of ALS from single-trial neural signals.
Published: 2024
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4. M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture

Author: Mabel N. Abraham, Ana Nedeljkovic-Kurepa, Tiago D. Fernandes, Omar Yaipen, Mariana R. Brewer, Daniel E. Leisman, Matthew D. Taylor, and Clifford S. Deutschman
Subjects: Sepsis, Sepsis-3, Organ dysfunction, Cecal ligation and puncture, Basal forebrain cholinergic system, Muscarinic receptors, Therapeutics. Pharmacology, RM1-950, Biochemistry, QD415-436
Abstract: Abstract Background The contribution of the central nervous system to sepsis pathobiology is incompletely understood. In previous studies, administration of endotoxin to mice decreased activity of the vagus anti-inflammatory reflex. Treatment with the centrally-acting M1 muscarinic acetylcholine (ACh) receptor (M1AChR) attenuated this endotoxin-mediated change. We hypothesize that decreased M1AChR-mediated activity contributes to inflammation following cecal ligation and puncture (CLP), a mouse model of sepsis. Methods In male C57Bl/6 mice, we quantified basal forebrain cholinergic activity (immunostaining), hippocampal neuronal activity, serum cytokine/chemokine levels (ELISA) and splenic cell subtypes (flow cytometry) at baseline, following CLP and following CLP in mice also treated with the M1AChR agonist xanomeline. Results At 48 h. post-CLP, activity in basal forebrain cells expressing choline acetyltransferase (ChAT) was half of that observed at baseline. Lower activity was also noted in the hippocampus, which contains projections from ChAT-expressing basal forebrain neurons. Serum levels of TNFα, IL-1β, MIP-1α, IL-6, KC and G-CSF were higher post-CLP than at baseline. Post-CLP numbers of splenic macrophages and inflammatory monocytes, TNFα+ and ILβ+ neutrophils and ILβ+ monocytes were higher than baseline while numbers of central Dendritic Cells (cDCs), CD4+ and CD8+ T cells were lower. When, following CLP, mice were treated with xanomeline activity in basal forebrain ChAT-expressing neurons and in the hippocampus was significantly higher than in untreated animals. Post-CLP serum concentrations of TNFα, IL-1β, and MIP-1α, but not of IL-6, KC and G-CSF, were significantly lower in xanomeline-treated mice than in untreated mice. Post-CLP numbers of splenic neutrophils, macrophages, inflammatory monocytes and TNFα+ neutrophils also were lower in xanomeline-treated mice than in untreated animals. Percentages of IL-1β+ neutrophils, IL-1β+ monocytes, cDCs, CD4 + T cells and CD8 + T cells were similar in xanomeline—treated and untreated post-CLP mice. Conclusion Our findings indicate that M1AChR-mediated responses modulate CLP-induced alterations in serum levels of some, but not all, cytokines/chemokines and affected splenic immune response phenotypes.
Published: 2024
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5. Single-cell RNA sequencing reveals Immune Education promotes T cell survival in mice subjected to the cecal ligation and puncture sepsis model

Author: Steven D. Ham, Mabel N. Abraham, Clifford S. Deutschman, and Matthew D. Taylor
Subjects: cecal ligation and puncture, mouse sepsis model, sepsis, T cell, CD4, CD8, Immunologic diseases. Allergy, RC581-607
Abstract: BackgroundIndividual T cell responses vary significantly based on the microenvironment present at the time of immune response and on prior induced T cell memory. While the cecal ligation and puncture (CLP) model is the most commonly used murine sepsis model, the contribution of diverse T cell responses has not been explored. We defined T cell subset responses to CLP using single-cell RNA sequencing and examined the effects of prior induced T cell memory (Immune Education) on these responses. We hypothesized that Immune Education prior to CLP would alter T cell responses at the single cell level at a single, early post-CLP time point.MethodsSplenic T cells were isolated from C57BL/6 mice. Four cohorts were studied: Control, Immune-Educated, CLP, and Immune-Educated CLP. At age 8 weeks, Immune-Educated and Immune-Educated CLP mice received anti-CD3ϵ antibody; Control and CLP mice were administered an isotype control. CLP (two punctures with a 22-gauge needle) was performed at 12-13 weeks of life. Mice were sacrificed at baseline or 24-hours post-CLP. Unsupervised clustering of the transcriptome library identified six distinct T cell subsets: quiescent naïve CD4+, primed naïve CD4+, memory CD4+, naïve CD8+, activated CD8+, and CD8+ cytotoxic T cell subsets. T cell subset specific gene set enrichment analysis and Hurdle analysis for differentially expressed genes (DEGs) were performed.ResultsT cell responses to CLP were not uniform – subsets of activated and suppressed T cells were identified. Immune Education augmented specific T cell subsets and led to genomic signatures favoring T cell survival in unoperated and CLP mice. Additionally, the combination of Immune Education and CLP effected the expression of genes related to T cell activity in ways that differed from CLP alone. Validating our finding that IL7R pathway markers were upregulated in Immune-Educated CLP mice, we found that Immune Education increased T cell surface IL7R expression in post-CLP mice.ConclusionImmune Education enhanced the expression of genes associated with T cell survival in unoperated and CLP mice. Induction of memory T cell compartments via Immune Education combined with CLP may increase the model’s concordance to human sepsis.
Published: 2024
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6. Phosphorylation of insulin receptor substrates (IRS-1 and IRS-2) is attenuated following cecal ligation and puncture in mice

Author: Deepa Mathew, Julia Barillas-Cerritos, Ana Nedeljkovic-Kurepa, Mabel Abraham, Matthew D. Taylor, and Clifford S. Deutschman
Subjects: Sepsis, Cecal ligation and puncture, CLP, Insulin, Insulin receptor substrate, Tyrosine phosphorylation, Therapeutics. Pharmacology, RM1-950, Biochemistry, QD415-436
Abstract: Abstract Background Sepsis is characterized as an insulin resistant state. However, the effects of sepsis on insulin’s signal transduction pathway are unknown. The molecular activity driving insulin signaling is controlled by tyrosine phosphorylation of the insulin receptor β-subunit (IRβ) and of insulin receptor substrate molecules (IRS) -1 and IRS-2. Hypothesis Cecal ligation and puncture (CLP) attenuates IRβ, IRS-1 and IRS-2 phosphorylation. Methods IACUC-approved studies conformed to ARRIVE guidelines. CLP was performed on C57BL/6 mice; separate cohorts received intraperitoneal insulin at baseline (T0) or at 23 or 47 h. post-CLP, 1 h before mice were euthanized. We measured levels of (1) glucose and insulin in serum, (2) IRβ, IRS-1 and IRS-2 in skeletal muscle and liver homogenate and (3) phospho-Irβ (pIRβ) in liver and skeletal muscle, phospho-IRS-1 (pIRS-1) in skeletal muscle and pIRS-2 in liver. Statistical significance was determined using ANOVA with Sidak’s post-hoc correction. Results CLP did not affect the concentrations of IRβ, IRS-1or IRS-2 in muscle or liver homogenate or of IRS-1 in liver. Muscle IRS-1 concentration at 48 h. post-CLP was higher than at T0. Post-CLP pIRS-1 levels in muscle and pIRβ and pIRS-2 levels in liver were indistinguishable from T0 levels. At 48 h. post-CLP pIRβ levels in muscle were higher than at T0. Following insulin administration, the relative abundance of pIRβ in muscle and liver at T0 and at both post-CLP time points was significantly higher than abundance in untreated controls. In T0 controls, the relative abundance of pIRS-1 in muscle and of pIRS-2 in liver following insulin administration was higher than in untreated mice. However, at both post-CLP time points, the relative abundance of pIRS-1 in muscle and of pIRS-2 in liver following insulin administration was not distinguishable from the abundance in untreated mice at the same time point. Serum glucose concentration was significantly lower than T0 at 24 h., but not 48 h., post-CLP. Glucose concentration was lower following insulin administration to T0 mice but not in post-CLP animals. Serum insulin levels were significantly higher than baseline at both post-CLP time points. Conclusions CLP impaired insulin-induced tyrosine phosphorylation of both IRS-1 in muscle and IRS-2 in liver. These findings suggest that the molecular mechanism underlying CLP-induced insulin resistance involves impaired IRS-1/IRS-2 phosphorylation.
Published: 2023
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7. Magic bubbles: utilizing histotripsy to modulate the tumor microenvironment and improve systemic anti-tumor immune responses

Author: Khan M. Imran, Anutosh Ganguly, Tamalika Paul, Manali Powar, Eli Vlaisavljevich, Clifford S. Cho, and Irving C. Allen
Subjects: Immunology, abscopal effect, cancer, innate immunity, adaptive immunity, immunotherapy, Medical technology, R855-855.5
Abstract: AbstractFocused Ultrasound (FUS) is emerging as a promising primary and adjunct therapy for the treatment of cancer. This includes histotripsy, which is a noninvasive, non-ionizing, non-thermal ultrasound guided ablation modality. As histotripsy has progressed from bench-to-bedside, it has become evident that this therapy has benefits beyond local tumor ablation. Specifically, histotripsy has the potential to shift the local tumor microenvironment from immunologically ‘cold’ to ‘hot’. This is associated with the production of damage associated molecular patterns, the release of a selection of proinflammatory mediators, and the induction of inflammatory forms of cell death in cells just outside of the treatment zone. In addition to the induction of this innate immune response, histotripsy can also improve engagement of the adaptive immune system and promote systemic anti-tumor immunity targeting distal tumors and metastatic lesions. These tantalizing observations suggest that, in settings of widely metastatic disease burden, selective histotripsy of a limited number of accessible tumors could be a means of maximizing responsiveness to systemic immunotherapy. More work is certainly needed to optimize treatment strategies that best synergize histotripsy parameters with innate and adaptive immune responses. Likewise, rigorous clinical studies are still necessary to verify the presence and repeatability of these phenomena in human patients. As this technology nears regulatory approval for clinical use, it is our expectation that the insights and immunomodulatory mechanisms summarized in this review will serve as directional guides for rational clinical studies to validate and optimize the potential immunotherapeutic role of histotripsy tumor ablation.
Published: 2023
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8. MEG language mapping using a novel automatic ECD algorithm in comparison with MNE, dSPM, and DICS beamformer

Author: Abbas Babajani-Feremi, Haatef Pourmotabbed, William A. Schraegle, Clifford S. Calley, Dave F. Clarke, and Andrew C. Papanicolaou
Subjects: magnetoencephalography, language lateralization, single equivalent current dipole, minimum norm estimation, dynamic statistical parametric mapping, dynamic imaging of coherent sources beamformer, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: IntroductionThe single equivalent current dipole (sECD) is the standard clinical procedure for presurgical language mapping in epilepsy using magnetoencephalography (MEG). However, the sECD approach has not been widely used in clinical assessments, mainly because it requires subjective judgements in selecting several critical parameters. To address this limitation, we developed an automatic sECD algorithm (AsECDa) for language mapping.MethodsThe localization accuracy of the AsECDa was evaluated using synthetic MEG data. Subsequently, the reliability and efficiency of AsECDa were compared to three other common source localization methods using MEG data recorded during two sessions of a receptive language task in 21 epilepsy patients. These methods include minimum norm estimation (MNE), dynamic statistical parametric mapping (dSPM), and dynamic imaging of coherent sources (DICS) beamformer.ResultsFor the synthetic single dipole MEG data with a typical signal-to-noise ratio, the average localization error of AsECDa was less than 2 mm for simulated superficial and deep dipoles. For the patient data, AsECDa showed better test-retest reliability (TRR) of the language laterality index (LI) than MNE, dSPM, and DICS beamformer. Specifically, the LI calculated with AsECDa revealed excellent TRR between the two MEG sessions across all patients (Cor = 0.80), while the LI for MNE, dSPM, DICS-event-related desynchronization (ERD) in the alpha band, and DICS-ERD in the low beta band ranged lower (Cor = 0.71, 0.64, 0.54, and 0.48, respectively). Furthermore, AsECDa identified 38% of patients with atypical language lateralization (i.e., right lateralization or bilateral), compared to 73%, 68%, 55%, and 50% identified by DICS-ERD in the low beta band, DICS-ERD in the alpha band, MNE, and dSPM, respectively. Compared to other methods, AsECDa’s results were more consistent with previous studies that reported atypical language lateralization in 20-30% of epilepsy patients.DiscussionOur study suggests that AsECDa is a promising approach for presurgical language mapping, and its fully automated nature makes it easy to implement and reliable for clinical evaluations.
Published: 2023
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9. Inhibition of DNA-PK may improve response to neoadjuvant chemoradiotherapy in rectal cancer

Author: Mary Smithson, Regina K. Irwin, Gregory Williams, M. Chandler McLeod, E. Karen Choi, Anutosh Ganguly, Ashley Pepple, Clifford S. Cho, Christopher D. Willey, Judith Leopold, and Karin M. Hardiman
Subjects: DNA-PK, DNA damage, Chemoradiaiton resistance, DNA-PK inhibitor, Rectal cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Treatment of locally advanced rectal cancer includes chemoradiation and surgery, but patient response to treatment is variable. Patients who have a complete response have improved outcomes; therefore, there is a critical need to identify mechanisms of resistance to circumvent them. DNA-PK is involved in the repair of DNA double-strand breaks caused by radiation, which we found to be increased in rectal cancer after treatment. We hypothesized that inhibiting this complex with a DNA-PK inhibitor, Peposertib (M3814), would improve treatment response.We assessed pDNA-PK in a rectal cancer cell line and mouse model utilizing western blotting, viability assays, γH2AX staining, and treatment response. The three treatment groups were: standard of care (SOC) (5-fluorouracil (5FU) with radiation), M3814 with radiation, and M3814 with SOC.SOC treatment of rectal cancer cells increased pDNA-PK protein and increased γH2AX foci, but this was abrogated by the addition of M3814. Mice with CT26 tumors treated with M3814 with SOC did not differ in average tumor size but individual tumor response varied. The clinical complete response rate improved significantly with the addition of M3814 but pathological complete response did not. We investigated alterations in DNA repair and found that Kap1 and pATM are increased after M3814 addition suggesting this may mediate resistance.When the DNA-PK inhibitor, M3814, is combined with SOC treatment, response improved in some rectal cancer models but an increase in other repair mechanisms likely diminishes the effect. A clinical trial is ongoing to further explore the role of DNA-PK inhibition in rectal cancer treatment.
Published: 2022
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10. Transcutaneous auricular vagus nerve stimulation (taVNS) for the treatment of pediatric nephrotic syndrome: a pilot study

Author: Kumail Merchant, Stavros Zanos, Timir Datta-Chaudhuri, Clifford S. Deutschman, and Christine B. Sethna
Subjects: Vagus nerve stimulation, taVNS, Nephrotic syndrome, Children, Minimal change disease, Focal segmental glomerular sclerosis, Medical technology, R855-855.5
Abstract: Abstract Background Children with frequently relapsing nephrotic syndrome (FRNS) and steroid resistant nephrotic syndrome (SRNS) are exposed to immunosuppressant medications with adverse side effects and variable efficacy. Transcutaneous auricular vagus nerve stimulation (taVNS) modulates the immune system via the inflammatory reflex and has become a therapy of interest for treating immune-mediated illnesses. Methods An open-label, pilot study of tavNS for five minutes daily for 26 weeks via a TENS 7000 unit was conducted. Results Three FRNS participants and 4 SRNS participants had a mean age of 9.5±4.2 years (range 4 to 17). Those with FRNS remained relapse-free during the study period; two participants continued treatment and remained in remission for 15 and 21 months, respectively. Three SRNS participants experienced a reduction in first morning UPC (mean of 42%, range 25-76%). Although UPC decreased (13.7%) in one SRNS participant with congenital nephrotic syndrome, UPC remained in nephrotic range. All but one participant (non-compliant with treatment) experienced a reduction in TNF (7.33pg/mL vs. 5.46pg/mL, p=0.03). No adverse events or side effects were reported. Conclusions taVNS was associated with clinical remission in FRNS and moderately reduced proteinuria in non-congenital SRNS. Further study of taVNS as a treatment for nephrotic syndrome in children is warranted. ClinicalTrials.gov Identifier: NCT04169776, Registered November 20, 2019, https://clinicaltrials.gov/ct2/show/NCT04169776 .
Published: 2022
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11. Spatiotemporal local and abscopal cell death and immune responses to histotripsy focused ultrasound tumor ablation

Author: Ashley L. Pepple, Joey L. Guy, Reliza McGinnis, Amy E. Felsted, Brian Song, Ryan Hubbard, Tejaswi Worlikar, Hannah Garavaglia, Joe Dib, Hannah Chao, Nicoleen Boyle, Michal Olszewski, Zhen Xu, Anutosh Ganguly, and Clifford S. Cho
Subjects: ablation, immunity, tumor, histotripsy, ultrasound, necroptosis, Immunologic diseases. Allergy, RC581-607
Abstract: IntroductionHistotripsy is a novel focused ultrasound tumor ablation modality with potent immunostimulatory effects.MethodsTo measure the spatiotemporal kinetics of local andabscopal responses to histotripsy, C57BL/6 mice bearing bilateral flank B16 melanoma or Hepa1-6 hepatocellular carcinoma tumors were treated with unilateral sham or partial histotripsy. Treated and contralateral untreated (abscopal) tumors were analyzed using multicolor immunofluorescence, digital spatial profiling, RNA sequencing (RNASeq), and flow cytometry.ResultsUnilateral histotripsy triggered abscopal tumor growth inhibition. Within the ablation zone, early high mobility group box protein 1 (HMGB1) release and necroptosis were accompanied by immunogenic cell death transcriptional responses in tumor cells and innate immune activation transcriptional responses in infiltrating myeloid and natural killer (NK) cells. Delayed CD8+ T cell intratumoral infiltration was spatiotemporally aligned with cancer cell features of ferroptosis; this effect was enhanced by CTLA-4 blockade and recapitulated in vitro when tumor-draining lymph node CD8+ T cells were co-cultured with tumor cells. Inoculation with cell-free tumor fractions generated by histotripsy but not radiation or freeze/thaw conferred partial protection from tumor challenge.DiscussionWe propose that histotripsy may evoke local necroptotic immunogenic cell death, priming systemic adaptive immune responses and abscopal ferroptotic cancer cell death.
Published: 2023
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12. The Surviving Sepsis Campaign: research priorities for the administration, epidemiology, scoring and identification of sepsis

Author: Mark E. Nunnally, Ricard Ferrer, Greg S. Martin, Ignacio Martin-Loeches, Flavia R. Machado, Daniel De Backer, Craig M. Coopersmith, Clifford S. Deutschman, and For the Surviving Sepsis Campaign Reasearch Committee
Subjects: Epidemiology, Organ dysfunction, Outcomes, Priorities, Research, Screening, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract: Abstract Objective To identify priorities for administrative, epidemiologic and diagnostic research in sepsis. Design As a follow-up to a previous consensus statement about sepsis research, members of the Surviving Sepsis Campaign Research Committee, representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine addressed six questions regarding care delivery, epidemiology, organ dysfunction, screening, identification of septic shock, and information that can predict outcomes in sepsis. Methods Six questions from the Scoring/Identification and Administration sections of the original Research Priorities publication were explored in greater detail to better examine the knowledge gaps and rationales for questions that were previously identified through a consensus process. Results The document provides a framework for priorities in research to address the following questions: (1) What is the optimal model of delivering sepsis care?; (2) What is the epidemiology of sepsis susceptibility and response to treatment?; (3) What information identifies organ dysfunction?; (4) How can we screen for sepsis in various settings?; (5) How do we identify septic shock?; and (6) What in-hospital clinical information is associated with important outcomes in patients with sepsis? Conclusions There is substantial knowledge of sepsis epidemiology and ways to identify and treat sepsis patients, but many gaps remain. Areas of uncertainty identified in this manuscript can help prioritize initiatives to improve an understanding of individual patient and demographic heterogeneity with sepsis and septic shock, biomarkers and accurate patient identification, organ dysfunction, and ways to improve sepsis care.
Published: 2021
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13. Induction of broadly reactive influenza antibodies increases susceptibility to autoimmunity

Author: Jocelyn G. Labombarde, Meenu R. Pillai, Marie Wehenkel, Chun-Yang Lin, Rachael Keating, Scott A. Brown, Jeremy Chase Crawford, David C. Brice, Ashley H. Castellaw, Alexandra H. Mandarano, Clifford S. Guy, Juan R. Mejia, Carlessia D. Lewis, Ti-Cheng Chang, Christine M. Oshansky, Sook-San Wong, Richard J. Webby, Mei Yan, Quan–Zhen Li, Tony N. Marion, Paul G. Thomas, and Maureen A. McGargill
Subjects: influenza, autoimmunity, universal influenza vaccine, antibody, Biology (General), QH301-705.5
Abstract: Summary: Infection and vaccination repeatedly expose individuals to antigens that are conserved between influenza virus subtypes. Nevertheless, antibodies recognizing variable influenza epitopes greatly outnumber antibodies reactive against conserved epitopes. Elucidating factors contributing to the paucity of broadly reactive influenza antibodies remains a major obstacle for developing a universal influenza vaccine. Here, we report that inducing broadly reactive influenza antibodies increases autoreactive antibodies in humans and mice and exacerbates disease in four distinct models of autoimmune disease. Importantly, transferring broadly reactive influenza antibodies augments disease in the presence of inflammation or autoimmune susceptibility. Further, broadly reactive influenza antibodies spontaneously arise in mice with defects in B cell tolerance. Together, these data suggest that self-tolerance mechanisms limit the prevalence of broadly reactive influenza antibodies, which can exacerbate disease in the context of additional risk factors.
Published: 2022
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14. The surviving sepsis campaign: basic/translational science research priorities

Author: Clifford S. Deutschman, Judith Hellman, Ricard Ferrer Roca, Daniel De Backer, Craig M. Coopersmith, and for the Research Committee of the Surviving Sepsis Campaign
Subjects: Basic science, Research, Sepsis, Surviving sepsis campaign, Translational science, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract: Abstract Objectives Expound upon priorities for basic/translational science identified in a recent paper by a group of experts assigned by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Data sources Original paper, search of the literature. Study selection This study is selected by several members of the original task force with specific expertise in basic/translational science. Data extraction and data synthesis are not available. Conclusions In the first of a series of follow-up reports to the original paper, several members of the original task force with specific expertise provided a more in-depth analysis of the five identified priorities directly related to basic/translational science. This analysis expounds on what is known about the question and what was identified as priorities for ongoing research. It is hoped that this analysis will aid the development of future research initiatives.
Published: 2020
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15. Impact evaluation of a brief online training module on physician use of the Maryland, USA, Prescription Drug Monitoring Program.

Author: Oluwasanmi O Adenaiye, Julia B Zirpoli, Marissa Tan, Brendan F Day, Olayiwola Bolaji, Clifford S Mitchell, and Marianne Cloeren
Subjects: Medicine, Science
Abstract: BackgroundPrescription Drug Monitoring Programs (PDMPs) are electronic databases that track controlled substance prescriptions in a state. They are underused tools in preventing opioid abuse. Most PDMP education research measures changes in knowledge or confidence rather than behavior.ObjectiveTo evaluate the impact of online case-based training on healthcare provider use of the Maryland (USA) PDMP.MethodsWe used e-mail distribution lists to recruit providers to complete a brief educational module. Using a pre-training and post-training survey in the module, we measured self-reported PDMP use patterns and perceived PDMP value in specific clinical situations and compared pre- and post-training responses. Within the module, we presented three fictional pain cases and asked participants how they would manage each, both before, and then after presenting prescription drug history simulating a PDMP report. We measured changes in the fictional case treatment plans before and after seeing prescription history. Finally, we measured and compared how often each participant accessed the Maryland PDMP database before and after completing the educational module. We used multivariate logistic regression to measure the effect of the intervention on actual PDMP use frequency.ResultsOne hundred and fifty participants enrolled and completed the training module, and we successfully retrieved real-world PDMP use data of 137 of them. Participants' decisions to prescribe opioids changed significantly after reviewing PDMP data in each of the fictional cases provided in the module. In the months following the training, the rate of PDMP use increased by a median of four use-cases per month among providers in practice for less than 20 years (p = 0.039) and two use-cases per month among infrequent opioid prescribers (p = 0.014).ConclusionA brief online case-based educational intervention was associated with a significant increase in the rate of PDMP use among infrequent opioid prescribers and those in practice less than 20 years.
Published: 2022
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16. Surviving Sepsis Campaign: Research Opportunities for Infection and Blood Purification Therapies

Author: Ignacio Martin-Loeches, MD, PhD, JFICMI, Mark E. Nunnally, MD, FCCM, Judith Hellman, MD, Ishaq Lat, PharmD, FCCM, Greg S. Martin, MD, FCCM, Sameer Jog, MD, Jozef Kesecioglu, MD, PhD, Daniel De Backer, MD, PhD, Craig M. Coopersmith, MD, MCCM, For the Research Committee of the Surviving Sepsis Campaign, Ignacio Martin-Loeches, Craig M. Coopersmith, Daniel De Backer, Clifford S Deutschman, Ricard Ferrer-Roca, Judith Hellman, Sameer Jog, Ishaq Lat, Flavia Machado, Greg Martin, and Mark E. Nunnally
Subjects: Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract: OBJECTIVES:. Patients with infection can develop sepsis, and their mortality can be high. An important aspect in the treatment of sepsis is adequate management of the infection. DATA SOURCES:. Using a modified Delphi approach, the Surviving Sepsis Campaign research committee recently published a series of 26 priorities for sepsis and septic shock. STUDY SELECTION:. Task force members with specific expertise were tasked with generating expanded reviews for all infection questions and a subset of adjunctive therapy questions from the larger list of sepsis priorities. Each question was addressed by one of the six task force members. DATA EXTRACTION:. In-depth reviews were then edited by the group as a whole, with added input from the committee cochairs. DATA SYNTHESIS:. Six questions were addressed: 1) should empiric antibiotic combination therapy be used in sepsis or septic shock? 2) does optimization of antimicrobial pharmacokinetics and pharmacodynamics impact patient outcomes in sepsis? 3) should viral reactivation resulting from sepsis-induced immunosuppression be treated with antiviral therapy in critically ill septic patients? 4) should rapid diagnostic tests be implemented in clinical practice? 5) what is the role of lung-protective ventilation in sepsis patients without acute respiratory distress syndrome? and 6) how do we determine the efficacy of “blood purification” therapies such as endotoxin absorbers, cytokine absorbers, and plasmapheresis. CONCLUSIONS:. The research committee members for the Surviving Sepsis Campaign aimed to explore research questions in order to provide existing evidence and highlight areas of uncertainty and future directions.
Published: 2021
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17. CCR2 Signaling Promotes Brain Infiltration of Inflammatory Monocytes and Contributes to Neuropathology during Cryptococcal Meningoencephalitis

Author: Jintao Xu, Anutosh Ganguly, Jessica Zhao, Michel Ivey, Rafael Lopez, John J. Osterholzer, Clifford S. Cho, and Michal A. Olszewski
Subjects: CCR2, cryptococcal meningoencephalitis, central nervous system infections, immunopathogenesis, inflammatory monocyte, Microbiology, QR1-502
Abstract: ABSTRACT Cryptococcal meningoencephalitis (CM) is a leading cause of central nervous system (CNS) infection-related mortality worldwide, with surviving patients often developing neurological deficiencies. While CNS inflammation has been implicated in the pathogenesis of CM, little is known about the relative contribution of the specific inflammatory/immune pathways to CNS pathology versus fungal clearance. Increased cerebrospinal fluid level of C-C chemokine receptor 2 (CCR2) ligand CCL2 is associated with disease deterioration in patients with CM. Using a murine model, we investigated the role of the CCR2 pathway in the development of CNS inflammation and pathology during CM. We found that CCR2-deficient mice exhibited improved 28-day survival and alleviated neurological disease scores despite a brain fungal burden higher than that of the WT mice. Reduced CM pathology in CCR2-deficient mice was accompanied by markedly decreased neuronal cell death around cryptococcal microcysts and restored expression of genes involved in neurotransmission, connectivity, and neuronal cell structure in the brains. Results show that CCR2 axis is the major pathway recruiting CD45hiCD11b+Ly6C+ inflammatory monocyte to the brain and indirectly modulates the accumulation of CD4+ T cells and CD8+ T cells. In particular, CCR2 axis promotes recruitment of interferon gamma (IFN-γ)-producing CD4+ T cells and classical activation of myeloid cells. In this context, CCR2 deletion limits the immune network dysregulation we see in CM and attenuates neuropathology. Thus, the CCR2 axis is a potential target for interventions aimed to limit inflammatory CNS pathology in CM patients. IMPORTANCE Cryptococcal meningoencephalitis (CM) causes nearly 200,000 deaths worldwide each year, and survivors frequently develop long-lasting neurological sequelae. The high rate of mortality and neurologic sequelae in CM patients indicate that antifungal therapies alone are often insufficient to control disease progression. Here, we reveal that CM disease progression in mice is accompanied by inflammatory monocytes infiltration at the periphery of the infected foci that overlap locally perturbed neuronal function and death. Importantly, we identified that CCR2 signaling is a critical pathway driving neuroinflammation, especially inflammatory monocyte recruitment, as well as CNS pathology and mortality in CM mice. Our results imply that targeting the CCR2 pathway may be beneficial as a therapy complementary to antifungal drug treatment, helping to reduce CNS damage and mortality in CM patients.
Published: 2021
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18. CD4 and CD8 T Cell Memory Interactions Alter Innate Immunity and Organ Injury in the CLP Sepsis Model

Author: Matthew D. Taylor, Tiago D. Fernandes, Alexander P. Kelly, Mabel N. Abraham, and Clifford S. Deutschman
Subjects: cecal ligation and puncture, sepsis, innate immunity, organ dysfunction, T cell memory, CD4 T Cells, Immunologic diseases. Allergy, RC581-607
Abstract: The role of T cell memory in sepsis is poorly understood. Recent work has demonstrated that mice exposed to frequent antigenic stimulation, in contrast to laboratory mice, better recapitulate the human T cell repertoire. This difference may profoundly alter responses to inflammatory insults. We induced isolated T cell memory by inoculating C57Bl/6 mice with an anti-CD3ϵ activating antibody, a process we term “immune education.” These mice were subjected to the cecal ligation and puncture (CLP) model of sepsis and responses were compared to those of isotype-treated controls. CLP-induced increases in 1) CD4 T cell production and serum levels of IFNγ, 2) CD8 T cell granzyme B levels, and 3) innate cell function were all more pronounced in educated mice than in control mice. Immune education increased CLP-induced liver injury and decreased survival. The differences in responses to CLP were not recapitulated in mice with either isolated CD4 or isolated CD8 T cell memory. Relative to controls, CLP in educated CD8−/− mice (isolated CD4 memory) increased monocyte-derived dendritic cells. Combined CD4 and CD8 memory did not increase monocyte-derived dendritic cells; this combination recapitulated increases in neutrophil and inflammatory monocyte numbers in educated wild-type mice. Induction of T cell memory prior to CLP alters immune responses, organ function, and survival. Both CD4 and CD8 memory T cells play important and independent roles in this response. These findings have profound implications for the development of murine models of human inflammatory disorders such as infection and sepsis.
Published: 2020
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19. CD4 T Follicular Helper Cells Prevent Depletion of Follicular B Cells in Response to Cecal Ligation and Puncture

Author: Matthew D. Taylor, Mariana R. Brewer, Ana Nedeljkovic-Kurepa, Yihe Yang, Kalpana S. Reddy, Mabel N. Abraham, Betsy J. Barnes, and Clifford S. Deutschman
Subjects: cecal ligation and puncture, sepsis, long-term effects, B cells, T follicular helper cells, CD4 T cells, Immunologic diseases. Allergy, RC581-607
Abstract: Recent studies have demonstrated that induction of a diverse repertoire of memory T cells (“immune education”) affects responses to murine cecal ligation and puncture (CLP), the most widely – used animal model of sepsis. Among the documented effects of immune education on CLP are changes in T cell, macrophage and neutrophil activity, more pronounced organ dysfunction and reduced survival. Little is known, however, about the effects of CLP on B cell responses, and how these responses might be altered by immune education. Importantly, effective B cell responses are modulated by IL21 produced by CD4+/CXCR5+/PD1+ T follicular helper (Tfh) cells. We examined the B cell population in control and immune educated mice 24 h and 60 days after CLP. Education alone increased Tfh cells. Twenty-four hours after CLP, Tfh cells were depleted. However, this reduction was less pronounced in immune educated mice than in controls and the percentage of CD4 T cells expressing a Tfh phenotype increased in the animals. CLP did not alter splenic architecture and decreased numbers of follicular, marginal, and germinal center B cells. CLP induced changes were not, however, noted following CLP in immune educated mice. At 60 days post – CLP, numbers of follicular, germinal center and marginal zone B cells were increased; this increase was more pronounced in immune educated mice. Finally, while CLP reduced the induction of antigen specific B cells in controls, this response was maintained following CLP in immune educated mice. Our data suggest that preexisting Tfh assists in rescuing the B cell response to CLP.
Published: 2020
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20. Interferon inducible GBPs restrict Burkholderia thailandensis motility induced cell-cell fusion.

Author: David E Place, Benoit Briard, Parimal Samir, Rajendra Karki, Anannya Bhattacharya, Clifford S Guy, Jennifer L Peters, Sharon Frase, Peter Vogel, Geoffrey Neale, Masahiro Yamamoto, and Thirumala-Devi Kanneganti
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: Innate immunity responds to pathogens by producing alarm signals and activating pathways that make host cells inhospitable for pathogen replication. The intracellular bacterium Burkholderia thailandensis invades the cytosol, hijacks host actin, and induces cell fusion to spread to adjacent cells, forming multinucleated giant cells (MNGCs) which promote bacterial replication. We show that type I interferon (IFN) restricts macrophage MNGC formation during B. thailandensis infection. Guanylate-binding proteins (GBPs) expressed downstream of type I IFN were required to restrict MNGC formation through inhibition of bacterial Arp2/3-dependent actin motility during infection. GTPase activity and the CAAX prenylation domain were required for GBP2 recruitment to B. thailandensis, which restricted bacterial actin polymerization required for MNGC formation. Consistent with the effects in in vitro macrophages, Gbp2-/-, Gbp5-/-, GbpChr3-KO mice were more susceptible to intranasal infection with B. thailandensis than wildtype mice. Our findings reveal that IFN and GBPs play a critical role in restricting cell-cell fusion and bacteria-induced pathology during infection.
Published: 2020
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21. Effects of Histotripsy on Local Tumor Progression in an in vivo Orthotopic Rodent Liver Tumor Model

Author: Tejaswi Worlikar, Mishal Mendiratta-Lala, Eli Vlaisavljevich, Ryan Hubbard, Jiaqi Shi, Timothy L. Hall, Clifford S. Cho, Fred T. Lee, Joan Greve, and Zhen Xu
Subjects: Medical technology, R855-855.5, Biotechnology, TP248.13-248.65
Abstract: Objective and Impact Statement. This is the first longitudinal study investigating the effects of histotripsy on local tumor progression in an in vivo orthotopic, immunocompetent rat hepatocellular carcinoma (HCC) model. Introduction. Histotripsy is the first noninvasive, nonionizing, nonthermal, mechanical ablation technique using ultrasound to generate acoustic cavitation to liquefy the target tissue into acellular debris with millimeter accuracy. Previously, histotripsy has demonstrated in vivo ablation of noncancerous liver tissue. Methods. N1-S1 HCC tumors were generated in the livers of immunocompetent rats (n=6, control; n=15, treatment). Real-time ultrasound-guided histotripsy was applied to ablate either 100% tumor volume+up to 2 mm margin (n=9, complete treatment) or 50-75% tumor volume (n=6, partial treatment) by delivering 1-2 cycle histotripsy pulses at 100 Hz PRF (pulse repetition frequency) with p−≥30 MPa using a custom 1 MHz transducer. Rats were monitored weekly using MRI (magnetic resonance imaging) for 3 months or until tumors reached ~25 mm. Results. MRI revealed effective post-histotripsy reduction of tumor burden with near-complete resorption of the ablated tumor in 14/15 (93.3%) treated rats. Histopathology showed
Published: 2020
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22. Improved soluble expression and use of recombinant human renalase.

Author: Clifford S Morrison, Elena E Paskaleva, Marvin A Rios, Thomas R Beusse, Elaina M Blair, Lucy Q Lin, James R Hu, Aidan H Gorby, David R Dodds, William B Armiger, Jonathan S Dordick, and Mattheos A G Koffas
Subjects: Medicine, Science
Abstract: Electrochemical bioreactor systems have enjoyed significant attention in the past few decades, particularly because of their applications to biobatteries, artificial photosynthetic systems, and microbial electrosynthesis. A key opportunity with electrochemical bioreactors is the ability to employ cofactor regeneration strategies critical in oxidative and reductive enzymatic and cell-based biotransformations. Electrochemical cofactor regeneration presents several advantages over other current cofactor regeneration systems, such as chemoenzymatic multi-enzyme reactions, because there is no need for a sacrificial substrate and a recycling enzyme. Additionally, process monitoring is simpler and downstream processing is less costly. However, the direct electrochemical reduction of NAD(P)+ on a cathode may produce adventitious side products, including isomers of NAD(P)H that can act as potent competitive inhibitors to NAD(P)H-requiring enzymes such as dehydrogenases. To overcome this limitation, we examined how nature addresses the adventitious formation of isomers of NAD(P)H. Specifically, renalases are enzymes that catalyze the oxidation of 1,2- and 1,6-NAD(P)H to NAD(P)+, yielding an effective recycling of unproductive NAD(P)H isomers. We designed several mutants of recombinant human renalase isoform 1 (rhRen1), expressed them in E. coli BL21(DE3) to enhance protein solubility, and evaluated the activity profiles of the renalase variants against NAD(P)H isomers. The potential for rhRen1 to be employed in engineering applications was then assessed in view of the enzyme's stability upon immobilization. Finally, comparative modeling was performed to assess the underlying reasons for the enhanced solubility and activity of the mutant enzymes.
Published: 2020
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23. Obesity and Metabolic Dysregulation in Children Provide Protective Influenza Vaccine Responses

Author: Mundeep K. Kainth, Joanna S. Fishbein, Teresa Aydillo, Alba Escalera, Rachael Odusanya, Kalliopi Grammatikopoulos, Tiffany Scotto, Christine B. Sethna, Adolfo García-Sastre, and Clifford S. Deutschman
Subjects: pediatric obesity, influenza vaccine, metabolic health, Microbiology, QR1-502
Abstract: The most effective intervention for influenza prevention is vaccination. However, there are conflicting data on influenza vaccine antibody responses in obese children. Cardio-metabolic parameters such as waist circumference, cholesterol, insulin sensitivity, and blood pressure are used to subdivide individuals with overweight or obese BMI into ‘healthy’ (MHOO) or ‘unhealthy’ (MUOO) metabolic phenotypes. The ever-evolving metabolic phenotypes in children may be elucidated by using vaccine stimulation to characterize cytokine responses. We conducted a prospective cohort study evaluating influenza vaccine responses in children. Participants were identified as either normal-weight children (NWC) or overweight/obese using BMI. Children with obesity were then characterized using metabolic health metrics. These metrics consisted of changes in serum cytokine and chemokine concentrations measured via multiplex assay at baseline and repeated at one month following vaccination. Changes in NWC, MHOO and MUOO were compared using Chi-square/Fisher’s exact test for antibody responses and Kruskal–Wallis test for cytokines. Differences in influenza antibody responses in normal, MHOO and MUOO children were statistically indistinguishable. IL-13 was decreased in MUOO children compared to NWC and MHOO children (p = 0.04). IL-10 approached a statistically significant decrease in MUOO compared to MHOO and NWC (p = 0.07). Influenza vaccination does not provoke different responses in NCW, MHOO, or MUOO children, suggesting that obesity, whether metabolically healthy or unhealthy, does not alter the efficacy of vaccination. IL-13 levels in MUO children were significantly different from levels in normal and MHOO children, indicating that the metabolically unhealthy phenotypes may be associated with an altered inflammatory response. A larger sample size with greater numbers of metabolically unhealthy children may lend more insight into the relationship of chronic inflammation secondary to obesity with vaccine immunity.
Published: 2022
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24. Medication adherence and persistence in patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis: a systematic literature review

Author: Murage MJ, Tongbram V, Feldman SR, Malatestinic WN, Larmore CJ, Muram TM, Burge RT, Bay C, Johnson N, Clifford S, and Araujo AB
Subjects: adherence, discontinuation, psoriasis, arthritis, systematic, review, Medicine (General), R5-920
Abstract: Mwangi J Murage,1 Vanita Tongbram,2 Steven R Feldman,3 William N Malatestinic,1 Cynthia J Larmore,1 Talia M Muram,1 Russel T Burge,1,4 Charles Bay,2 Nicole Johnson,2 Sarah Clifford,5 Andre B Araujo1 1Eli Lilly and Company, Indianapolis, IN, USA; 2ICON Plc, New York, NY, USA; 3Wake Forest University School of Medicine, Winston-Salem, NC, USA; 4University of Cincinnati, Division of Pharmaceutical Sciences, Winkle College of Pharmacy, Cincinnati, OH, USA; 5ICON Plc, San Francisco, CA, USA Purpose: Proper adherence and persistence to medications are crucial for better quality of life and improved outcomes in rheumatoid arthritis (RA), psoriasis (PsO), and psoriatic arthritis (PsA). We systematically describe current adherence and persistence patterns for RA, PsO, and PsA, with a focus on biologics and identifying factors associated with adherence and persistence. Patients and methods: Using various databases, a systematic literature review of US-based studies published from 2000 to 2015 on medication adherence and persistence to biologics and associated factors was conducted among patients with RA, PsO, and PsA. Results: Using the medication possession ratio or the percentage of days covered >80%, RA and PsO adherence rates for etanercept, adalimumab, and infliximab ranged from 16% to 73%, 21% to 70%, and 38% to 81%, respectively. Using the criteria of a ≥45-day gap, RA persistence rates for etanercept, adalimumab, and infliximab ranged from 46% to 89%, 42% to 94%, and 41% to 76%, respectively. In PsO, persistence rates for etanercept and adalimumab ranged from 34% to 50% and 50% to 62%, respectively. Similar persistence rates were observed in PsA. Experienced biologics users showed better adherence and persistence. Younger age, female gender, higher out-of-pocket costs, greater disease severity, and more comorbidities were associated with lower adherence and persistence rates. Qualitative surveys revealed that nonpersistence was partly due to perceived ineffectiveness and safety/tolerability concerns. Conclusion: Biologic adherence and persistence rates in RA, PsO, and PsA in the United States were low, with significant opportunity for improvement. Various factors – including decrease in disease severity; reduction of comorbidities; lower out-of-pocket costs; refilling at specialty pharmacies; and awareness of drug effectiveness, safety, and tolerability – can inform targeted approaches to improve these rates. Keywords: biologics, compliance, nonadherence, nonpersistence, factors, discontinuation
Published: 2018

25. Co-transfer of tumor-specific effector and memory CD8+ T cells enhances the efficacy of adoptive melanoma immunotherapy in a mouse model

Author: Amanda Contreras, Megan V. Beems, Andrew J. Tatar, Siddhartha Sen, Prakrithi Srinand, M. Suresh, Tahra K. Luther, and Clifford S. Cho
Subjects: Adoptive transfer, Immunotherapy, T cell, Memory, Effector, Melanoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Adoptive cell transfer (ACT) is a promising cancer immunotherapeutic strategy that remains ineffective for a large subset of patients. ACT with memory CD8+ T cells (Tmem) has been shown to have superior efficacy compared to traditional ACT with effector CD8+ T cells (Teff). Teff and Tmem have complementary physiological advantages for immunotherapy, but previous publications have not examined ACT using a combination of Teff and Tmem. Methods Splenocytes harvested from Ly5.1+/C57BL/6 mice during and after infection with lymphocytic choriomeningitis virus (LCMV) were used to generate bona fide effector and memory CD8+ T cells specific for the LCMV epitope peptide GP33. Congenic Ly5.2+/C57BL/6 mice were inoculated with B16F10 melanoma cells transfected to express very low levels of GP33, then treated with ACT 7 days later with GP33-specific Teff, Tmem, or a combination of Teff + Tmem. Results Inhibition of melanoma growth was strongest in mice receiving combinatorial ACT. Although combinatorial ACT and memory ACT resulted in maximal intratumoral infiltration of CD8+ T cells, combinatorial ACT induced stronger infiltration of endogenous CD8+ T cells than Tmem ACT and a stronger systemic T cell responsiveness to tumor antigen. In vitro assays revealed rapid but transient melanoma inhibition with Teff and gradual but prolonged melanoma inhibition with Tmem; the addition of Tmem enhanced the ability of Teff to inhibit melanoma in a manner that could be reproduced using conditioned media from activated Tmem and blocked by the addition of anti-IL-2 blocking antibody. Conclusions These findings suggest that a novel combinatorial approach that takes advantage of the unique and complementary strengths of tumor-specific Teff and Tmem may be a way to optimize the efficacy of adoptive immunotherapy.
Published: 2018
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26. In vivo clearance of nanoparticles by transcytosis across alveolar epithelial cells.

Author: Pascal Detampel, Anutosh Ganguly, Sara Tehranian, Francis Green, Santiswarup Singha, Pere Santamaria, Ayodeji A Jeje, Clifford S Cho, Björn Petri, and Matthias W Amrein
Subjects: Medicine, Science
Abstract: Nanoparticles in polluted air or aerosolized drug nanoparticles predominantly settle in the alveolar lung. Here, we describe a novel, highly effective pathway for the particles to cross the alveolar epithelium and reach the lymph and bloodstream. Amorphous silica nanoparticles, suspended in perfluorocarbon, were instilled into the lungs of mice for intravital microscopy. Particles formed agglomerates that settled on the alveolar wall, half of which were removed from the lung within 30 minutes. TEM histology showed agglomerates in stages of crossing the alveolar epithelium, in large compartments inside the epithelial cells and crossing the basal membrane into the interstitium. This pathway is consistent with published kinetic studies in rats and mice, using a host of (negatively) charged and polar nanoparticles.
Published: 2019
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27. M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture

Author: Abraham, Mabel N., Nedeljkovic-Kurepa, Ana, Fernandes, Tiago D., Yaipen, Omar, Brewer, Mariana R., Leisman, Daniel E., Taylor, Matthew D., and Deutschman, Clifford S.
Published: 2024
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28. Science in the Supply Chain: Collaboration Opportunities for Advancing Sustainable Agriculture in the United States

Author: Allison M. Thomson, Stewart Ramsey, Ed Barnes, Bruno Basso, Marlen Eve, Sasha Gennet, Patricio Grassini, Brandon Kliethermes, Marty Matlock, Eileen McClellen, Ed Spevak, Clifford S. Snyder, Mark D. Tomer, Chris van Kessel, Tristram West, and Grant Wick
Subjects: Agriculture, Environmental sciences, GE1-350
Abstract: Consumers and corporations are increasingly interested in understanding the sustainability of agricultural supply chains and reducing the environmental impacts of food, fiber, feed, and fuel production. This emerging need to quantify environmental impacts from agricultural production creates an opportunity for collaboration with the scientific community. Without such collaboration, sustainability efforts risk failure by adopting unrealistic goals or misguided approaches. This commentary explores the role of science in Field to Market, a nonprofit organization developing a sustainability program for US commodity crops, and highlights opportunities to address emerging science challenges. We evaluate changes over the past 35 years in key environmental impacts of crop production used to inform land managers as well as companies that are committed to improvements. Achieving improvements will only be possible if three key gaps are addressed regarding available simulation models and data, scale of implementation and uncertainty, and effectiveness of conservation practices. Filling these gaps presents an opportunity for dialogue between scientists, farmers, and private-sector stakeholders to advance scientific knowledge and promote the common objective of sustainable agriculture.
Published: 2017
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29. Extracellular Signal-Regulated Kinase Signaling in CD4-Expressing Cells Inhibits Osteochondromas

Author: Maureen A. McGargill, Marie Wehenkel, Maripat Corr, Clifford S. Guy, Benjamin A. Edwards, Ashley H. Castellaw, Christopher Calabrese, Gilles Pagès, Jacques Pouysségur, and Peter Vogel
Subjects: cartilage, extracellular signal-regulated kinase, osteochondroma, chondrocyte, animal model, bone, Immunologic diseases. Allergy, RC581-607
Abstract: Defects in cartilage homeostasis can give rise to various skeletal disorders including osteochondromas. Osteochondromas are benign bone tumors caused by excess accumulation of chondrocytes, the main cell type of cartilage. The extracellular signal-regulated kinase (ERK) pathway is a major signaling node that functions within chondrocytes to regulate their growth and differentiation. However, it is not known whether the ERK pathway in other cell types regulates cartilage homeostasis. We show here that mice with a germline deficiency of Erk1 and a conditional deletion of Erk2 in cells that express CD4, or expressed CD4 at one point in development, unexpectedly developed bone deformities. The bone lesions were due to neoplastic outgrowths of chondrocytes and disordered growth plates, similar to tumors observed in the human disease, osteochondromatosis. Chondrocyte accumulation was not due to deletion of Erk2 in the T cells. Rather, CD4cre was expressed in cell types other than T cells, including a small fraction of chondrocytes. Surprisingly, the removal of T cells accelerated osteochondroma formation and enhanced disease severity. These data show for the first time that T cells impact the growth of osteochondromas and describe a novel model to study cartilage homeostasis and osteochondroma formation.
Published: 2017
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30. Climate change effects on rangelands and rangeland management: affirming the need for monitoring

Author: Daniel W. Mccollum, John A. Tanaka, Jack A. Morgan, John E. Mitchell, William E. Fox, Kristie A. Maczko, Lori Hidinger, Clifford S. Duke, and Urs P. Kreuter
Subjects: adaptive management, climate change, indicators, monitoring, rangelands, resilience, uncertainty, vulnerability, Ecology, QH540-549.5
Abstract: Uncertainty as to the extent and magnitude of changes in conditions that might occur due to climate change poses a problem for land and resource managers as they seek to adapt to changes and mitigate effects of climate variability. We illustrate using scenarios of projected future conditions on rangelands in the Northern Great Plains and Desert Southwest of the United States. These two regions are different in the ways climate change is projected to affect the regions. Projection of a longer and warmer growing season in the Northern Great Plains could lead to increased forage production and land productivity. Highly uncertain effects on summer monsoons that primarily control rangeland productivity in the Desert Southwest, combined with the possibility of more intense and/or frequent drought events, could present land managers with challenges stemming from decreased forage production and land productivity. Climate projections, though uncertain, provide land managers with basic insight into future conditions they might encounter. They need more. A focus on vulnerability and resilience, with explicit recognition of interactions between ecological and socio‐economic factors, coupled with systematic monitoring and assessment of observable conditions on the land to supplement information based on climate projections, will more effectively provide critical and specific information managers need to adaptively manage rangelands under uncertain climate futures.
Published: 2017
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31. What Surgical Options Are Available for Patients With Colon Cancer, Including Those Who Present With Acute Obstruction?

Author: Cho, Clifford S., primary
Published: 2024
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32. How Should Patients With a Solitary Liver Metastasis From Colon Cancer Be Evaluated and Treated?

Author: Cho, Clifford S., primary
Published: 2024
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33. Nucleophosmin integrates within the nucleolus via multi-modal interactions with proteins displaying R-rich linear motifs and rRNA

Author: Diana M Mitrea, Jaclyn A Cika, Clifford S Guy, David Ban, Priya R Banerjee, Christopher B Stanley, Amanda Nourse, Ashok A Deniz, and Richard W Kriwacki
Subjects: nucleolus, phase separation, NPM1/B23/nucleophosmin, nucleolar localization, intrinsically disordered proteins, single molecule fluorescence, Medicine, Science, Biology (General), QH301-705.5
Abstract: The nucleolus is a membrane-less organelle formed through liquid-liquid phase separation of its components from the surrounding nucleoplasm. Here, we show that nucleophosmin (NPM1) integrates within the nucleolus via a multi-modal mechanism involving multivalent interactions with proteins containing arginine-rich linear motifs (R-motifs) and ribosomal RNA (rRNA). Importantly, these R-motifs are found in canonical nucleolar localization signals. Based on a novel combination of biophysical approaches, we propose a model for the molecular organization within liquid-like droplets formed by the N-terminal domain of NPM1 and R-motif peptides, thus providing insights into the structural organization of the nucleolus. We identify multivalency of acidic tracts and folded nucleic acid binding domains, mediated by N-terminal domain oligomerization, as structural features required for phase separation of NPM1 with other nucleolar components in vitro and for localization within mammalian nucleoli. We propose that one mechanism of nucleolar localization involves phase separation of proteins within the nucleolus.
Published: 2016
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34. Physician Payments from Industry Are Associated with Greater Medicare Part D Prescribing Costs.

Author: Roy H Perlis and Clifford S Perlis
Subjects: Medicine, Science
Abstract: BACKGROUND:The U.S. Physician Payments Sunshine Act mandates the reporting of payments or items of value received by physicians from drug, medical device, and biological agent manufacturers. The impact of these payments on physician prescribing has not been examined at large scale. METHODS:We linked public Medicare Part D prescribing data and Sunshine Act data for 2013. Physician payments were examined descriptively within specialties, and then for association with prescribing costs and patterns using regression models. Models were adjusted for potential physician-level confounding features, including sex, geographic region, and practice size. RESULTS:Among 725,169 individuals with Medicare prescribing data, 341,644 had documented payments in the OPP data (47.1%). Among all physicians receiving funds, mean payment was $1750 (SD $28336); median was $138 (IQR $48-$394). Across the 12 specialties examined, a dose-response relationship was observed in which greater payments were associated with greater prescribing costs per patient. In adjusted regression models, being in the top quintile of payment receipt was associated with incremental prescribing cost per patient ranging from $27 (general surgery) to $2931 (neurology). Similar associations were observed with proportion of branded prescriptions written. CONCLUSIONS:While distribution and amount of payments differed widely across medical specialties, for each of the 12 specialties examined the receipt of payments was associated with greater prescribing costs per patient, and greater proportion of branded medication prescribing. We cannot infer a causal relationship, but interventions aimed at those physicians receiving the most payments may present an opportunity to address prescribing costs in the US.
Published: 2016
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35. Von Neumann-Morgenstern Stability and Internal Closedness in Matching Theory

Author: Faenza, Yuri, Stein, Clifford S., Wan, Jia, Goos, Gerhard, Series Editor, Hartmanis, Juris, Founding Editor, van Leeuwen, Jan, Series Editor, Hutchison, David, Editorial Board Member, Kanade, Takeo, Editorial Board Member, Kittler, Josef, Editorial Board Member, Kleinberg, Jon M., Editorial Board Member, Kobsa, Alfred, Series Editor, Mattern, Friedemann, Editorial Board Member, Mitchell, John C., Editorial Board Member, Naor, Moni, Editorial Board Member, Nierstrasz, Oscar, Series Editor, Pandu Rangan, C., Editorial Board Member, Sudan, Madhu, Series Editor, Terzopoulos, Demetri, Editorial Board Member, Tygar, Doug, Editorial Board Member, Deshpande, R.D., Series Editor, Vardi, Moshe Y, Series Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Woeginger, Gerhard, Editorial Board Member, Vygen, Jens, editor, and Byrka, Jarosław, editor
Published: 2024
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36. Pectobacterium carotovorum Elicits Plant Cell Death with DspE/F but the P. carotovorum DspE Does Not Suppress Callose or Induce Expression of Plant Genes Early in Plant–Microbe Interactions

Author: Hye-Sook Kim, Phanit Thammarat, Steven A. Lommel, Clifford S. Hogan, and Amy O. Charkowski
Subjects: Microbiology, QR1-502, Botany, QK1-989
Abstract: The broad-host-range bacterial soft rot pathogen Pectobacterium carotovorum causes a DspE/F-dependent plant cell death on Nicotiana benthamiana within 24 h postinoculation (hpi) followed by leaf maceration within 48 hpi. P. carotovorum strains with mutations in type III secretion system (T3SS) regulatory and structural genes, including the dspE/F operon, did not cause hypersensitive response (HR)-like cell death and or leaf maceration. A strain with a mutation in the type II secretion system caused HR-like plant cell death but no maceration. P. carotovorum was unable to impede callose deposition in N. benthamiana leaves, suggesting that P. carotovorum does not suppress this basal immunity function. Within 24 hpi, there was callose deposition along leaf veins and examination showed that the pathogen cells were localized along the veins. To further examine HR-like plant cell death induced by P. carotovorum, gene expression profiles in N. benthamiana leaves inoculated with wild-type and mutant P. carotovorum and Pseudomonas syringae strains were compared. The N. benthamiana gene expression profile of leaves infiltrated with Pectobacterium carotovorum was similar to leaves infiltrated with a Pseudomonas syringae T3SS mutant. These data support a model where Pectobacterium carotovorum uses the T3SS to induce plant cell death in order to promote leaf maceration rather than to suppress plant immunity.
Published: 2011
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37. Medication adherence and community pharmacy: a review of education, policy and research in England

Author: Clifford S, Garfield S, Eliasson L, and Barber N
Subjects: Medication Adherence, Pharmacists, Education, Pharmacy, United Kingdom, Therapeutics. Pharmacology, RM1-950, Pharmacy and materia medica, RS1-441
Abstract: Objective: The objective of this narrative review was to identify and describe the current policy, education and research related to community pharmacy and medication adherence in England.Methods: Medline, Embase, International Pharmaceutical Abstracts and Pharmline were used to search for relevant research articles. Current policy documents were identified via the websites of the Department of Health in England, the Royal Pharmaceutical Society of Great Britain, the National Pharmacy Association, the Pharmaceutical Services Negotiating Committee and NHS Employers. All pharmacy schools in England were contacted to obtain information about the adherence-related courses they provide to undergraduate and postgraduate pharmacy students.Results: National policies and guidelines in England are conducive to an increasing role for community pharmacists to support patients with medication adherence. Many pharmacy schools cover the issue of adherence in their undergraduate and postgraduate courses. Research in this area has tested the effectiveness of pharmacists providing adherence support in the form of compliance aids, education, involvement in discharge planning, and tailored interventions. Conclusion: In community pharmacy in England, current policy and funding arrangements suggest there is great scope for pharmacists to support patients with medication adherence. Further research is necessary to identify the most useful, cost-effective and sustainable approach in practice.
Published: 2010

38. Video Laryngoscopy in Critically Ill Adults: Nascent, Evolving, or Established?*

Author: Jabaley, Craig S., Pendergrast, Tricia R., Aslakson, Rebecca A., and Deutschman, Clifford S.
Published: 2024
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39. A New Paradigm for Pandemic Preparedness

Author: Fefferman, Nina H., McAlister, John S., Akpa, Belinda S., Akwataghibe, Kelechi, Azad, Fahim Tasneema, Barkley, Katherine, Bleichrodt, Amanda, Blum, Michael J., Bourouiba, L., Bromberg, Yana, Candan, K. Selçuk, Chowell, Gerardo, Clancey, Erin, Cothran, Fawn A., DeWitte, Sharon N., Fernandez, Pilar, Finnoff, David, Flaherty, D. T., Gibson, Nathaniel L., Harris, Natalie, He, Qiang, Lofgren, Eric T., Miller, Debra L., Moody, James, Muccio, Kaitlin, Nunn, Charles L., Papeș, Monica, Paschalidis, Ioannis Ch., Pasquale, Dana K., Reed, J. Michael, Rogers, Matthew B., Schreiner, Courtney L., Strand, Elizabeth B., Swanson, Clifford S., Szabo-Rogers, Heather L., and Ryan, Sadie J.
Published: 2023
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40. Polymeric micelles for apoptosis-targeted optical imaging of cancer and intraoperative surgical guidance.

Author: Hyunah Cho, Clifford S Cho, Guilherme L Indig, Afsaneh Lavasanifar, Mohammad Reza Vakili, and Glen S Kwon
Subjects: Medicine, Science
Abstract: In a two-step strategy, an intraperitoneal (IP) injection of poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) micelles containing paclitaxel (PTX), cyclopamine (CYP), and gossypol (GSP) at 30, 30, and 30 mg/kg, respectively, debulked tumor tissues by 1.3-fold, based on loss of bioluminescence with
Published: 2014
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41. Ralstonia solanacearum Requires PopS, an Ancient AvrE-Family Effector, for Virulence and To Overcome Salicylic Acid-Mediated Defenses during Tomato Pathogenesis

Author: Jonathan M. Jacobs, Annett Milling, Raka M. Mitra, Clifford S. Hogan, Florent Ailloud, Philippe Prior, and Caitilyn Allen
Subjects: Microbiology, QR1-502
Abstract: ABSTRACT During bacterial wilt of tomato, the plant pathogen Ralstonia solanacearum upregulates expression of popS, which encodes a type III-secreted effector in the AvrE family. PopS is a core effector present in all sequenced strains in the R. solanacearum species complex. The phylogeny of popS mirrors that of the species complex as a whole, suggesting that this is an ancient, vertically inherited effector needed for association with plants. A popS mutant of R. solanacearum UW551 had reduced virulence on agriculturally important Solanum spp., including potato and tomato plants. However, the popS mutant had wild-type virulence on a weed host, Solanum dulcamara, suggesting that some species can avoid the effects of PopS. The popS mutant was also significantly delayed in colonization of tomato stems compared to the wild type. Some AvrE-type effectors from gammaproteobacteria suppress salicylic acid (SA)-mediated plant defenses, suggesting that PopS, a betaproteobacterial ortholog, has a similar function. Indeed, the popS mutant induced significantly higher expression of tomato SA-triggered pathogenesis-related (PR) genes than the wild type. Further, pretreatment of roots with SA exacerbated the popS mutant virulence defect. Finally, the popS mutant had no colonization defect on SA-deficient NahG transgenic tomato plants. Together, these results indicate that this conserved effector suppresses SA-mediated defenses in tomato roots and stems, which are R. solanacearum’s natural infection sites. Interestingly, PopS did not trigger necrosis when heterologously expressed in Nicotiana leaf tissue, unlike the AvrE homolog DspEPcc from the necrotroph Pectobacterium carotovorum subsp. carotovorum. This is consistent with the differing pathogenesis modes of necrosis-causing gammaproteobacteria and biotrophic R. solanacearum. IMPORTANCE The type III-secreted AvrE effector family is widely distributed in high-impact plant-pathogenic bacteria and is known to suppress plant defenses for virulence. We characterized the biology of PopS, the only AvrE homolog made by the bacterial wilt pathogen Ralstonia solanacearum. To our knowledge, this is the first study of R. solanacearum effector function in roots and stems, the natural infection sites of this pathogen. Unlike the functionally redundant R. solanacearum effectors studied to date, PopS is required for full virulence and wild-type colonization of two natural crop hosts. R. solanacearum is a biotrophic pathogen that causes a nonnecrotic wilt. Consistent with this, PopS suppressed plant defenses but did not elicit cell death, unlike AvrE homologs from necrosis-causing plant pathogens. We propose that AvrE family effectors have functionally diverged to adapt to the necrotic or nonnecrotic lifestyle of their respective pathogens.
Published: 2013
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42. Root traits regulate the capacity of the rhizosphere to support multiple ecosystem services under intercropping and phosphorus fertilization

Author: Tao, Dongxue, Gao, Yingzhi, Revillini, Daniel, Yan, An, Zhou, Guiyao, Swanson, Clifford S., He, Qiang, Ma, Huimin, Yu, Xiaoqian, and Delgado-Baquerizo, Manuel
Published: 2024
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43. Maize-alfalfa intercropping alleviates the dependence of multiple ecosystem services on nonrenewable fertilization

Author: Tao, Dongxue, Delgado-Baquerizo, Manuel, Zhou, Guiyao, Revillini, Daniel, He, Qiang, Swanson, Clifford S., and Gao, Yingzhi
Published: 2024
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44. The type III secreted effector DspE is required early in solanum tuberosum leaf infection by Pectobacterium carotovorum to cause cell death, and requires Wx(3-6)D/E motifs.

Author: Clifford S Hogan, Beth M Mole, Sarah R Grant, David K Willis, and Amy O Charkowski
Subjects: Medicine, Science
Abstract: Pectobacterium species are enterobacterial plant-pathogens that cause soft rot disease in diverse plant species. Unlike hemi-biotrophic plant pathogenic bacteria, the type III secretion system (T3SS) of Pectobacterium carotovorum subsp. carotovorum (P. carotovorum) appears to secrete only one effector protein, DspE. Previously, we found that the T3SS regulator HrpL and the effector DspE are required for P. carotovorum pathogenesis on leaves. Here, we identified genes up-regulated by HrpL, visualized expression of dspE in leaves, and established that DspE causes host cell death. DspE required its full length and WxxxE-like motifs, which are characteristic of the AvrE-family effectors, for host cell death. We also examined expression in plant leaves and showed that hrpL is required for the expression of dspE and hrpN, and that the loss of a functional T3SS had unexpected effects on expression of other genes during leaf infection. These data support a model where P. carotovorum uses the T3SS early in leaf infection to initiate pathogenesis through elicitation of DspE-mediated host cell death.
Published: 2013
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45. Enhanced Hsp70 expression protects against acute lung injury by modulating apoptotic pathways.

Author: Gabriella Aschkenasy, Zohar Bromberg, Nichelle Raj, Clifford S Deutschman, and Yoram G Weiss
Subjects: Medicine, Science
Abstract: The Acute respiratory distress syndrome (ARDS) is a highly lethal inflammatory lung disorder. Apoptosis plays a key role in its pathogenesis. We showed that an adenovirus expressing the 70 kDa heat shock protein Hsp70 (AdHSP) protected against sepsis-induced lung injury. In this study we tested the hypothesis that AdHSP attenuates apoptosis in sepsis-induced lung injury. Sepsis was induced in rats via cecal ligation and double puncture (2CLP). At the time of 2CLP PBS, AdHSP or AdGFP (an adenoviral vector expressing green fluorescent protein) were injected into the tracheas of septic rats. 48 hours later, lungs were isolated. One lung was fixed for TUNEL staining and immunohistochemistry. The other was homogenized to isolate cytosolic and nuclear protein. Immunoblotting, gel filtration and co-immunoprecipitation were performed in these extracts. In separate experiments MLE-12 cells were incubated with medium, AdHSP or AdGFP. Cells were stimulated with TNFα. Cytosolic and nuclear proteins were isolated. These were subjected to immunoblotting, co-immunoprecipitation and a caspase-3 activity assay. TUNEL assay demonstrated that AdHSP reduced alveolar cell apoptosis. This was confirmed by immunohistochemical detection of caspase 3 abundance. In lung isolated from septic animals, immunoblotting, co-immunoprecipitation and gel filtration studies revealed an increase in cytoplasmic complexes containing caspases 3, 8 and 9. AdHSP disrupted these complexes. We propose that Hsp70 impairs apoptotic cellular pathways via interactions with caspases. Disruption of large complexes resulted in stabilization of lower molecular weight complexes, thereby, reducing nuclear caspase-3. Prevention of apoptosis in lung injury may preserve alveolar cells and aid in recovery.
Published: 2011
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46. Survival disparities in rural versus urban patients with pancreatic neuroendocrine tumor: A multi-institutional study from the US neuroendocrine tumor study group

Author: Mirza, Muhammad Bilal, Baechle, Jordan J., Marincola Smith, Paula, Dillhoff, Mary, Poultsides, George, Rocha, Flavio G., Cho, Clifford S., Winslow, Emily R., Fields, Ryan C., Maithel, Shishir K., and Idrees, Kamran
Published: 2024
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47. Phosphorylation of insulin receptor substrates (IRS-1 and IRS-2) is attenuated following cecal ligation and puncture in mice

Author: Mathew, Deepa, Barillas-Cerritos, Julia, Nedeljkovic-Kurepa, Ana, Abraham, Mabel, Taylor, Matthew D., and Deutschman, Clifford S.
Published: 2023
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48. Alternating polarity as a novel strategy for building synthetic microbial communities capable of robust Electro-Methanogenesis

Author: Yao, Shiyun, Swanson, Clifford S., Cheng, Zhang, He, Qiang, and Yuan, Heyang
Published: 2024
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49. Immunomodulatory therapy in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS, MIS-C; RECOVERY): a randomised, controlled, open-label, platform trial

Author: Faust, Saul N, Haynes, Richard, Jones, Christine E, Staplin, Natalie, Whittaker, Elizabeth, Jaki, Thomas, Juszczak, Ed, Spata, Enti, Wan, Mandy, Bamford, Alasdair, Dimitri, Paul, Finn, Adam, Furness, John, Ramanan, Athimalaipet V, Gale, Christopher, Cathie, Katrina, Drysdale, Simon, Bernatoniene, Jolanta, Murray, Clare, Roehr, Charles C, Fleming, Paul, Riordan, Andrew, Bandi, Srini, Jyothish, Deepthi, Evans, Jennifer, Emonts, Marieke, Kelly, Dominic, Pathan, Nazima, Davies, Patrick, Hague, Rosie, Pollock, Louisa, Semple, Malcolm G, Peto, Leon, Baillie, J Kenneth, Buch, Maya, Jeffery, Katie, Knight, Marian, Lim, Wei Shen, Montgomery, Alan, Mukherjee, Aparna, Mumford, Andrew, Rowan, Kathryn, Thwaites, Guy, Mafham, Marion, Emberson, Jonathan, Landray, Martin J, Horby, Peter W, Chappell, Lucy, Day, Jeremy, Dung, DV, Quang, NN, Binh, Prof, Burhan, E, Alisjahbana, B, Koirala, J, Basnet, S, Kestelyn, E, Basnyat, B, Gyanwali, P, Hamers, RL, Sandercock, P, Darbyshire, J, DeMets, D, Fowler, R, Lalloo, D, Munavvar, M, Roberts, I, Warris, A, Wittes, J, Craddock-Bamford, A, Barton, J, Basoglu, A, Brown, R, Brudlo, W, Denis, E, Fletcher, L, Howard, S, Musini, S, Taylor, K, Cui, G, Goodenough, B, King, A, Lay, M, Murray, D, Stevens, W, Wallendszus, K, Welsh, R, Crichton, C, Davies, J, Goldacre, R, Harper, C, Knight, F, Nunn, M, Salih, H, Welch, J, Campbell, M, Pessoa-Amorim, G, Zayed, M, Wiles, J, Bagley, G, Cameron, S, Chamberlain, S, Farrell, B, Freeman, H, Kennedy, A, Whitehouse, A, Wilkinson, S, Wood, C, Reith, C, Davies, K, Halls, H, Holland, L, Truell, R, Wilson, K, Lingwood, Emma, Howie, L, Lunn, M, Rodgers, Penelope, Amuasi, J, Baird, K, Bao, T, Bittaye, M, Bonney, J, D'Alessandro, U, Dhimal, M, Huyen, T, Jagne, A, Karkey, A, Maiga, O, Matey, E, Nadjm, B, Nel, J, Pant, S, Puspatriani, K, Rahardjani, M, Raijal, S, Rees, H, Rimainar, A, Roberts, C, Rocca, A, Shrestha, S, Usuf, E, Vidaillic, C, Wulandari, F, Alexander, A, Amezaga, M, Armah, C, Asghar, A, Aubrey, P, Barker-Williams, K, Barnard, A, Bartholomew, J, Beaumont-Jewell, D, Beddows, S, Beety, J, Birch, C, Boyle, P, Brend, M, Brookes, M, Callens, C, Campbell, D, Campbell, H, Cate, H, Chambers, E, Chapman, K, Coe, A, Collins, J, Crawshaw, S, Das, S, De Soyza, A, Denton, E, Dicks, P, Dolman, M, Donaldson, K, Dowden, L, Dowling, S, Drake, C, Duckles-Leech, H, Duffy, H, Gerdes, L, Gibbons, K, Gill, L, Gilmour, K, Goodwin, J, Graham, J, Green, C, Hall, C, Hall, A, Hampshire, K, Hanson, J, Harman, T, Harper, H, Harrison, S, Hicks, J, Hodgson, H, Hough, M, Jackson, S, Johnson, G, Kirk, J, Lemoine, N, Levett, C, Lock, S, Lockett, T, Logan, M, Lomme, K, Luo, J, McMillan, N, Membrey, H, Mguni, N, Minton, J, Monaghan, H, Murphy, S, Muzengi, N, Naz, M, Nickson, I, Odam, M, Ohia, U, Okell, E, Oliver, A, Pearson, K, Pine, K, Pleass, R, Porter, D, Porter, L, Potter, A, Poustie, V, Pratt, S, Price, A, Priest, A, Rodgers, A, Rook, C, Ryan, P, Sam, S, Sharratt, P, Sheffield, J, Shenton, J, Shirley, K, Skinner, T, Slade, H, Sutu, M, Taylor, J, Thomas, E, Tinkler, H, Unsworth, A, Usher, R, van't Hoff, W, Walker, S, Walters, J, Walton, E, Warmington, J, Wayman, E, Williams, P, Williamson, J, Williamson, D, Yelnoorkar, F, Knight, M, Hodson, K, Pavord, S, Williamson, C, Bowman, L, Chen, F, Clarke, R, Goonasekara, M, Herrington, W, Judge, P, Ng, S, Preiss, D, Sammons, E, Zhu, D, Arkley, C, Bowker, P, Bruce, J, Byrne-Watts, V, Chapman, G, Coleman, G, Denwood, T, Gray, J, Harrison, D, Mather, N, Pinches, H, Rees, A, Rees, S, Turner, G, Abani, O, Abbas, A, Abbas, F, Abbas, J, Abbas, K, Abbas, M, Abbasi, S, Abbass, H, Abbott, A, Abdallah, N, Abdelaziz, A, Abdelfattah, M, Abdelqader, B, Abdul, A, Abdul, B, Abdul, S, Abdul Rasheed, A, Abdulakeem, A, Abdul-Kadir, R, Abdullah, A, Abdulmumeen, A, Abdul-Raheem, R, Abdulshukkoor, N, Abdusamad, K, Abed El Khaleq, Y, Abedalla, M, Abeer Ul Amna, A, Abel, L, Abernethy, K, Abeywickrema, M, Abhinaya, C, Aboaba, A, Aboagye-Odei, A, Aboelela, H, Abo-Leyah, H, Abouelela, K, Abou-Haggar, A, Abouibrahim, M, Abousamra, A, Abouzaid, M, Abraham, M, Abraham, T, Abraheem, A, Abrams, J, Abrams, R, Abu, H, Abu-Arafeh, A, Abubacker, S, Abung, A, Abusamra, Y, Aceampong, Y, Achara, A, Acharya, D, Acheampong, S, Acheampong, P, Acheson, J, Achieng, S, Acosta, A, Acquah, R, Acton, C, Adabie-Ankrah, J, Adair, P, Adam, F, Adam, M, Adamali, H, Adamczyk, M, Adams, C, Adams, D, Adams, K, Adams, L, Adams, N, Adams, R, Adams, T, Adamu-Ikeme, L, Adati, K, Adcock, K, Addo, A, Adeagbo, O, Adebiyi, A, Adedeji, O, Adegeye, Y, Adegoke, K, Adell, V, Adenwalla, S, Adeoye, F, Adesemoye, O, Adewunmi, E, Adeyanju, A, Adeyemi, J, Adeyemo, T, Adhikary, R, Aditya, A, Adkins, G, Adnan, A, Aeron-Thomas, J, Affleck, D, Afnan, C, Afridi, M, Aftab, Z, Agarwal, M, Agbeko, R, Agbo, C, Aggarwal, S, Aghababaie, A, Aguilar Jimenez, L, Ahamed Sadiq, S, Ahammed Nazeer, M, Ahmed, A, Ahmed, B, Ahmed, F, Ahmed, H, Ahmed, I, Ahmed, K, Ahmed, L, Ahmad, M, Ahmed, N, Ahmed, O, Ahmed, R, Ahmad, S, Ahmed, S H, Ahmed Ali, R, Ahmed Mohamud, B, Ahmer, S, Ahonia, A, Aiken, C, Ail, D, Ainsworth, M, Aissa, M, Aitken, L, Ajay, B, Ajibode, A, Ajmi, A, Akhtar, N, Akili, S, Akinbiyi, B, Akindolie, O, Akinfenwa, Y, Akinkugbe, O, Akinpelu, I, Akram, M, Aktinade, O, Akudi, U, Al Aaraj, A, Al Balushi, A, Al Dakhola, M, Al Swaifi, A, Al-Abadi, E, Alabi, A, Aladangady, N, Alafifi, M, Alam, A, Alam, S, Al-Asadi, A, Alatzoglou, K, Albert, P, Albon, L, Alcala, A, Alcorn, G, Alcorn, S, Aldana, A, Alderdice, D, Aldesouki, A, Aldouri, R, Aldridge, J, Aldridge, N, Alegria, A, Alexander, C, Alexander, J, Alexander, P, Al-Fori, J, Alghazawi, L, Alhabsha, O, Al-Hakim, B, Alhameed, R, Al-Hayali, M, Al-Hity, S, Ali, A, Ali, F, Ali, J, Ali, M, Ali, N, Ali, O, Ali, R, Ali, S, Aliberti, E, Alin, J, Alina, A, Alipustain, A, Aliyuda, F, Alizaedeh, K, Al-Jibury, M, Al-Juboori, S, Al-Khalil, M, Alkhudhayri, A, Alkhusheh, M, Allan, F, Allan, N, Allanson, A, Allcock, R, Allen, E, Allen, J, Allen, K, Allen, L, Allen, P, Allen, R, Allen, S, Allen, T, Alli, A, Allison, K, Allman, B, Allsup, D, Allsop, H, Allsop, L, Almahroos, A, Al-Moasseb, H, Al-Obaidi, M, Alomari, L, Al-Rabahi, A, Al-Ramadhani, B, Al-Saadi, Z, Al-Sammarraie, R, Alshaer, I, Al-Shahi Salman, R, Al-Shamkhani, W, Alsheikh, F, Al-Sheklly, B, Altaf, S, Alty, A, Alvarez, M, Alvarez Corral, M, Alveyn, E, Alzetani, M, Amamou, S, Amar, N, Ambalavanan, S, Ambrogetti, R, Ambrose, C, Ameen, A, Ames, K, Amin, A, Amin, K, Amin, S, Amin, T, Amit, B, Amjad, A, Amjad, N, Amosun, V, Amsal, M, Amsha, K, Amutio Martin, N, Amy, P, Anada, A, Anand, A, Anandappa, S, Anantapatnaikuni, S, Anderson, E, Anderson, J, Anderson, L, Anderson, M, Anderson, N, Anderson, R, Anderson, S, Anderson, W, Andreou, P, Andrews, A, Andrews, J, Aneke, K, Ang, A, Ang, W, Angel, T, Angela, A, Angelini, P, Anguvaa, L, Anichtchik, O, Anim-Somuah, M, Aniruddhan, K, Annett, J, Anning, L, Anstey, P, Anstey, R, Anthony, A, Anthony-Pillai, A, Antill, P, Antonnia, Z, Anu, V, Anwar, M, Apetri, E, Apostolopoulos, A, Appleby, S, Appleyard, D, Aquino, M, Araba, B, Aransiola, S, Araujo, M, Archer, A, Archer, D, Archer, S, Arcoria, D, Ardley, C, Arias, A, Aribike, O, Arimoto, R, Armata, I, Armistead, J, Armitage, A, Armstrong, C, Armstrong, M, Armstrong, S, Armstrong, W, Armtrong, P, Arndt, H, Arnison-Newgass, C, Arnold, D, Arnold, R, Arnott, A, Arora, D, Arora, R, Arora, K, Arora, P, Arter, A, Arumaithurai, A, Arya, A, Arya, R, Asandei, D, Asghar, M, Ashab, M, Ashbrook-Raby, C, Ashby, H, Ashcroft, J, Ashcroft, S, Asher, G, Ashfak, Z, Ashfaq, A, Ashish, A, Ashley, D, Ashman-Flavell, S, Ashok, S, Ashour, A, Ashraf, S, Ashraf, M, Ashraq, M, Ashton, D, Ashton, S, Ashworth, A, Ashworth, F, Ashworth, R, Aslam, A, Aslam, I, Aslam, S, Aslett, L, Asogan, H, Asrar, A, Assaf, O, Astin-Chamberlain, R, Athorne, D, Atkins, B, Atkins, C, Atkins, S, Atkinson, J, Atkinson, V, Atomode, A, Atraskiewicz, B, Attia, A, Attubato, E, Attwood, M, Auer, Z, Aujayeb, A, Aung, A, Aung, H, Aung, K, Aung, N, Aung, Y, Aung, Z, Austin, E, Austin, K, Auwal, A, Avari, M, Avery, M, Aveyard, N, Avis, J, Aviss, G, Avram, C, Avram, P, Awadelkareem, A, Awadzi, G, Awaly, M, Awan, A, Awoseyila, A, Aya, A, Ayaz, E, Ayers, A, Azam, J, Azeem, A, Azharuddin, M, Aziz, A, Aziz, G, Aziz, I, Aziz, N, Azkoul, A, Azman Shah, A, Azzopardi, G, Azzoug, H, Babatunde, F, Babi, M, Babiker, B, Babington, G, Babirecki, M, Babores, M, Babs-Osibodu, A, Bacciarelli, S, Bachar, R, Bachour, M, Bacon, G, Bacon, J, Badal, B, Bader, M, Badhan, G, Badhrinarayanan, S, Bae, J, Baggaley, A, Baggott, A, Bagmane, D, Bagshaw, L, Bahadori, K, Bailey, A, Bailey, J, Bailey, K, Bailey, L, Bailey, M, Bailey, P, Bailey, S, Baillie, H, Baillie, J, Bain, J, Bains, V, Baird, D, Baird, E, Baird, S, Baird, T, Baird, Y, Bajandouh, A, Baker, D, Baker, E, Baker, J, Baker, K, Baker, M, Baker, R, Baker, T, Baker, V, Bakere, H, Bakerly, N, Baker-Moffatt, M, Bakhai, A, Bakhtiar, N, Bakoulas, P, Bakthavatsalam, D, Balachandran, N, Balan, A, Balasingam, P, Balaskas, T, Balasubramania, M, Balatoni, N, Balcombe, A, Baldwin, A, Baldwin, C, Baldwin, D, Baldwin, F, Baldwin-Jones, R, Bale, N, Balfour, J, Ball, R, Ball, M, Ballard, K, Balluz, I, Balmforth, C, Balogh, E, Baltmr, A, Baluwala, A, Bambridge, G, Bamford, P, Bamford, A, Bamgboye, A, Bancroft, H, Bancroft, E, Banda, J, Bandaru, K, Bandla, N, Bandyopadhyam, S, Banerjee, A, Banerjee, R, Bani-Saad, O, Banks, H, Banks, L, Banks, P, Bann, C, Bannister, H, Bannister, O, Banton, L, Baptist, M, Baqai, T, Baral, A, Baramova, D, Barbe, R, Barbon, E, Barbosa, M, Barbour, J, Barclay, A, Barclay, C, Bardsley, G, Bareford, S, Bari, S, Barker, A, Barker, D, Barker, E, Barker, H, Barker, J, Barker, L, Barker, O, Barkha, S, Barla, J, Barlow, G, Barlow, R, Barlow, V, Barnacle, J, Barnes, D, Barnes, N, Barnes, R, Barnes, T, Barnetson, C, Barnett, A, Barnett-Vanes, A, Barnsley, W, Barr, A, Barr, C, Barr, D, Barr, J, Barratt, N, Barratt, S, Barrera, M, Barrett, A, Barrett, F, 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Zulaikha, R, Zulfikar, S, Zullo, C, and Zuriaga-Alvaro, A
Published: 2024
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50. Translating Animal Studies to Human Disease: Language Matters*

Author: Deutschman, Clifford S.
Published: 2024
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