Publications by authors named "Brian Miller"

365 Publications

The Hospital Readmissions Reduction Program: Inconvenient Observations.

J Hosp Med 2021 Jul;16(7):448

Division of Hospital Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.12788/jhm.3663DOI Listing
July 2021

Metabolic heterogeneous zone assessed by FDG-PET is predictive of postablation mortality in patients with ventricular tachycardia.

J Cardiovasc Electrophysiol 2021 Jun 23. Epub 2021 Jun 23.

Division of Cardiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Purpose: We sought to study the predictive value of the metabolic heterogeneous zone (HZ) as determined by Fluorodeoxyglucose ( FDG) positron emission tomography (PET) viability studies in ventricular tachycardia (VT) patients.

Methods: PET studies utilizing Rubidium ( Rb) tracer for perfusion and FDG tracer for viability were analyzed using PMOD (PMOD Technologies) and further analyzed using 684-segment plots. FDG uptake was normalized to the area with maximal perfusion on the rest Rb study. Metabolic scar, HZ, and healthy segments were defined with perfusion-normalized FDG uptake between 0%-50%, 50%-70%, and >70%, respectively.

Results: Thirty-four VT patients (age, 63 ± 12 years) were evaluated with FDG-PET viability study. Most (n = 31) patients underwent VT ablation. Patients were categorized to HZ < median versus HZ ≥ median based on a median HZ area size of 21.0 cm . HZ size was significantly larger in the deceased group than the alive group (35.2 cm vs. 18.1 cm , p = .01). Deaths were significantly higher in HZ ≥ 21 cm group than HZ < 21 cm group (58.8% vs. 11.8%, p = .005). Survival analysis showed significantly higher mortality in the HZ ≥ 21 cm group than the HZ < 21 cm group (HR = 4.1, 95% CI: 1.3-12.6, p = .016). In a multivariable analysis, HZ was found to be an independent predictor for all-cause mortality (HR = 1.07, 95% CI: 1.02-1.12, p = .01) CONCLUSIONS: Increased HZ size of myocardium was associated with increased mortality. Metabolic HZ quantification may be of value in risk stratification and management of ischemic and nonischemic patients with VT.
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http://dx.doi.org/10.1111/jce.15130DOI Listing
June 2021

Evidence for Deleterious Antigenic Imprinting in SARS-CoV-2 Immune Response.

bioRxiv 2021 Jun 9. Epub 2021 Jun 9.

A previous report demonstrated the strong association between the presence of antibodies binding to an epitope region from SARS-CoV-2 nucleocapsid, termed Ep9, and COVID-19 disease severity. Patients with anti-Ep9 antibodies (Abs) had hallmarks of antigenic imprinting (AIM), including early IgG upregulation and cytokine-associated injury. Thus, the immunological memory of a previous infection was hypothesized to drive formation of suboptimal anti-Ep9 Abs in severe COVID-19 infections. This study identifies a putative primary antigen capable of stimulating production of cross-reactive, anti-Ep9 Abs. Binding assays with patient blood samples directly show cross-reactivity between Abs binding to Ep9 and only one bioinformatics-derived, homologous potential antigen, a sequence derived from the neuraminidase protein of H3N2 Influenza A virus. This cross-reactive binding is highly influenza strain specific and sensitive to even single amino acid changes in epitope sequence. The neuraminidase protein is not present in the influenza vaccine, and the anti-Ep9 Abs likely resulted from the widespread influenza infection in 2014. Therefore, AIM from a previous infection could underlie some cases of COVID-19 disease severity.

Importance: Infections with SARS-COV-2 result in diverse disease outcomes, ranging from asymptomatic to fatal. The mechanisms underlying different disease outcomes remain largely unexplained. Previously, our laboratory identified a strong association between the presence of an antibody and increased disease severity in a subset of COVID-19 patients. Here, we report that this severity-associated antibody cross-reacts with viral proteins from an influenza A viral strain from 2014. Therefore, we speculate that antibodies generated against previous infections, like the 2014 influenza A, play a significant role in directing some peoples’ immune responses against SARS-COV-2. Such understanding of the sources and drivers of COVID-19 disease severity can help early identification and pre-emptive treatment.
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http://dx.doi.org/10.1101/2021.05.21.445201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202420PMC
June 2021

Evidence for Deleterious Antigenic Imprinting in SARS-CoV-2 Immune Response.

bioRxiv 2021 Jun 9. Epub 2021 Jun 9.

A previous report demonstrated the strong association between the presence of antibodies binding to an epitope region from SARS-CoV-2 nucleocapsid, termed Ep9, and COVID-19 disease severity. Patients with anti-Ep9 antibodies (Abs) had hallmarks of antigenic imprinting (AIM), including early IgG upregulation and cytokine-associated injury. Thus, the immunological memory of a previous infection was hypothesized to drive formation of suboptimal anti-Ep9 Abs in severe COVID-19 infections. This study identifies a putative primary antigen capable of stimulating production of cross-reactive, anti-Ep9 Abs. Binding assays with patient blood samples directly show cross-reactivity between Abs binding to Ep9 and only one bioinformatics-derived, homologous potential antigen, a sequence derived from the neuraminidase protein of H3N2 Influenza A virus. This cross-reactive binding is highly influenza strain specific and sensitive to even single amino acid changes in epitope sequence. The neuraminidase protein is not present in the influenza vaccine, and the anti-Ep9 Abs likely resulted from the widespread influenza infection in 2014. Therefore, AIM from a previous infection could underlie some cases of COVID-19 disease severity.

Importance: Infections with SARS-COV-2 result in diverse disease outcomes, ranging from asymptomatic to fatal. The mechanisms underlying different disease outcomes remain largely unexplained. Previously, our laboratory identified a strong association between the presence of an antibody and increased disease severity in a subset of COVID-19 patients. Here, we report that this severity-associated antibody cross-reacts with viral proteins from an influenza A viral strain from 2014. Therefore, we speculate that antibodies generated against previous infections, like the 2014 influenza A, play a significant role in directing some peoples’ immune responses against SARS-COV-2. Such understanding of the sources and drivers of COVID-19 disease severity can help early identification and pre-emptive treatment.
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http://dx.doi.org/10.1101/2021.05.21.445201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202420PMC
June 2021

Disruption of a ∼23-24 nucleotide small RNA pathway elevates DNA damage responses in .

Mol Biol Cell 2021 07 19;32(15):1335-1346. Epub 2021 May 19.

Biology Department, Western Washington University, Bellingham, WA 98225.

Endogenous RNA interference (RNAi) pathways regulate a wide range of cellular processes in diverse eukaryotes, yet in the ciliated eukaryote, , the cellular purpose of RNAi pathways that generate ∼23-24 nucleotide (nt) small (s)RNAs has remained unknown. Here, we investigated the phenotypic and gene expression impacts on vegetatively growing cells when genes involved in ∼23-24 nt sRNA biogenesis are disrupted. We observed slower proliferation and increased expression of genes involved in DNA metabolism and chromosome organization and maintenance in sRNA biogenesis mutants Δ, Δ, and Δ. In addition, Δ and Δ cells frequently exhibited enlarged chromatin extrusion bodies, which are nonnuclear, DNA-containing structures that may be akin to mammalian micronuclei. Expression of homologous recombination factor Rad51 was specifically elevated in Δ and Δ strains, with Rad51 and double-stranded DNA break marker γ-H2A.X localized to discrete macronuclear foci. In addition, an increase in Rad51 and γ-H2A.X foci was also found in knockouts of TWI8, a macronucleus-localized PIWI protein. Together, our findings suggest that an evolutionarily conserved role for RNAi pathways in maintaining genome integrity may be extended even to the early branching eukaryotic lineage that gave rise to .
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http://dx.doi.org/10.1091/mbc.E20-10-0631DOI Listing
July 2021

Monitoring for myocarditis during treatment initiation with clozapine.

Acta Psychiatr Scand 2021 Aug 3;144(2):194-200. Epub 2021 Jun 3.

Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, GA, USA.

Objective: Clozapine use is associated with myocarditis. In this study, we investigated what clinical signs and symptoms, and/or laboratory test(s), alert clinicians to presumptive myocarditis (PrMy) most accurately and at the earliest time point. We also investigated the incidence of PrMy during the initial exposure to clozapine versus in patients restarted on clozapine after extended interruption of prior prolonged treatment.

Methods: 100 patients admitted to state psychiatric hospital started on clozapine were recruited into the study. 76 patients were treated with clozapine for the first time and 24 patients were restarts. Creatine kinase (CK), troponin I (TROP), eosinophil count (EOS), and C-reactive protein (CRP) were obtained at baseline and weeks 1, 2, 3, and 4. Descriptive statistics were calculated for demographic and clinical variables. Student's t test and chi-squared test were used to compare means and proportions between initial exposure and restart groups.

Results: Clinical features and laboratory tests suggestive of PrMy were seen in 4 patients (5.3%) in initial exposure group and none in restart group. 3.5% of TROP levels were abnormal in initial exposure group and no abnormal levels were found in the restart group. 30% and 46% of CK, 23% and 39% of CRP, and 14% and 23% of EOS were abnormal in initial exposure group and restart groups, respectively.

Conclusions: PrMy was common (5.3%) during clozapine initiation. Prospective management through serial laboratory monitoring with weekly TROP levels was sensitive enough to allow for timely clozapine discontinuation.
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http://dx.doi.org/10.1111/acps.13328DOI Listing
August 2021

Comfort Level and Perceived Barriers to Clozapine Use: Survey of General Psychiatry Residents.

Acad Psychiatry 2021 May 12. Epub 2021 May 12.

Medical College of Georgia at Augusta University, Augusta, GA, USA.

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http://dx.doi.org/10.1007/s40596-021-01468-1DOI Listing
May 2021

Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity.

Nature 2021 Jul 5;595(7866):309-314. Epub 2021 May 5.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape. Here, to identify factors that modulate the immune sensitivity of cancer cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumour models treated with immune checkpoint blockade. We identified the H3K9 methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape. We also found that amplification of SETDB1 (1q21.3) in human tumours is associated with immune exclusion and resistance to immune checkpoint blockade. SETDB1 represses broad domains, primarily within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune clusters associated with segmental duplication events, a central mechanism of genome evolution. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and TE-encoded retroviral antigens in these regions, and triggers TE-specific cytotoxic T cell responses in vivo. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses tumour-intrinsic immunogenicity, and thus represents a candidate target for immunotherapy.
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http://dx.doi.org/10.1038/s41586-021-03520-4DOI Listing
July 2021

Predicting COVID-19 Severity with a Specific Nucleocapsid Antibody plus Disease Risk Factor Score.

mSphere 2021 04 28;6(2). Epub 2021 Apr 28.

Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, California, USA

Effective methods for predicting COVID-19 disease trajectories are urgently needed. Here, enzyme-linked immunosorbent assay (ELISA) and coronavirus antigen microarray (COVAM) analysis mapped antibody epitopes in the plasma of COVID-19 patients ( = 86) experiencing a wide range of disease states. The experiments identified antibodies to a 21-residue epitope from nucleocapsid (termed Ep9) associated with severe disease, including admission to the intensive care unit (ICU), requirement for ventilators, or death. Importantly, anti-Ep9 antibodies can be detected within 6 days post-symptom onset and sometimes within 1 day. Furthermore, anti-Ep9 antibodies correlate with various comorbidities and hallmarks of immune hyperactivity. We introduce a simple-to-calculate, disease risk factor score to quantitate each patient's comorbidities and age. For patients with anti-Ep9 antibodies, scores above 3.0 predict more severe disease outcomes with a 13.42 likelihood ratio (96.7% specificity). The results lay the groundwork for a new type of COVID-19 prognostic to allow early identification and triage of high-risk patients. Such information could guide more effective therapeutic intervention. The COVID-19 pandemic has resulted in over two million deaths worldwide. Despite efforts to fight the virus, the disease continues to overwhelm hospitals with severely ill patients. Diagnosis of COVID-19 is readily accomplished through a multitude of reliable testing platforms; however, prognostic prediction remains elusive. To this end, we identified a short epitope from the SARS-CoV-2 nucleocapsid protein and also a disease risk factor score based upon comorbidities and age. The presence of antibodies specifically binding to this epitope plus a score cutoff can predict severe COVID-19 outcomes with 96.7% specificity.
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http://dx.doi.org/10.1128/mSphere.00203-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092137PMC
April 2021

VEGFR-1/Flt-1 inhibition increases angiogenesis and improves muscle function in a mouse model of Duchenne muscular dystrophy.

Mol Ther Methods Clin Dev 2021 Jun 23;21:369-381. Epub 2021 Mar 23.

Shire Human Genetic Therapies, a Takeda company, Lexington, MA, USA.

Duchenne muscular dystrophy is characterized by structural degeneration of muscle, which is exacerbated by localized functional ischemia due to loss of nitric oxide synthase-induced vasodilation. Treatment strategies aimed at increasing vascular perfusion have been proposed. Toward this end, we have developed monoclonal antibodies (mAbs) that bind to the vascular endothelial growth factor (VEGF) receptor VEGFR-1 (Flt-1) and its soluble splice variant isoform (sFlt-1) leading to increased levels of free VEGF and proangiogenic signaling. The lead chimeric mAb, 21B3, had high affinity and specificity for both human and mouse sFlt-1 and inhibited VEGF binding to sFlt-1 in a competitive manner. Proof-of-concept studies in the mouse model of Duchenne muscular dystrophy showed that intravenous administration of 21B3 led to elevated VEGF levels, increased vascularization and blood flow to muscles, and decreased fibrosis after 6-12 weeks of treatment. Greater muscle strength was also observed after 4 weeks of treatment. A humanized form of the mAb, 27H6, was engineered and demonstrated a comparable pharmacologic effect. Overall, administration of anti-Flt-1 mAbs in mice inhibited the VEGF:Flt-1 interaction, promoted angiogenesis, and improved muscle function. These studies suggest a potential therapeutic benefit of Flt-1 inhibition for patients with Duchenne muscular dystrophy.
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http://dx.doi.org/10.1016/j.omtm.2021.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055526PMC
June 2021

Immune-inflammatory markers and psychosis risk: A systematic review and meta-analysis.

Psychoneuroendocrinology 2021 May 13;127:105200. Epub 2021 Mar 13.

Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA, United States.

Subclinical inflammation has been associated with psychosis; however, it remains unknown whether this phenomenon appears also in the premorbid phase. Therefore, we performed a systematic review and meta-analysis of studies comparing peripheral blood levels of C-reactive protein (CRP) and cytokines between individuals at risk of psychosis and controls. Moreover, we tested the hypothesis that the levels of these markers may be different in high-risk converters versus non-converters. Two independent reviewers searched electronic databases until Dec 16th, 2020. After reviewing publication records, 16 studies (548 high-risk individuals and 559 controls) were included. Random-effects meta-analyses with Hedges' g as the effect size estimate were performed. Individuals at clinical risk of psychosis had significantly higher levels of interleukin-6 (IL-6) compared to controls (g = 0.33, 95%CI: 0.06-0.60, p = 0.018). Heterogeneity was not significant in this subgroup analysis. Changes in the levels of IL-6 in subjects at familial risk of psychosis were not significant (g = 0.04, 95%CI: -0.24 to 0.31, p = 0.798). The use of antidepressants was associated with significantly higher levels of IL-6 in high-risk individuals (Beta = 1.56, 95%CI: 0.60-2.53, p = 0.001). No significant differences in the levels of immune-inflammatory markers were found between high-risk converters and non-converters. Our findings suggest that individuals at clinical risk of psychosis show subclinical inflammation in terms of elevated IL-6 levels. This phenomenon might be related to the use of antidepressants. The present meta-analysis does not support the usefulness of single immune-inflammatory markers in predicting transition to psychosis.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105200DOI Listing
May 2021

Time to Revisit a Voluntary FDA Comparative Effectiveness Pathway.

Ther Innov Regul Sci 2021 07 10;55(4):643-645. Epub 2021 Feb 10.

Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Given the renewed policy focus on drug pricing and pharmaceutical innovation, this article examines the historical backdrop of efforts to integrate comparative effectiveness research into the FDA drug review process. Noting previous policy efforts over a decade ago, we characterize industry challenges and suggest a path forward.
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http://dx.doi.org/10.1007/s43441-021-00261-4DOI Listing
July 2021

Evaluation of scatter rejection and correction performance of 2D antiscatter grids in cone beam computed tomography.

Med Phys 2021 Apr 4;48(4):1846-1858. Epub 2021 Mar 4.

Department of Radiation Oncology, University of Colorado School of Medicine, 1665 Aurora Court, Suite 1032, Mail stop F-706, Aurora, CO, 80045, USA.

Purpose: We have been investigating two-dimensional (2D) antiscatter grids (2D ASGs) to reduce scatter fluence and improve image quality in cone beam computed tomography (CBCT). In this work, two different aspects of 2D ASGs, their scatter rejection and correction capability, were investigated in CBCT experiments. To correct residual scatter transmitted through the 2D ASG, it was used as a scatter measurement device with a novel method: grid-based scatter sampling.

Methods: Three focused 2D ASG prototypes with grid ratios of 8, 12, and 16 were developed for linac-mounted offset detector CBCT geometry. In the first phase, 2D ASGs were used as a scatter rejection device, and the effect of grid ratio on CT number accuracy and contrast-to-noise ratio (CNR) evaluated in CBCT images. In the second phase, a grid-based scatter sampling method which exploits the signal modulation characteristics of the 2D ASG's septal shadows to measure and correct residual scatter transmitted through the grid was implemented. To evaluate CT number accuracy, the percent change in CT numbers was measured by changing the phantom from head to pelvis size and configuration.

Results: When 2D ASG was used as a scatter rejection device, CT number accuracy increased and the CT number variation due to change in phantom dimensions was reduced from 23% to 2-6%. A grid ratio of 16 yielded the lowest CT number variation. All three 2D ASGs yielded improvement in CNR, up to a factor of two in pelvis-sized phantoms. When 2D ASG prototypes were used for both scatter rejection and correction, CT number variations were reduced further, to 1.3-2.6%. In comparisons with a clinical CBCT system and a high-performance radiographic ASG, 2D ASG provided higher CT number accuracy under the same imaging conditions.

Conclusions: When 2D ASG is used solely as a scatter rejection device, substantial improvement in CT number accuracy can be achieved by increasing the grid ratio. Two-dimensional ASGs also provided significant CNR improvement even at lower grid ratios. Two-dimensional ASGs used in conjunction with the grid-based scatter sampling method provided further improvement in CT number accuracy, irrespective of the grid ratio, while preserving 2D ASGs' capacity to improve CNR. The combined effect of scatter rejection and residual scatter correction by 2D ASG may accelerate implementation of new techniques in CBCT that require high quantitative accuracy, such as radiotherapy dose calculation and dual energy CBCT.
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http://dx.doi.org/10.1002/mp.14756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058321PMC
April 2021

An open access dataset for developing automated detectors of Antarctic baleen whale sounds and performance evaluation of two commonly used detectors.

Sci Rep 2021 01 12;11(1):806. Epub 2021 Jan 12.

Korea Polar Research Institute, Incheon, 21990, South Korea.

Since 2001, hundreds of thousands of hours of underwater acoustic recordings have been made throughout the Southern Ocean south of 60° S. Detailed analysis of the occurrence of marine mammal sounds in these circumpolar recordings could provide novel insights into their ecology, but manual inspection of the entirety of all recordings would be prohibitively time consuming and expensive. Automated signal processing methods have now developed to the point that they can be applied to these data in a cost-effective manner. However training and evaluating the efficacy of these automated signal processing methods still requires a representative annotated library of sounds to identify the true presence and absence of different sound types. This work presents such a library of annotated recordings for the purpose of training and evaluating automated detectors of Antarctic blue and fin whale calls. Creation of the library has focused on the annotation of a representative sample of recordings to ensure that automated algorithms can be developed and tested across a broad range of instruments, locations, environmental conditions, and years. To demonstrate the utility of the library, we characterise the performance of two automated detection algorithms that have been commonly used to detect stereotyped calls of blue and fin whales. The availability of this library will facilitate development of improved detectors for the acoustic presence of Southern Ocean blue and fin whales. It can also be expanded upon to facilitate standardization of subsequent analysis of spatiotemporal trends in call-density of these circumpolar species.
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http://dx.doi.org/10.1038/s41598-020-78995-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804014PMC
January 2021

Evaluating the Hypothesis That Schizophrenia Is an Inflammatory Disorder.

Focus (Am Psychiatr Publ) 2020 Oct 5;18(4):391-401. Epub 2020 Nov 5.

Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia (Miller); Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta (Goldsmith).

The investigation of immune system abnormalities in schizophrenia, although ongoing for decades, has become a popular area of research. The authors present a selected review of studies informing on schizophrenia as a potential inflammatory disorder, emphasizing replicated findings. The authors summarize evidence for inflammation over the illness course, discuss relationships between inflammation and psychopathology, present studies of imaging of neuroinflammation, consider inflammation as a marker of treatment response and treatment target, and review potential mechanisms for the effects of inflammation on the brain in schizophrenia. Although there is not clear and convincing evidence to support the assertion that schizophrenia is an inflammatory disorder, this area of study shows promise toward a greater understanding of the etiopathophysiology of this heterogeneous disorder.
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http://dx.doi.org/10.1176/appi.focus.20200015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725151PMC
October 2020

Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity.

Cell 2020 12 9;183(7):1848-1866.e26. Epub 2020 Dec 9.

Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Obesity is a major cancer risk factor, but how differences in systemic metabolism change the tumor microenvironment (TME) and impact anti-tumor immunity is not understood. Here, we demonstrate that high-fat diet (HFD)-induced obesity impairs CD8 T cell function in the murine TME, accelerating tumor growth. We generate a single-cell resolution atlas of cellular metabolism in the TME, detailing how it changes with diet-induced obesity. We find that tumor and CD8 T cells display distinct metabolic adaptations to obesity. Tumor cells increase fat uptake with HFD, whereas tumor-infiltrating CD8 T cells do not. These differential adaptations lead to altered fatty acid partitioning in HFD tumors, impairing CD8 T cell infiltration and function. Blocking metabolic reprogramming by tumor cells in obese mice improves anti-tumor immunity. Analysis of human cancers reveals similar transcriptional changes in CD8 T cell markers, suggesting interventions that exploit metabolism to improve cancer immunotherapy.
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http://dx.doi.org/10.1016/j.cell.2020.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064125PMC
December 2020

Longitudinal study of inflammatory markers and psychopathology in schizophrenia.

Schizophr Res 2020 10 22;224:58-66. Epub 2020 Oct 22.

Department of Psychiatry, Augusta University, Augusta, GA, United States. Electronic address:

Objective: Schizophrenia is associated with abnormal levels of blood inflammatory markers, which may be correlated with levels of psychopathology. Few previous studies have explored whether baseline inflammatory marker levels predict longitudinal changes in psychopathology. In the present study, we explored this association in a cohort of patients with schizophrenia.

Method: We investigated inflammatory markers and psychopathology after 3, 6, and 12 months of antipsychotic treatment for subjects with baseline and follow-up data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial. Linear regression models, controlling for multiple potential confounding factors, were used to investigate these associations.

Results: There was a significant decrease in monocyte, ICAM, and adiponectin levels between baseline and 12 months. Higher baseline blood interleukin-6 (IL-6) predicted greater reduction in PANSS total and general subscale scores at 3 and 6 months, and PANSS negative subscale scores at 3 months (β = -0.10 to -0.16, p < 0.05 for each). Higher baseline blood leptin levels predicted greater reduction in PANSS total, negative and general subscale scores at 6 months (β = -0.09 to -0.11, p < 0.05 for each). In post-hoc analyses, associations between baseline IL-6 levels and symptom reduction were strongest in patients treated with either ziprasidone or quetiapine. Changes in blood inflammatory markers were generally not associated with changes in psychopathology.

Conclusions: Our findings provide additional support that measuring blood inflammatory markers may be relevant to the clinical care of patients with schizophrenia. Specifically, these markers may help guide selection of antipsychotic treatment towards more personalized medicine approaches for patients with schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2020.10.003DOI Listing
October 2020

Longitudinal study of inflammatory markers and psychopathology in schizophrenia.

Schizophr Res 2020 10 22;224:58-66. Epub 2020 Oct 22.

Department of Psychiatry, Augusta University, Augusta, GA, United States. Electronic address:

Objective: Schizophrenia is associated with abnormal levels of blood inflammatory markers, which may be correlated with levels of psychopathology. Few previous studies have explored whether baseline inflammatory marker levels predict longitudinal changes in psychopathology. In the present study, we explored this association in a cohort of patients with schizophrenia.

Method: We investigated inflammatory markers and psychopathology after 3, 6, and 12 months of antipsychotic treatment for subjects with baseline and follow-up data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial. Linear regression models, controlling for multiple potential confounding factors, were used to investigate these associations.

Results: There was a significant decrease in monocyte, ICAM, and adiponectin levels between baseline and 12 months. Higher baseline blood interleukin-6 (IL-6) predicted greater reduction in PANSS total and general subscale scores at 3 and 6 months, and PANSS negative subscale scores at 3 months (β = -0.10 to -0.16, p < 0.05 for each). Higher baseline blood leptin levels predicted greater reduction in PANSS total, negative and general subscale scores at 6 months (β = -0.09 to -0.11, p < 0.05 for each). In post-hoc analyses, associations between baseline IL-6 levels and symptom reduction were strongest in patients treated with either ziprasidone or quetiapine. Changes in blood inflammatory markers were generally not associated with changes in psychopathology.

Conclusions: Our findings provide additional support that measuring blood inflammatory markers may be relevant to the clinical care of patients with schizophrenia. Specifically, these markers may help guide selection of antipsychotic treatment towards more personalized medicine approaches for patients with schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2020.10.003DOI Listing
October 2020

Computer-based inhibitory control training in children with Attention-Deficit/Hyperactivity Disorder (ADHD): Evidence for behavioral and neural impact.

PLoS One 2020 30;15(11):e0241352. Epub 2020 Nov 30.

Department of Psychology and Neuroscience, University of North Carolina, Chapel Hill, NC, United States of America.

Attention-deficit hyperactivity disorder (ADHD) is the most commonly diagnosed psychological disorder of childhood. Medication and cognitive behavioral therapy are effective treatments for many children; however, adherence to medication and therapy regimens is low. Thus, identifying effective adjunct treatments is imperative. Previous studies exploring computerized training programs as supplementary treatments have targeted working memory or attention. However, many lines of research suggest inhibitory control (IC) plays a central role in ADHD pathophysiology, which makes IC a potential intervention target. In this randomized control trial (NCT03363568), we target IC using a modified stop-signal task (SST) training designed by NeuroScouting, LLC in 40 children with ADHD, aged 8 to 11 years. Children were randomly assigned to adaptive treatment (n = 20) or non-adaptive control (n = 20) with identical stimuli and task goals. Children trained at home for at least 5 days a week (about 15m/day) for 4-weeks. Relative to the control group, the treatment group showed decreased relative theta power in resting EEG and trending improvements in parent ratings of attention (i.e. decreases in inattentive behaviors). Both groups showed improved SST performance. There was not evidence for treatment effects on hyperactivity or teacher ratings of symptoms. Results suggest training IC alone has potential to positively impact symptoms of ADHD and provide evidence for neural underpinnings of this impact (change in theta power; change in N200 latency). This shows promising initial results for the use of computerized training of IC in children with ADHD as a potential adjunct treatment option for children with ADHD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241352PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703966PMC
December 2020

Computer-based inhibitory control training in children with Attention-Deficit/Hyperactivity Disorder (ADHD): Evidence for behavioral and neural impact.

PLoS One 2020 30;15(11):e0241352. Epub 2020 Nov 30.

Department of Psychology and Neuroscience, University of North Carolina, Chapel Hill, NC, United States of America.

Attention-deficit hyperactivity disorder (ADHD) is the most commonly diagnosed psychological disorder of childhood. Medication and cognitive behavioral therapy are effective treatments for many children; however, adherence to medication and therapy regimens is low. Thus, identifying effective adjunct treatments is imperative. Previous studies exploring computerized training programs as supplementary treatments have targeted working memory or attention. However, many lines of research suggest inhibitory control (IC) plays a central role in ADHD pathophysiology, which makes IC a potential intervention target. In this randomized control trial (NCT03363568), we target IC using a modified stop-signal task (SST) training designed by NeuroScouting, LLC in 40 children with ADHD, aged 8 to 11 years. Children were randomly assigned to adaptive treatment (n = 20) or non-adaptive control (n = 20) with identical stimuli and task goals. Children trained at home for at least 5 days a week (about 15m/day) for 4-weeks. Relative to the control group, the treatment group showed decreased relative theta power in resting EEG and trending improvements in parent ratings of attention (i.e. decreases in inattentive behaviors). Both groups showed improved SST performance. There was not evidence for treatment effects on hyperactivity or teacher ratings of symptoms. Results suggest training IC alone has potential to positively impact symptoms of ADHD and provide evidence for neural underpinnings of this impact (change in theta power; change in N200 latency). This shows promising initial results for the use of computerized training of IC in children with ADHD as a potential adjunct treatment option for children with ADHD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241352PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703966PMC
December 2020

Preparatory immunity: Seasonality of mucosal skin defences and Batrachochytrium infections in Southern leopard frogs.

J Anim Ecol 2021 02 29;90(2):542-554. Epub 2020 Nov 29.

Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.

Accurately predicting the impacts of climate change on wildlife health requires a deeper understanding of seasonal rhythms in host-pathogen interactions. The amphibian pathogen, Batrachochytrium dendrobatidis (Bd), exhibits seasonality in incidence; however, the role that biological rhythms in host defences play in defining this pattern remains largely unknown. The aim of this study was to examine whether host immune and microbiome defences against Bd correspond with infection risk and seasonal fluctuations in temperature and humidity. Over the course of a year, five populations of Southern leopard frogs (Rana [Lithobates] sphenocephala) in Tennessee, United States, were surveyed for host immunity, microbiome and pathogen dynamics. Frogs were swabbed for pathogen load and skin bacterial diversity and stimulated to release stored antimicrobial peptides (AMPs). Secretions were analysed to estimate total hydrophobic peptide concentrations, presence of known AMPs and effectiveness of Bd growth inhibition in vitro. The diversity and proportion of bacterial reads with a 99% match to sequences of isolates known to inhibit Bd growth in vitro were used as an estimate of predicted anti-Bd function of the skin microbiome. Batrachochytrium dendrobatidis dynamics followed the expected seasonal fluctuations-peaks in cooler months-which coincided with when host mucosal defences were most potent against Bd. Specifically, the concentration and expression of stored AMPs cycled synchronously with Bd dynamics. Although microbiome changes followed more linear trends over time, the proportion of bacteria that can function to inhibit Bd growth was greatest when risk of Bd infection was highest. We interpret the increase in peptide storage in the fall and the shift to a more anti-Bd microbiome over winter as a preparatory response for subsequent infection risk during the colder periods when AMP synthesis and bacterial growth is slow and pathogen pressure from this cool-adapted fungus is high. Given that a decrease in stored AMP concentrations as temperatures warm in spring likely means greater secretion rates, the subsequent decrease in prevalence suggests seasonality of Bd in this host may be in part regulated by annual immune rhythms, and dominated by the effects of temperature.
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http://dx.doi.org/10.1111/1365-2656.13386DOI Listing
February 2021

Prenatal exposure to viral infection and neuropsychiatric disorders in offspring: A review of the literature and recommendations for the COVID-19 pandemic.

Brain Behav Immun 2021 01 3;91:756-770. Epub 2020 Nov 3.

Emory University School of Medicine, Atlanta, GA, USA; Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA. Electronic address:

The SARS-CoV-2 virus has emerged as a striking 21st century pandemic. Communities across the globe have experienced significant infection rates and widespread psychosocial stress and trauma, leading to calls for increased allocation of resources for mental health screening and treatment. In addition to the burden of psychosocial stress, there is increasing evidence of direct viral neuroinvasion of the central nervous system through physical contact with the nasal mucosa. In a parallel fashion, there is a significant body of ongoing research related to the risk of in utero viral transmission and the resulting neurodevelopmental impact in the fetus. Aberrant neurodevelopment secondary to viral transmission has previously been related to the later development of psychosis, schizophrenia, and schizophrenia spectrum disorders, generating the hypothesis that this population of individuals exposed to SARS-CoV-2 may see an increased incidence in future decades. We discuss the current understanding of the possible neurotropism and vertical transmission of SARS-CoV-2, and relate this to the history of viral pandemics to better understand the relationship of viral infection, aberrant immune response and neurodevelopment, and the risk for schizophrenia disorder.
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http://dx.doi.org/10.1016/j.bbi.2020.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759331PMC
January 2021

Acutely ill psychiatric inpatients and antimicrobial exposure.

Ann Clin Psychiatry 2020 11;32(4):229-238

Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA 30912 USA. E-MAIL:

Background: Patients with schizophrenia, bipolar disorder, and major depressive disorder (MDD) have increased infections. We explored the association between recent antimicrobial exposure and acute psychiatric illness.

Methods: We performed a retrospective chart review of 267 acutely ill patients age 18 to 65. There were 92 patients with schizophrenia, 42 with bipolar disorder, 61 with MDD, and 72 with alcohol use disorders (hospitalized controls). Recent antimicrobial exposure was defined as occurring within 3 days of psychiatric hospitalization.

Results: The prevalence of recent antimicrobial exposure was significantly increased in acutely ill patients with schizophrenia (16%), bipolar disorder (21%), and MDD (18%) compared with patients who had alcohol use disorders (4%, P ≤ .01 for each). After controlling for potential confounders, participants with schizophrenia or mood disorders were 5 to 7 times more likely to have recent antimicrobial exposure than participants with alcohol use disorders (schizophrenia: odds ratio [OR] = 4.5, 95% confidence interval [CI] 1.0-21.0, P = .053; bipolar disorder: OR = 6.9, 95% CI 1.3-35.7, P = .022; MDD: OR = 5.7, 95% CI 1.2-28.3, P = .032). Among participants with mood disorders, the association was stronger for participants with depression and affective psychosis compared with participants with alcohol use disorders.

Conclusions: We found an increased prevalence of recent antimicrobial exposure in acutely ill patients with schizophrenia and mood disorders. The findings provide additional evidence that infections are relevant to acute psychiatric illness.
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http://dx.doi.org/10.12788/acp.0002DOI Listing
November 2020

Antibody Response to a Nucleocapsid Epitope as a Marker for COVID-19 Disease Severity.

bioRxiv 2020 Oct 16. Epub 2020 Oct 16.

Characterization of antibody response to SARS-CoV-2 is urgently needed to predict COVID-19 disease trajectories. Ineffective antibodies or antibody-dependent enhancement (ADE) could derail patients' immune responses, for example. ELISA and coronavirus antigen microarray (COVAM) analysis epitope-mapped plasma from 86 COVID-19 patients. The experiments identified antibodies to a 21-residue epitope from nucleocapsid (termed Ep9) associated with severe disease, including ICU stay, requirement for ventilators, and death. Furthermore, anti-Ep9 antibodies correlate both with various comorbidities and ADE hallmarks, including increased IL-6 levels and early IgG response. Importantly, anti-Ep9 antibodies can be detected within five days post-symptom onset and sometimes within one day. The results lay the groundwork for a new type of COVID-19 diagnostic for the early prediction of disease severity to guide more effective therapeutic interventions.

One Sentence Summary: Antibodies targeting a specific location within a SARS-CoV-2 structural protein are linked to poor COVID-19 disease outcomes.
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http://dx.doi.org/10.1101/2020.10.15.341743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574261PMC
October 2020

Point-of-care ultrasound, anchoring bias, and acute pulmonary embolism: A cautionary tale and report.

Radiol Case Rep 2020 Dec 12;15(12):2617-2620. Epub 2020 Oct 12.

Lehigh Valley Health Network, Department of Emergency and Hospital Medicine/USF Morsani College of Medicine, Cedar Crest Boulevard & I-78, Allentown, PA 18103 USA.

Emergency physicians often rely on heuristics to facilitate clinical decisions due to the large volume of patients they see daily. Consequently, they are vulnerable to error and bias. We report the case of a 69-year-old male that presented to the emergency department (ED) with shortness of breath, productive cough, and dyspnea on exertion. One day prior to ED admission, he was diagnosed with bronchitis; however, point-of-care ultrasound (POCUS) in the ED identified acute pulmonary embolism. This case illustrates the potential dangers of anchoring bias and shows the benefits of using point-of-care ultrasound of the lungs and heart to assist in the diagnosis of acute pulmonary embolism.
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http://dx.doi.org/10.1016/j.radcr.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550182PMC
December 2020

Probing the 14-3-3 Isoform-Specificity Profile of Protein-Protein Interactions Stabilized by Fusicoccin A.

ACS Omega 2020 Oct 24;5(39):25029-25035. Epub 2020 Sep 24.

Department of Chemistry and Biochemistry, Florida State University, 95 Chieftan Way, Tallahassee, Florida 32306, United States.

Fusicoccin A (FC) is a fungal phytotoxin that stabilizes protein-protein interactions (PPIs) between 14-3-3 adapter proteins and their phosphoprotein interaction partners. Recently, FC has emerged as an important chemical probe of human 14-3-3 PPIs involved in cancer and neurobiology. These previous studies have established the structural requirements for FC-induced stabilization of 14-3-3·client phosphoprotein complexes; however, the effect of 14-3-3 isoforms on FC activity remains underexplored. This is a relevant question for the continued development of FC variants because there are seven isoforms of 14-3-3 in humans. Despite their sequence and structural similarities, a growing body of experimental evidence supports both tissue-specific expression of 14-3-3 isoforms and isoform-specific functions . Herein, we interrogate the isoform-specificity profile of FC using recombinant 14-3-3 isoforms and a library of fluorescein-labeled hexaphosphopeptides mimicking the C-terminal recognition domains of client proteins that are characterized targets of FC . Our results reveal modest isoform preferences for individual client phospholigands and demonstrate that FC differentially stabilizes PPIs involving 14-3-3σ. Together, these data support the feasibility of developing FC variants with enhanced isoform selectivity.
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http://dx.doi.org/10.1021/acsomega.0c01454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542595PMC
October 2020

Hospital Star Ratings and Sociodemographics: A Scoring System in Need of Revision.

J Hosp Med 2020 10;15(10):637-638

Johns Hopkins University School of Nursing, Baltimore, Maryland.

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http://dx.doi.org/10.12788/jhm.3420DOI Listing
October 2020

High-resolution, single-particle digital autoradiography of actinide sources using microcapillary array collimators and the iQID camera.

Appl Radiat Isot 2020 Dec 31;166:109348. Epub 2020 Jul 31.

Pacific Northwest National Laboratory, Richland, WA, USA.

Characterization of the homogeneity of thin actinide deposits prior to and after irradiation is important to ensure measurement of high-quality nuclear data in nuclear physics experiments. Autoradiography is frequently used to assess homogeneity, but geometric blur from source thickness, particle range, and source-detector gap can significantly degrade image resolution and introduce bias when estimating source uniformity and activity. We establish a method for minimizing geometric blur using a new autoradiography imaging technique with microcapillary array collimators and a new method to characterize the homogeneity of an imaged deposit. Also, we demonstrate that beta-/gamma-blind imaging is possible for alpha-particle autoradiography with ZnS:Ag scintillators and the ionizing-radiation quantum imaging detector (iQID), a digital autoradiography system with intrinsic spatial resolutions up to 20 μm for alphas. This iQID imaging approach can successfully discriminate alphas in the presence of a beta-gamma source in samples containing >10 dynamic range in activity. We apply this feature to characterize the uniformity of plutonium deposits before and after accelerator irradiation in the presence of a large beta-gamma background.
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http://dx.doi.org/10.1016/j.apradiso.2020.109348DOI Listing
December 2020

Affinity purification of human alpha galactosidase utilizing a novel small molecule biomimetic of alpha-D-galactose.

Protein Expr Purif 2021 01 16;177:105752. Epub 2020 Sep 16.

Takeda Pharmaceuticals, Cambridge, MA, 02142, USA.

Alpha galactosidase (a-Gal) is an acidic hydrolase that plays a critical role in hydrolyzing the terminal alpha-galactoyl moiety from glycolipids and glycoproteins. There are over a hundred mutations reported for the GLA gene that encodes a-Gal that result in reduced protein synthesis, protein instability, and reduction in function. The deficiencies of a-Gal can cause Fabry disease, a rare lysosomal storage disorder (LSD) caused by the failure to catabolize alpha-d-galactoyl glycolipid moieties. The current standard of care for Fabry disease is enzyme replacement therapy (ERT) where the purified recombinant form of human a-Gal is given to patients. The manufacture of a-Gal is currently performed utilizing traditional large-scale chromatography processes. Developing an affinity resin for the purification of a-Gal would reduce the complexity of the manufacturing process, reduce costs, and potentially produce a higher quality a-Gal. After the evaluation of many small molecules, a commercially available small molecule biomimetic, N-5-Carboxypentyl-1-deoxygalactonojirimycin (N5C-DGJ), was utilized for the development of a novel small molecule biomimetic affinity resin for a-Gal. Affinity purified a-Gal demonstrated a purity greater than 90%, exhibited expected thermal stability and specific activity. Complementing this affinity purification is the development of an elution buffer system that confers an increased thermal stability to a-Gal. The N5C-DGJ affinity resin tolerated sodium hydroxide sanitization with no loss of binding capacity, making it amenable to large scale purification processes and potential use in manufacturing. This novel method for purifying the challenging a-Gal enzyme can be extended to other enzyme replacement therapies.
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http://dx.doi.org/10.1016/j.pep.2020.105752DOI Listing
January 2021
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