Now showing items 1-20 of 2665

    • Management of Lung Nodules and Lung Cancer Screening During the COVID-19 Pandemic: CHEST Expert Panel Report

      Mazzone, P.J.; Gould, M.K.; White, C.S. (Elsevier Inc, 2020)
      Background: The risks from potential exposure to coronavirus disease 2019 (COVID-19), and resource reallocation that has occurred to combat the pandemic, have altered the balance of benefits and harms that informed current (pre-COVID-19) guideline recommendations for lung cancer screening and lung nodule evaluation. Consensus statements were developed to guide clinicians managing lung cancer screening programs and patients with lung nodules during the COVID-19 pandemic. Methods: An expert panel of 24 members, including pulmonologists (n = 17), thoracic radiologists (n = 5), and thoracic surgeons (n = 2), was formed. The panel was provided with an overview of current evidence, summarized by recent guidelines related to lung cancer screening and lung nodule evaluation. The panel was convened by video teleconference to discuss and then vote on statements related to 12 common clinical scenarios. A predefined threshold of 70% of panel members voting agree or strongly agree was used to determine if there was a consensus for each statement. Items that may influence decisions were listed as notes to be considered for each scenario. Results: Twelve statements related to baseline and annual lung cancer screening (n = 2), surveillance of a previously detected lung nodule (n = 5), evaluation of intermediate and high-risk lung nodules (n = 4), and management of clinical stage I non-small cell lung cancer (n = 1) were developed and modified. All 12 statements were confirmed as consensus statements according to the voting results. The consensus statements provide guidance about situations in which it was believed to be appropriate to delay screening, defer surveillance imaging of lung nodules, and minimize nonurgent interventions during the evaluation of lung nodules and stage I non-small cell lung cancer. Conclusions: There was consensus that during the COVID-19 pandemic, it is appropriate to defer enrollment in lung cancer screening and modify the evaluation of lung nodules due to the added risks from potential exposure and the need for resource reallocation. There are multiple local, regional, and patient-related factors that should be considered when applying these statements to individual patient care.
    • Cortical hyperactivation at low working memory load: A primary processing abnormality in people with schizophrenia?

      Hahn, B.; Robinson, B.M.; Gold, J.M. (Elsevier Inc., 2020)
      A frequent finding when studying substrates of working memory (WM) deficits in people with schizophrenia (PSZ) is task-induced hyperactivation relative to healthy control subjects (HCS) when WM load is low. Hyperactivation accompanying similar performance is commonly attributed to cognitive deficits rendering relatively easy operations more resource-consuming. To test if hyperactivation at low load really is secondary to cognitive impairment in PSZ, we re-analyzed functional MRI data showing left posterior parietal cortex (PPC) hyperactivation in PSZ when holding a single color-item in WM. In subgroups matched for the number of items successfully stored in WM (K) by excluding the highest-performing HCS and lowest-performing PSZ, performance was almost identical across all set sizes (1-7). While BOLD activation at the larger set sizes did not differ between groups, PSZ still robustly hyperactivated left PPC when a single item had to be maintained. The same pattern was observed in subgroups matched for model-based estimates of WM capacity or attentional lapse rate. Given that in the K-matched subsamples PSZ performed as well as HCS even in the most challenging load conditions and that no BOLD signal difference was seen at high loads, it is implausible that PSZ over-recruited WM-related neural structures because they were more challenged by maintaining a single item in WM. Instead, the findings are consistent with a primary schizophrenia-related processing abnormality as proposed by the hyperfocusing hypothesis, which suggests that an abnormally narrow but intense focusing of processing resources is central to many aspects of impaired cognition in PSZ. Copyright 2020 The Author(s)
    • Point supervised extended scenario nuclear analysis framework based on LSTM-CFCN

      Sui, D.; Guo, M.; Zhang, L. (Institute of Electrical and Electronics Engineers Inc., 2020)
      Cells and cell like particles detection and segmentation are of significant interest to many biological and clinical studies. Traditionally, these tasks are usually performed by visual inspection, which is time consuming, labor intensity and prone to induce subjective bias between different people. These make automatic cell analysis protocols essential for large-scale and objective studies. In recent years, imaging technical has been significantly advanced following the great success by computer vision. In addition, these technologies enable the cross module microscopy analysis, and make the task of cell analysis extremely challenging. Over these decades, computer aided cell detection, counting and segmentation have evolved from earlier filter based methods to the state-of-art deep learning protocols. However, there are still few suitable frameworks that can process multiple source cell images at the same time. In this paper, we seek a different route and propose a novel efficient framework for robust cell analysis based on Long Short Term Memory Channeled Fully Convolution Neural Networks (LSTM-CFCN). The results demonstrates that our framework is able to perform most of cell detection, counting and segmentation tasks from different cell type, and it can also cover most kinds of microscopy images scenarios including dark field, bright field, pathological and electron images. We have perform substantial experiments on several benchmark datasets, the LSTM-CFCN achieves the highest or at least top-2 performance in terms of F1-score, compared with other state-of-the-art methods.
    • Experimental study of the performance of a novel vertical-axiswind turbine

      Agbormbai, J.; Zhu, W. (MDPI AG, 2020)
      Basic equations for estimating the aerodynamic power captured by the Anderson vertical-axis wind turbine (AVAWT) are derived from a solution of Navier-Stokes (N-S) equations for a baroclinic inviscid flow. In a nutshell, the pressure difference across the AVAWT is derived from the Bernoulli's equation-an upshot of the integration of the Euler's momentum equation, which is the N-S momentum equation for a baroclinic inviscid flow. The resulting expression for the pressure difference across the AVAWT rotor is plotted as a function of the free-stream speed. Experimentally determined airstream speeds at the AVAWT inlet and outlet, coupled with corresponding free-stream speeds, are used in estimating the aerodynamic power captured. The aerodynamic power of the AVAWT is subsequently used in calculating its aerodynamic power coefficient. The actual power coefficient is calculated from the power generated by the AVAWT at various free-stream speeds and plotted as a function of the latter. Experimental results show that at all free-stream speeds and tip-speed ratios, the aerodynamic power coefficient of the AVAWT is higher than its actual power coefficient. Consequently, the power generated by the AVAWT prototype is lower than the aerodynamic power captured, given the same inflow wind conditions. Besides the foregoing, the main purpose of this experiment is to investigate the technical feasibility of the AVAWT. This proof of concept enables the inventor to commercialize the AVAWT. Copyright 2020 by the authors.
    • Immunotherapy and radiation therapy for gastrointestinal malignancies: Hope or hype?

      Badiyan, S.; Kaiser, A.; Eastman, B. (AME Publishing Company, 2020)
      Immunotherapy represents the newest pillar in cancer care. Although there are increasing data showing the efficacy of immunotherapy there is a spectrum of response across unselected populations of cancer patients. In fact, response rates can be poor even among patients with immunogenic tumors for reasons that remain poorly understood. A promising clinical strategy to improve outcomes, which is supported by an abundance of preclinical data, is combining immunotherapy with radiation therapy. Here we review the existing evidence and future directions for combining immunotherapy and radiation therapy for patients with gastrointestinal cancers.
    • Novel malaria antigen Plasmodium yoelii E140 induces antibody-mediated sterile protection in mice against malaria challenge

      Smith, E.C.; Limbach, K.J.; Sacci, J.B. Jr (Public Library of Science, 2020)
      Only a small fraction of the antigens expressed by malaria parasites have been evaluated as vaccine candidates. A successful malaria subunit vaccine will likely require multiple antigenic targets to achieve broad protection with high protective efficacy. Here we describe protective efficacy of a novel antigen, Plasmodium yoelii (Py) E140 (PyE140), evaluated against P. yoelii challenge of mice. Vaccines targeting PyE140 reproducibly induced up to 100% sterile protection in both inbred and outbred murine challenge models. Although PyE140 immunization induced high frequency and multifunctional CD8+ T cell responses, as well as CD4+ T cell responses, protection was mediated by PyE140 antibodies acting against blood stage parasites. Protection in mice was long-lasting with up to 100% sterile protection at twelve weeks post-immunization and durable high titer anti-PyE140 antibodies. The E140 antigen is expressed in all Plasmodium species, is highly conserved in both P. falciparum lab-adapted strains and endemic circulating parasites, and is thus a promising lead vaccine candidate for future evaluation against human malaria parasite species. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
    • Colorectal cancer and probiotics: Are bugs really drugs?

      Lamichhane, P.; Maiolini, M.; Lamichhane, N. (MDPI AG, 2020)
      Colorectal cancer (CRC) is one of the most common types of cancer worldwide. There are many factors that predispose a patient to the disease such as age, family history, ethnicity, and lifestyle. There are different genetic factors and diseases that also increase a person's risk for developing CRC. Studies have found associations between gut microbiome and the risk for developing versus protection against CRC. Normal gut microbiome aid in daily functions of the human body such as absorption, metabolism, detoxification, and regulation of inflammation. While some species of bacteria prevent CRC development and aid in therapeutic responses to various treatment regiments, other species seem to promote CRC pathogenesis. In this regard, many studies have been conducted to not only understand the biology behind these opposing different bacterial species; but also to determine if supplementation of these tumor opposing bacterial species as probiotics lends toward decreased risk of CRC development and improved therapeutic responses in patients with CRC. In this literature review, we aim to discuss the basics on colorectal cancer (epidemiology, risk factors, targets, treatments), discuss associations between different bacterial strains and CRC, and discuss probiotics and their roles in CRC prevention and treatment. Copyright 2020 by the authors.
    • Identification of Differentially Expressed Genes and Key Pathways in the Dorsal Root Ganglion After Chronic Compression

      Du, Z.; Jia, X.; Zhang, Y. (Frontiers Media S.A., 2020)
      Neuropathic pain (NP) is caused by primary or secondary impairment of the peripheral or central nervous systems. Its etiology is complex and involves abnormal patterns of gene expression and pathway activation. Using bioinformatics analysis, we aimed to identify NP-associated changes in genes and pathways in L4 and L5 dorsal root ganglia (DRG) in a rat model of NP induced by chronic compression of the DRG (CCD). Genome-wide transcriptional analyses were used to elucidate the molecular mechanisms underlying NP. We screened differentially expressed genes (DEGs) 7 days after CCD in comparison with sham-operated controls. Quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting were used to confirm the presence of key DEGs. Kyoto Encyclopedia of Genes and Genomes (KEGG)-pathway analysis of DEGs and global signal transduction network analysis of DEGs were also conducted. The CCD group developed clear mechanical and thermal allodynia in the ipsilateral hind paw compared with the sham group. This comparison identified 1,887 DEGs, with 1156 upregulated and 731 downregulated DEGs, and 123 DEG-enriched pathways. We identified the key candidate genes that might play a role in the development of NP, namely syndecan 1 (Sdc1), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma (Pi3k), Janus kinase 2 (Jak2), jun proto-oncogene, AP-1 transcription factor subunit (Jun), and interleukin 6 (IL-6) by analyzing the global signal transduction network. RT-qPCR and western blot analysis confirmed the microarray results. The DEGs Sdc1, Pi3k, Jak2, Jun, and IL-6, and the cytokine signaling pathway, the neuroactive ligand-receptor interaction, the toll-like receptor signaling pathway, and the PI3K-Akt signaling pathway may have decisive modulatory roles in both nerve regeneration and NP. These results provide deeper insight into the mechanism underlying NP and promising therapeutic targets for its treatment. Copyright 2020 The Authors
    • Multimodal Analysis of STRADA Function in Brain Development

      Iffland, II, P.H.; Barnes, A.E.; Baybis, M.; Crino, P.B. (Frontiers Media S.A., 2020)
      mTORopathies are a heterogeneous group of neurological disorders characterized by malformations of cortical development (MCD), enhanced cellular mechanistic target of rapamycin (mTOR) signaling, and epilepsy that results from mutations in mTOR pathway regulatory genes. Homozygous mutations (del exon 9–13) in the pseudokinase STE20-related kinase adaptor alpha (STRAD-α; STRADA), an mTOR modulator, are associated with Pretzel Syndrome (PS), a neurodevelopmental disorder within the Old Order Mennonite Community characterized by megalencephaly, intellectual disability, and intractable epilepsy. To study the cellular mechanisms of STRADA loss, we generated CRISPR-edited Strada mouse N2a cells, a germline mouse Strada knockout (KO−/−) strain, and induced pluripotent stem cell (iPSC)-derived neurons from PS individuals harboring the STRADA founder mutation. Strada KO in vitro leads to enhanced mTOR signaling and iPSC-derived neurons from PS individuals exhibit enhanced cell size and mTOR signaling activation, as well as subtle alterations in electrical firing properties e.g., increased input resistance, a more depolarized resting membrane potential, and decreased threshold for action potential (AP) generation. Strada−/− mice exhibit high rates of perinatal mortality and out of more than 100 litters yielding both WT and heterozygous pups, only eight Strada−/− animals survived past P5. Strada−/− mice are hypotonic and tremulous. Histopathological examination (n = 5 mice) revealed normal gross brain organization and lamination but all had ventriculomegaly. Ectopic neurons were seen in all five Strada−/− brains within the subcortical white matter mirroring what is observed in human PS brain tissue. These distinct experimental platforms demonstrate that STRADA modulates mTOR signaling and is a key regulator of cell size, neuronal excitability, and cortical lamination. Copyright 2020 The Authors.
    • Defensins: A Double-Edged Sword in Host Immunity

      Xu, D.; Lu, W. (Frontiers Media S.A., 2020)
      Defensins are a major family of host defense peptides expressed predominantly in neutrophils and epithelial cells. Their broad antimicrobial activities and multifaceted immunomodulatory functions have been extensively studied, cementing their role in innate immunity as a core host-protective component against bacterial, viral and fungal infections. More recent studies, however, paint defensins in a bad light such that they are "alleged" to promote viral and bacterial infections in certain biological settings. This mini review summarizes the latest findings on the potential pathogenic properties of defensins against the backdrop of their protective roles in antiviral and antibacterial immunity. Further, a succinct description of both tumor-proliferative and -suppressive activities of defensins is also given to highlight their functional and mechanistic complexity in antitumor immunity. We posit that given an enabling environment defensins, widely heralded as the "Swiss army knife," can function as a "double-edged sword" in host immunity. Copyright 2020 Xu and Lu.
    • Joy in Work for Clinicians and Staff: Identifying Remedial Predictors of Burnout from the Mini Z Survey

      Khanna, N.; Montgomery, R.; Klyushnenkova, E. (American Board of Family Medicine., 2020)
      PURPOSE: The CMS Transforming Clinical Practice Initiative (TCPI) provided coaching and learning support to practices during transition to new models of value-based care. Maryland ambulatory practices participated in the Garden Practice Transformation Network (GPTN) as a part of the TCPI. During practices assessment, we measured prevalence of burnout and identified its remediable predictors among GPTN-Maryland practices. METHODS: A modified Mini Z tool survey was distributed among clinicians and staff in November 2018 - July 2019. Association between presence of burnout and burnout drivers was assessed using a Generalized Estimating Equation regression model for ordinal outcome. RESULTS: Data from 166 responses were analyzed. Prevalence of burnout symptoms was 22%, with 35% enjoying their work. A 100-point Time Constraints/Teamwork (T/T) score was constructed using factors significantly associated with burnout symptoms. T/T score increase by 1 unit was associated with 10% increase in the odds of moving from the group experiencing burnout or stress to the group who found 'joy in work' (OR = 1.1, 95% CI 1.07, 1.13, p < 0.0001). CONCLUSIONS: The Mini Z-derived T/T score could be useful for quick assessment of the degree of burnout and identifying burnout drivers related to effective organizational structure and supportive teamwork in practice personnel.
    • Histone Demethylase JMJD1A Promotes Tumor Progression via Activating Snail in Prostate Cancer

      Fan, L.-L.; Geng, X.-Y.; Fu, D.-X.; Xu, S.-H. (American Association for Cancer Research., 2020)
      The histone demethylase JMJD1A plays a key functional role in spermatogenesis, sex determination, stem cell renewal, and cancer via removing mono- and di-methyl groups from H3K9 to epigenetically control gene expression. However, its role in prostate cancer progression remains unclear. Here, we found JMJD1A was significantly elevated in prostate cancer tissue compared with matched normal tissue. Ectopic JMJD1A expression in prostate cancer cells promoted proliferation, migration, and invasion in vitro, and tumorigenesis in vivo; JMJD1A knockdown exhibited the opposite effects. Mechanically, we revealed that JMJD1A directly interacted with the Snail gene promoter and regulated its transcriptional activity, promoting prostate cancer progression both in vitro and in vivo. Furthermore, we found that JMJD1A transcriptionally activated Snail expression via H3K9me1 and H3K9me2 demethylation at its special promoter region. In summary, our studies reveal JMJD1A plays an important role in regulating proliferation and progression of prostate cancer cells though Snail, and thus highlight JMJD1A as potential therapeutic target for advanced prostate cancer. IMPLICATIONS: Our studies identify that JMJD1A promotes the proliferation and progression of prostate cancer cells through enabling Snail transcriptional activation, and thus highlight JMJD1A as potential therapeutic target for advanced prostate cancer.
    • The Antimicrobial Peptide Human Beta-Defensin 2 Inhibits Biofilm Production of Pseudomonas aeruginosa Without Compromising Metabolic Activity

      Parducho, K.R.; Beadell, B.; Lu, W. (Frontiers Media S.A., 2020)
      Biofilm production is a key virulence factor that facilitates bacterial colonization on host surfaces and is regulated by complex pathways, including quorum sensing, that also control pigment production, among others. To limit colonization, epithelial cells, as part of the first line of defense, utilize a variety of antimicrobial peptides (AMPs) including defensins. Pore formation is the best investigated mechanism for the bactericidal activity of AMPs. Considering the induction of human beta-defensin 2 (HBD2) secretion to the epithelial surface in response to bacteria and the importance of biofilm in microbial infection, we hypothesized that HBD2 has biofilm inhibitory activity. We assessed the viability and biofilm formation of a pyorubin-producing Pseudomonas aeruginosa strain in the presence and absence of HBD2 in comparison to the highly bactericidal HBD3. At nanomolar concentrations, HBD2 - independent of its chiral state - significantly reduced biofilm formation but not metabolic activity, unlike HBD3, which reduced biofilm and metabolic activity to the same degree. A similar discrepancy between biofilm inhibition and maintenance of metabolic activity was also observed in HBD2 treated Acinetobacter baumannii, another Gram-negative bacterium. There was no evidence for HBD2 interference with the regulation of biofilm production. The expression of biofilm-related genes and the extracellular accumulation of pyorubin pigment, another quorum sensing controlled product, did not differ significantly between HBD2 treated and control bacteria, and in silico modeling did not support direct binding of HBD2 to quorum sensing molecules. However, alterations in the outer membrane protein profile accompanied by surface topology changes, documented by atomic force microscopy, was observed after HBD2 treatment. This suggests that HBD2 induces structural changes that interfere with the transport of biofilm precursors into the extracellular space. Taken together, these data support a novel mechanism of biofilm inhibition by nanomolar concentrations of HBD2 that is independent of biofilm regulatory pathways. Copyright 2020 The Autors.
    • Using Administrative Data to Predict Suicide After Psychiatric Hospitalization in the Veterans Health Administration System

      Kessler, R.C.; Bauer, M.S.; Kreyenbuhl, J. (Frontiers Media S.A., 2020)
      There is a very high suicide rate in the year after psychiatric hospital discharge. Intensive postdischarge case management programs can address this problem but are not cost-effective for all patients. This issue can be addressed by developing a risk model to predict which inpatients might need such a program. We developed such a model for the 391,018 short-term psychiatric hospital admissions of US veterans in Veterans Health Administration (VHA) hospitals 2010-2013. Records were linked with the National Death Index to determine suicide within 12 months of hospital discharge (n=771). The Super Learner ensemble machine learning method was used to predict these suicides for time horizon between 1 week and 12 months after discharge in a 70% training sample. Accuracy was validated in the remaining 30% holdout sample. Predictors included VHA administrative variables and small area geocode data linked to patient home addresses. The models had AUC=.79-.82 for time horizons between 1 week and 6 months and AUC=.74 for 12 months. An analysis of operating characteristics showed that 22.4%-32.2% of patients who died by suicide would have been reached if intensive case management was provided to the 5% of patients with highest predicted suicide risk. Positive predictive value (PPV) at this higher threshold ranged from 1.2% over 12 months to 3.8% per case manager year over 1 week. Focusing on the low end of the risk spectrum, the 40% of patients classified as having lowest risk account for 0%-9.7% of suicides across time horizons. Variable importance analysis shows that 51.1% of model performance is due to psychopathological risk factors accounted, 26.2% to social determinants of health, 14.8% to prior history of suicidal behaviors, and 6.6% to physical disorders. The paper closes with a discussion of next steps in refining the model and prospects for developing a parallel precision treatment model. Copyright 2020 Kessler, et. al.
    • Complexity and ultrastructure of infectious extracellular vesicles from cells infected by non-enveloped virus

      Yang, J.E.; Winbigler, H.; Jackson, W.T. (Nature Research, 2020)
      Enteroviruses support cell-to-cell viral transmission prior to their canonical lytic spread of virus. Poliovirus (PV), a prototype for human pathogenic positive-sense RNA enteroviruses, and picornaviruses in general, transport multiple virions en bloc via infectious extracellular vesicles, 100~1000 nm in diameter, secreted from host cells. Using biochemical and biophysical methods we identify multiple components in secreted microvesicles, including mature PV virions; positive-sense genomic and negative-sense replicative, template viral RNA; essential viral replication proteins; and cellular proteins. Using cryo-electron tomography, we visualize the near-native three-dimensional architecture of secreted infectious microvesicles containing both virions and a unique morphological component that we describe as a mat-like structure. While the composition of these mat-like structures is not yet known, based on our biochemical data they are expected to be comprised of unencapsidated RNA and proteins. In addition to infectious microvesicles, CD9-positive exosomes released from PV-infected cells are also infectious and transport virions. Thus, our data show that, prior to cell lysis, non-enveloped viruses are secreted within infectious vesicles that also transport viral unencapsidated RNAs, viral and host proteins. Understanding the structure and function of these infectious particles helps elucidate the mechanism by which extracellular vesicles contribute to the spread of non-enveloped virus infection. Copyright 2020, The Author(s).
    • Consumer sleep technology: accuracy and impact on behavior among healthy individuals

      Khosla, S.; Wickwire, E.M. (The American Academy of Sleep Medicine, 2020)
    • Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

      Montasser, M.E.; O'Connell, J.R.; Ryan, K.; Shuldiner, A.R. (Nature Research, 2020)
    • Correlations of Calf Muscle Macrophage Content With Muscle Properties and Walking Performance in Peripheral Artery Disease

      Kosmac, K.; Gonzalez-Freire, M.; Guralnik, J.M. (Wiley-Blackwell, 2020)
      Background Peripheral artery disease (PAD) is a manifestation of atherosclerosis characterized by reduced blood flow to the lower extremities and mobility loss. Preliminary evidence suggests PAD damages skeletal muscle, resulting in muscle impairments that contribute to functional decline. We sought to determine whether PAD is associated with an altered macrophage profile in gastrocnemius muscles and whether muscle macrophage populations are associated with impaired muscle phenotype and walking performance in patients with PAD. Methods and Results Macrophages, satellite cells, and extracellular matrix in gastrocnemius muscles from 25 patients with PAD and 7 patients without PAD were quantified using immunohistochemistry. Among patients with PAD, both the absolute number and percentage of cluster of differentiation (CD) 11b+CD206+ M2-like macrophages positively correlated to satellite cell number (r=0.461 [P=0.023] and r=0.416 [P=0.042], respectively) but not capillary density or extracellular matrix. The number of CD11b+CD206- macrophages negatively correlated to 4-meter walk tests at normal (r=-0.447, P=0.036) and fast pace (r=-0.510, P=0.014). Extracellular matrix occupied more muscle area in PAD compared with non-PAD (8.72±2.19% versus 5.30±1.03%, P<0.001) and positively correlated with capillary density (r=0.656, P<0.001). Conclusions Among people with PAD, higher CD206+ M2-like macrophage abundance was associated with greater satellite cell numbers and muscle fiber size. Lower CD206- macrophage abundance was associated with better walking performance. Further study is needed to determine whether CD206+ macrophages are associated with ongoing reparative processes enabling skeletal muscle adaptation to damage with PAD. Registration URL: https://www.clini?caltr?; Unique identifiers: NCT00693940, NCT01408901, NCT0224660.