Showing papers by "Loma Linda University published in 2021"
Fred Hutchinson Cancer Research Center1, Stanford University2, University of Cincinnati3, Vanderbilt University Medical Center4, Vanderbilt University5, Harvard University6, Broad Institute7, University of Lausanne8, University of Hawaii9, University of Colorado Denver10, Thomas Jefferson University11, Mayo Clinic12, Loyola University Medical Center13, Houston Methodist Hospital14, Emory University15, Beth Israel Deaconess Medical Center16, University of Florida17, McGill University Health Centre18, University of California, San Diego19, Case Western Reserve University20, St. Elizabeth Healthcare21, Icahn School of Medicine at Mount Sinai22, University of Kentucky23, Brown University24, Tufts Medical Center25, University of Michigan26, Henry Ford Health System27, Intermountain Healthcare28, George Washington University29, Cleveland Clinic30, Duke University31, Montefiore Medical Center32, Columbia University33, University of Connecticut34, Mount Auburn Hospital35, University of Kansas36, University of California, San Francisco37, Baylor College of Medicine38, Cancer Treatment Centers of America39, Ohio State University40, Penn State Cancer Institute41, University of Texas Health Science Center at San Antonio42, Loma Linda University43, University of California, Davis44, Medical University of South Carolina45, University of North Carolina at Chapel Hill46, Rutgers University47, Washington University in St. Louis48, LSU Health Sciences Center New Orleans49, University of Miami50
TL;DR: In this article, the authors analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies.
185 citations
TL;DR: In this paper, the authors applied both human monoclonal anti-SARS-Cov-2 antibodies (spike protein, nucleoprotein) and rabbit polyclonal SARS-CoV-2 antibody (envelope protein, membrane protein) to 55 different tissue antigens.
Abstract: We sought to determine whether immune reactivity occurs between anti-SARS-CoV-2 protein antibodies and human tissue antigens, and whether molecular mimicry between COVID-19 viral proteins and human tissues could be the cause. We applied both human monoclonal anti-SARS-Cov-2 antibodies (spike protein, nucleoprotein) and rabbit polyclonal anti-SARS-Cov-2 antibodies (envelope protein, membrane protein) to 55 different tissue antigens. We found that SARS-CoV-2 antibodies had reactions with 28 out of 55 tissue antigens, representing a diversity of tissue groups that included barrier proteins, gastrointestinal, thyroid and neural tissues, and more. We also did selective epitope mapping using BLAST and showed similarities and homology between spike, nucleoprotein, and many other SARS-CoV-2 proteins with the human tissue antigens mitochondria M2, F-actin and TPO. This extensive immune cross-reactivity between SARS-CoV-2 antibodies and different antigen groups may play a role in the multi-system disease process of COVID-19, influence the severity of the disease, precipitate the onset of autoimmunity in susceptible subgroups, and potentially exacerbate autoimmunity in subjects that have pre-existing autoimmune diseases. Very recently, human monoclonal antibodies were approved for use on patients with COVID-19. The human monoclonal antibodies used in this study are almost identical with these approved antibodies. Thus, our results can establish the potential risk for autoimmunity and multi-system disorders with COVID-19 that may come from cross-reactivity between our own human tissues and this dreaded virus, and thus ensure that the badly-needed vaccines and treatments being developed for it are truly safe to use against this disease.
183 citations
TL;DR: In this article, the authors used single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics to identify a signature in multisystem inflammatory syndrome in children (MIS-C) patients that correlated with disease severity.
123 citations
TL;DR: In this article, the authors characterized the TCR repertoire of multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, and found a profound expansion of TCRβ variable gene 11-2, with up to 24% of clonal T cell space occupied by TRBV11-2 T cells, which correlated with MIS-C severity and serum cytokine levels.
Abstract: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. Superantigen specificity for different Vβ chains results in Vβ skewing, whereby T cells with specific Vβ chains and diverse antigen specificity are overrepresented in the T cell receptor (TCR) repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCRβ variable gene 11-2 (TRBV11-2), with up to 24% of clonal T cell space occupied by TRBV11-2 T cells, which correlated with MIS-C severity and serum cytokine levels. Analysis of TRBJ gene usage and complementarity-determining region 3 (CDR3) length distribution of MIS-C expanded TRBV11-2 clones revealed extensive junctional diversity. Patients with TRBV11-2 expansion shared HLA class I alleles A02, B35, and C04, indicating what we believe is a novel mechanism for CDR3-independent T cell expansion. In silico modeling indicated that polyacidic residues in the Vβ chain encoded by TRBV11-2 (Vβ21.3) strongly interact with the superantigen-like motif of SARS-CoV-2 spike glycoprotein, suggesting that unprocessed SARS-CoV-2 spike may directly mediate TRBV11-2 expansion. Overall, our data indicate that a CDR3-independent interaction between SARS-CoV-2 spike and TCR leads to T cell expansion and possibly activation, which may account for the clinical presentation of MIS-C.
114 citations
TL;DR: In this article, the authors used proteomics, RNA sequencing, autoantibody arrays, and B cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission.
Abstract: Multisystem inflammatory syndrome in children (MIS-C) manifests as a severe and uncontrolled inflammatory response with multiorgan involvement, occurring weeks after SARS-CoV-2 infection. Here, we utilized proteomics, RNA sequencing, autoantibody arrays, and B cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission. Inflammation markers, humoral immune responses, neutrophil activation, and complement and coagulation pathways were highly enriched in MIS-C patient serum, with a more hyperinflammatory profile in severe than in mild MIS-C cases. We identified a strong autoimmune signature in MIS-C, with autoantibodies targeted to both ubiquitously expressed and tissue-specific antigens, suggesting autoantigen release and excessive antigenic drive may result from systemic tissue damage. We further identified a cluster of patients with enhanced neutrophil responses as well as high anti-Spike IgG and autoantibody titers. BCR sequencing of these patients identified a strong imprint of antigenic drive with substantial BCR sequence connectivity and usage of autoimmunity-associated immunoglobulin heavy chain variable region (IGHV) genes. This cluster was linked to a TRBV11-2 expanded T cell receptor (TCR) repertoire, consistent with previous studies indicating a superantigen-driven pathogenic process. Overall, we identify a combination of pathogenic pathways that culminate in MIS-C and may inform treatment.
89 citations
TL;DR: Wang et al. as mentioned in this paper performed a systemic review and meta-analysis to evaluate the prevalence and the duration of shedding of fecal RNA in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection in the gastrointestinal tract and likely infectivity.
Abstract: INTRODUCTION: The prevalence and shedding of fecal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA indicate coronavirus disease 2019 (COVID-19) infection in the gastrointestinal (GI) tract and likely infectivity. We performed a systemic review and meta-analysis to evaluate the prevalence and the duration of shedding of fecal RNA in patients with COVID-19 infection. METHODS: PubMed, Embase, Web of Science, and Chinese databases Chinese National Knowledge Infrastructure and Wanfang Data up to June 2020 were searched for studies evaluating fecal SARS-CoV-2 RNA, including anal and rectal samples, in patients with confirmed COVID-19 infection. The pooled prevalence of fecal RNA in patients with detectable respiratory RNA was estimated. The days of shedding and days to loss of fecal and respiratory RNA from presentation were compared. RESULTS: Thirty-five studies (N = 1,636) met criteria. The pooled prevalence of fecal RNA in COVID-19 patients was 43% (95% confidence interval [CI] 34%-52%). Higher proportion of patients with GI symptoms (52.4% vs 25.9%, odds ratio = 2.4, 95% CI 1.2-4.7) compared with no GI symptoms, specifically diarrhea (51.6% vs 24.0%, odds ratio = 3.0, 95% CI 1.9-4.8), had detectable fecal RNA. After loss of respiratory RNA, 27% (95% CI 15%-44%) of the patients had persistent shedding of fecal RNA. Days of RNA shedding in the feces were longer than respiratory samples (21.8 vs 14.7 days, mean difference = 7.1 days, 95% CI 1.2-13.0). Furthermore, days to loss of fecal RNA lagged respiratory RNA by a mean of 4.8 days (95% CI 2.2-7.5). DISCUSSION: Fecal SARS-CoV-2 RNA is commonly detected in COVID-19 patients with a 3-fold increased risk with diarrhea. Shedding of fecal RNA lasted more than 3 weeks after presentation and a week after last detectable respiratory RNA.
87 citations
TL;DR: In this article, the first-in-human results using 177Lu-FAP-2286 for peptide-targeted radionuclide therapy (PTRT) were presented.
Abstract: Fibroblast activation protein (FAP) is a promising target for diagnosis and therapy of numerous malignant tumors. FAP-2286 is the conjugate of a FAP-binding peptide, which can be labeled with radionuclides for theranostic applications. We present the first-in-human results using 177Lu-FAP-2286 for peptide-targeted radionuclide therapy (PTRT).
Methods: PTRT using 177Lu-FAP-2286 was performed in 11 patients with advanced adenocarcinomas of pancreas, breast, rectum and ovary after prior confirmation of uptake on 68Ga-FAP-2286/-FAPI-04- PET/CT.
Results: Administration of 177Lu-FAP-2286 (5.8 ± 2.0 GBq; range, 2.4–9.9 GBq) was well tolerated, with no adverse symptoms or clinically detectable pharmacologic effects being noticed or reported in any of the patients. The whole-body effective doses were 0.07 ± 0.02 Gy/GBq (range 0.04 – 0.1). The mean absorbed doses for kidneys and red marrow were 1.0 ± 0.6 Gy/GBq (range 0.4 – 2.0) and 0.05 ± 0.02 Gy/GBq (range 0.03 – 0.09), respectively. Significant uptake and long tumor retention of 177Lu-FAP-2286 resulted in high absorbed tumor doses, e.g., 3.0 ± 2.7 Gy/GBq (range 0.5 – 10.6) in bone metastases. No grade (G) 4 adverse events were observed. G3 events occurred in 3 patients – 1 pancytopenia, 1 leukocytopenia and 1 pain flare-up; 3 patients reported pain-response.
Conclusion:177Lu-FAP-2286 PTRT, applied in a broad spectrum of cancers, was relatively well-tolerated with acceptable side effects and demonstrated long retention of the radiopeptide. Prospective clinical studies are warranted.
80 citations
University of Ibadan1, Monash University2, University of Melbourne3, Universidade Federal do Rio Grande do Sul4, Loma Linda University5, Cairo University6, University College Hospital, Ibadan7, Menzies Research Institute8, University of Washington9, Masaryk University10, Lund University11, Danube University Krems12, Auckland University of Technology13
TL;DR: In this paper, the authors provide an overview of the current situation regarding primary prevention services, estimate the cost of stroke and stroke prevention, and identify deficiencies in existing guidelines and gaps in primary prevention.
Abstract: Stroke is the second leading cause of death and the third leading cause of disability worldwide and its burden is increasing rapidly in low-income and middle-income countries, many of which are unable to face the challenges it imposes. In this Health Policy paper on primary stroke prevention, we provide an overview of the current situation regarding primary prevention services, estimate the cost of stroke and stroke prevention, and identify deficiencies in existing guidelines and gaps in primary prevention. We also offer a set of pragmatic solutions for implementation of primary stroke prevention, with an emphasis on the role of governments and population-wide strategies, including task-shifting and sharing and health system re-engineering. Implementation of primary stroke prevention involves patients, health professionals, funders, policy makers, implementation partners, and the entire population along the life course.
71 citations
68 citations
Harvard University1, Stanford University2, Geisinger Medical Center3, University of Wisconsin-Madison4, University of Minnesota5, Grady Memorial Hospital6, Anschutz Medical Campus7, Veterans Health Administration8, Brigham and Women's Hospital9, Loma Linda University10, University of California, Riverside11, University of California, Davis12, Cornell University13, Duke University14
TL;DR: A systematic review from members of the American Contact Dermatitis Society highlights cases of occupational dermatitis to facial protective equipment including potential offending allergens to help in the diagnosis and treatment of healthcare workers with facial occupational dermatopathy.
Abstract: Background Prolonged wear of facial protective equipment can lead to occupational dermatoses. Objective To identify important causes of occupational dermatoses from facial protective equipment. Methods A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed using PubMed and Embase databases. Articles were included if they reported occupational dermatoses caused by surgical/procedure masks or N95 respirators, or both. Results We identified 344 articles, and 16 were suitable for inclusion in this review. Selected articles focused on facial occupational dermatoses in health care workers. Allergic contact dermatitis to the elastic straps, glue, and formaldehyde released from the mask fabric was reported. Irritant contact dermatitis was common on the cheeks and nasal bridge due to pressure and friction. Irritant dermatitis was associated with personal history of atopic dermatitis and prolonged mask wear (>6 hours). Acneiform eruption was reported due to prolonged wear and occlusion. Contact urticaria was rare. Limitations Only publications listed in PubMed or Embase were included. Most publications were case reports and retrospective studies. Conclusion This systematic review from members of the American Contact Dermatitis Society highlights cases of occupational dermatitis to facial protective equipment, including potential offending allergens. This work may help in the diagnosis and treatment of health care workers with facial occupational dermatitis.
66 citations
University of California, Irvine1, University of Southern California2, Cedars-Sinai Medical Center3, University of California, Los Angeles4, Loma Linda University5, University Health System6, University of California, San Diego7, Sharp Memorial Hospital8, Scripps Health9, Santa Barbara Cottage Hospital10
TL;DR: In this article, a multicenter retrospective analysis of all trauma patients presenting to 11 American College of Surgeons levels I and II trauma centers spanning seven counties in California was performed, and the authors hypothesized an increase in rates of penetrating trauma, gunshot wounds, suicide attempts, and domestic violence in the Southern California trauma population after the COVID-19 pandemic.
Abstract: BACKGROUND: The COVID-19 pandemic resulted in a statewide stay-at-home (SAH) order in California beginning March 19, 2020, forcing large-scale behavioral changes and taking an emotional and economic toll. The effects of SAH orders on the trauma population remain unknown. We hypothesized an increase in rates of penetrating trauma, gunshot wounds, suicide attempts, and domestic violence in the Southern California trauma population after the SAH order. METHODS: A multicenter retrospective analysis of all trauma patients presenting to 11 American College of Surgeons levels I and II trauma centers spanning seven counties in California was performed. Demographic data, injury characteristics, clinical data, and outcomes were collected. Patients were divided into three groups based on injury date: before SAH from January 1, 2020, to March 18, 2020 (PRE), after SAH from March 19, 2020, to June 30, 2020 (POST), and a historical control from March 19, 2019, to June 30, 2019 (CONTROL). POST was compared with both PRE and CONTROL in two separate analyses. RESULTS: Across all periods, 20,448 trauma patients were identified (CONTROL, 7,707; PRE, 6,022; POST, 6,719). POST had a significantly increased rate of penetrating trauma (13.0% vs. 10.3%, p < 0.001 and 13.0% vs. 9.9%, p < 0.001) and gunshot wounds (4.5% vs. 2.4%, p = 0.002 and 4.5% vs. 3.7%, p = 0.025) compared with PRE and CONTROL, respectively. POST had a suicide attempt rate of 1.9% and a domestic violence rate of 0.7%, which were similar to PRE (p = 0.478, p = 0.514) and CONTROL (p = 0.160, p = 0.618). CONCLUSION: This multicenter Southern California study demonstrated an increased rate of penetrating trauma and gunshot wounds after the COVID-19 SAH orders but no difference in attempted suicide or domestic violence rates. These findings may provide useful information regarding resource utilization and a target for societal intervention during the current or future pandemic(s). LEVEL OF EVIDENCE: Epidemiological, level IV.
National Institutes of Health1, University of Washington2, Seattle Children's3, Seattle Children's Research Institute4, University of California, San Diego5, Boston Children's Hospital6, University of Utah7, University of Hong Kong8, Loma Linda University9, University of Missouri–Kansas City10, University of California, Berkeley11, Dartmouth–Hitchcock Medical Center12, University of Minnesota13, Rutgers University14, Manipal University15, University of California, Los Angeles16, Dupont Hospital17, Alberta Children's Hospital18, University of Pennsylvania19, Children's National Medical Center20, Keio University21, University of Oklahoma22, McMaster University23, GeneDx24, Michigan State University25, University of California, San Francisco26, St. George's University27, University of Tennessee28, Stanford University29, University of Melbourne30, Harvard University31, University of Oklahoma Health Sciences Center32, Indiana University33, Children's Hospital of Philadelphia34, University of Arkansas for Medical Sciences35
TL;DR: In this paper, the authors formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype.
Abstract: The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.
TL;DR: Computational molecular docking approach and virtual screening identified some promising candidate SARS-CoV-2 drugs that may be considered for further clinical studies.
Abstract: The pandemic of novel coronavirus disease 2019 (COVID-19) is rampaging the world with more than 1 4 million of confirmed cases and more than 85,000 of deaths across world by April 9th, 2020 There is an urgent need to identify effective drugs to fight against the virus Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to the family of coronaviruses consisting of four structural and 16 non-structured proteins Three non-structural proteins such as main protease, papain like protease, and RNA-dependent RNA polymerase are believed to play a crucial role in the virus replication We applied a computational ligand-receptor binding modeling and performed a comprehensive virtual screening on the FDA-approved drugs against these three SARS-CoV-2 proteins using AutoDock Vina Our computational studies indicated that Simeprevir, Ledipasvir, Idarubicin, Saquinavir, Ledipasivir, Partitaprevir, Glecaprevir, and Velpatasvir are all promising inhibitors, which displayed a lower binding energy (higher inhibitory effect) than Remdesivir, Lopinavir, and Ritonavir However, we found that chloroquine and hydroxychloroquine, which showed efficacy in treating the COVID-19 in recent clinical studies, had high binding energy with all three proteins, suggesting they may work through a different mechanism We also identified several novel drugs as potential inhibitors against SARS-CoV-2, including antiviral Raltegravir;antidiabetic Amaryl;antibiotics Retapamulin, Rifimixin, and Rifabutin;antiemetic Fosaprepitant and Netupitant In summary, our computational molecular docking approach and virtual screening identified some promising candidate SARS-CoV-2 drugs that may be considered for further clinical studies
TL;DR: The COVIDPoops19 dashboard as discussed by the authors was developed to disseminate information regarding sites, universities, research institutions and private laboratories in countries involved in WBE for SARS-CoV-2.
Abstract: A year since the declaration of the global coronavirus disease 2019 (COVID-19) pandemic there have been over 110 million cases and 2.5 million deaths. Using methods to track community spread of other viruses such as poliovirus, environmental virologists and those in the wastewater based epidemiology (WBE) field quickly adapted their existing methods to detect SARS-CoV-2 RNA in wastewater. Unlike COVID-19 case and mortality data, there was not a global dashboard to track wastewater monitoring of SARS-CoV-2 RNA worldwide. This study describes the development of the "COVIDPoops19" dashboard to disseminate information regarding sites, universities, research institutions and private laboratories in countries that are involved in WBE for SARS-CoV-2. Methods to assemble the dashboard combined standard literature review, direct submissions, and daily, social media keyword searches. Over 200 universities, 1,000 sites, and 50 countries with 59 dashboards monitor wastewater for SARS-CoV-2 RNA. However, monitoring is inequitably distributed in high-income countries and data are not widely shared publicly or accessible to researchers to inform public health actions, meta-analysis, better coordinate, and determine equitable distribution of monitoring sites. For WBE to be used to its full potential during COVID-19 and beyond, show us the data.
Medical University of South Carolina1, Emory University2, Vanderbilt University Medical Center3, Grady Memorial Hospital4, Michigan State University5, Saint Louis University6, University of Calgary7, The Ohio State University Wexner Medical Center8, Loma Linda University9, University of Southern California10, Washington University in St. Louis11, University of Miami12, University of Pittsburgh13, Anschutz Medical Campus14, Wake Forest University15, Boston Medical Center16, Beaumont Health17, Oakland University18, University Hospitals of Cleveland19, Northwestern University20, Columbia University Medical Center21, Indiana University22, Loyola University Medical Center23, Icahn School of Medicine at Mount Sinai24, Memorial Sloan Kettering Cancer Center25, Stony Brook University26, University of Virginia27, Henry Ford Health System28, Dartmouth College29, Veterans Health Administration30, University of Oklahoma Health Sciences Center31, University of California, Los Angeles32, Medical College of Wisconsin33, Johns Hopkins University34, McMaster University35, University of Manitoba36, University of Michigan37
TL;DR: Among patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common but the majority were mild and their presence was not associated with a more severe clinical course.
TL;DR: Int-777 attenuated NLRP3-ASC inflammasome-dependent neuroinflammation in the EBI after SAH, partially via TGR5/cAMP/PKA signaling pathway, and may serve as a potential therapeutic strategy for EBI management in the setting of SAH.
Abstract: Background Inflammasome-mediated neuroinflammation plays an important role in the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH). The activation of the TGR5 receptor has been shown to be neuroprotective in a variety of neurological diseases. This study aimed to investigate the effects of the specific synthetic TGR5 agonist, INT-777, in attenuating NLRP3-ASC inflammasome activation and reducing neuroinflammation after SAH. Methods One hundred and eighty-four male Sprague Dawley rats were used. SAH was induced by the endovascular perforation. INT-777 was administered intranasally at 1 h after SAH induction. To elucidate the signaling pathway involved in the effect of INT-777 on inflammasome activation during EBI, TGR5 knockout CRISPR and PKA inhibitor H89 were administered intracerebroventricularly and intraperitoneally at 48 h and 1 h before SAH. The SAH grade, short- and long-term neurobehavioral assessments, brain water content, western blot, immunofluorescence staining, and Nissl staining were performed. Results The expressions of endogenous TGR5, p-PKA, and NLRP3-ASC inflammasome were increased after SAH. INT-777 administration significantly decreased NLRP3-ASC inflammasome activation in microglia, reduced brain edema and neuroinflammation, leading to improved short-term neurobehavioral functions at 24 h after SAH. The administration of TGR5 CRISPR or PKA inhibitor (H89) abolished the anti-inflammation effects of INT-777, on NLRP3-ASC inflammasome, pro-inflammatory cytokines (IL-6, IL-1β, and TNF-a), and neutrophil infiltration at 24 h after SAH. Moreover, early administration of INT-777 attenuated neuronal degeneration in hippocampus on 28 d after SAH. Conclusions INT-777 attenuated NLRP3-ASC inflammasome-dependent neuroinflammation in the EBI after SAH, partially via TGR5/cAMP/PKA signaling pathway. Early administration of INT-777 may serve as a potential therapeutic strategy for EBI management in the setting of SAH.
TL;DR: Intranasal administration of sodium butyrate activated PI3K/Akt via GPR41/Gβγ and attenuated neuronal apoptosis after MCAO, and activation of the GPR active subunit was confirmed.
Abstract: Sodium butyrate, a short-chain fatty acid, is predominantly produced by gut microbiota fermentation of dietary fiber and serves as an important neuromodulator in the central nervous system. Recent ...
TL;DR: The incorporation of CAD/CAM technology into complete denture design and fabrication streamlines the clinical and laboratory processes and provides improved physical properties that enhance denture quality.
Abstract: Purpose CAD/CAM complete dentures have increased in popularity and a wide variety of systems are currently available. These prostheses present many advantages for clinicians, technicians and patients. Subtractive manufacturing is used by most of the available systems while a few manufacturers use an additive manufacturing technique. This article describes the currently available systems and materials available for the fabrication of CAD/CAM complete dentures and reviews the literature relative to their physical properties. Methods A comprehensive review of the literature was completed to enumerate the currently available techniques to fabricate CAD/CAM complete dentures and discuss their physical properties. A search of English language peer-reviewed literature was undertaken using MEDLINE and PubMed on research articles published between 2000 and 2019. A hand search of relevant dental journals was also completed. Results The literature indicates the physical properties of CAD/CAM milled poly(methylmethacrylate) or PMMA as it is commonly described is superior to conventionally processed PMMA for the fabrication of complete dentures. Conclusion The incorporation of CAD/CAM technology into complete denture design and fabrication streamlines the clinical and laboratory processes and provides improved physical properties that enhance denture quality.
TL;DR: Plant-based diets, defined as including both vegan and lacto-ovo-vegetarian diets, are growing in popularity throughout the Western world for various reasons, including concerns for human health and the health of the planet as mentioned in this paper.
Abstract: Plant-based diets, defined here as including both vegan and lacto-ovo-vegetarian diets, are growing in popularity throughout the Western world for various reasons, including concerns for human health and the health of the planet. Plant-based diets are more environmentally sustainable than meat-based diets and have a reduced environmental impact, including producing lower levels of greenhouse gas emissions. Dietary guidelines are normally formulated to enhance the health of society, reduce the risk of chronic diseases, and prevent nutritional deficiencies. We reviewed the scientific data on plant-based diets to summarize their preventative and therapeutic role in cardiovascular disease, cancer, diabetes, obesity, and osteoporosis. Consuming plant-based diets is safe and effective for all stages of the life cycle, from pregnancy and lactation, to childhood, to old age. Plant-based diets, which are high in fiber and polyphenolics, are also associated with a diverse gut microbiota, producing metabolites that have anti-inflammatory functions that may help manage disease processes. Concerns about the adequate intake of a number of nutrients, including vitamin B12, calcium, vitamin D, iron, zinc, and omega-3 fats, are discussed. The use of fortified foods and/or supplements as well as appropriate food choices are outlined for each nutrient. Finally, guidelines are suggested for health professionals working with clients consuming plant-based diets.
TL;DR: This review focuses on programmed cell necrosis (i.e., necroptosis) as a promising research direction that will help in understanding the molecular and cellular processes behind different pathological conditions, such as chronic inflammation, neurodegeneration, and cardiovascular diseases.
TL;DR: In this paper, the effects of ketogenic diets on common chronic diseases, as well as their impact on diet quality and possible risks associated with their use are examined, given often-temporary improvements, unfavorable effects on dietary intake, and inadequate data demonstrating long-term safety.
Abstract: Very-low-carbohydrate ketogenic diets have been long been used to reduce seizure frequency and more recently have been promoted for a variety of health conditions, including obesity, diabetes, and liver disease. Ketogenic diets may provide short-term improvement and aid in symptom management for some chronic diseases. Such diets affect diet quality, typically increasing intake of foods linked to chronic disease risk and decreasing intake of foods found to be protective in epidemiological studies. This review examines the effects of ketogenic diets on common chronic diseases, as well as their impact on diet quality and possible risks associated with their use. Given often-temporary improvements, unfavorable effects on dietary intake, and inadequate data demonstrating long-term safety, for most individuals, the risks of ketogenic diets may outweigh the benefits.
TL;DR: Consumers should be informed of the nutritional profile and potential health benefits of plant-based dairy alternatives as the nutritional content can vary greatly between the different types of beverages.
Abstract: Concerns about environmental impact and sustainability, animal welfare, and personal health issues have fueled consumer demand for dairy alternatives. The aim of this study was to conduct a cross-sectional survey of plant-based non-dairy beverages from three different continents (USA, Australia, and Western Europe) to assess their nutritional content and health profile. A total of 148 non-dairy beverages were analyzed from the nutrition label and ingredients listed on the commercial package or from the information located on the website of the manufacturer or retailer. The different types of beverages were extracts of nuts or seeds (n = 49), grains (n = 38), legumes (n = 36), coconut (n = 10), and mixed blends (n = 15). On average, the plant-based beverages generally scored well in terms of not containing high levels of sodium, saturated fat, or calories. Over half of the beverages were fortified with calcium to levels equal to or greater than that of dairy milk. The protein content varied from 0 to 10 g/serving. Levels of vitamin D and B12 fortification were quite low. Consumers should be informed of the nutritional profile and potential health benefits of plant-based dairy alternatives as the nutritional content can vary greatly between the different types of beverages.
TL;DR: Way in which oxidative stress has the potential to impact fertility in a negative way is seen, as well as subtle variations in the ways reactive oxygen species can operate.
Abstract: The effects of reactive oxygen species on male fertility are governed by the oxidative paradox, defined by a delicate balance between oxidative stress and antioxidant capacity. When regulated appropriately, reactive oxygen species ensure effective function; however, when uninhibited, they represent key players in male factor infertility. Mechanisms responsible for this include oxidative destruction of sperm lipid membranes, damage to gamete DNA both by gene mutation and by direct breakdown of the DNA backbone, mitochondrial dysfunction and apoptotic cell death. Utilizing various male pathologies as case studies, we see ways in which oxidative stress has the potential to impact fertility in a negative way. Varicocele, erectile dysfunction, testicular cancer and even idiopathic male infertility highlight common mechanistic pathways, as well as subtle variations in the ways reactive oxygen species can operate. Oxidative biomarkers have emerged to better study male infertility, predict reproductive success and modify assisted reproductive technologies to minimize oxidative stress.
University of Sydney1, Stanford University2, Laval University3, The George Institute for Global Health4, Manipal University5, Imperial College London6, University of Leeds7, University of Tokyo8, Lilavati Hospital and Research Centre9, National Institute for Health Research10, University of Southampton11, University of Leicester12, Leicester General Hospital13, Loma Linda University14
TL;DR: In this article, a panel of international experts from across the spectrum of metabolic diseases come together to identify the challenges and provide perspectives on building a framework for a virtual primary care-driven, patient-centred, multidisciplinary model to deliver holistic care for patients with metabolic dysfunction-associated fatty liver disease and associated metabolic diseases.
TL;DR: In this paper, the editing dynamics and DNA repair profiles after the delivery of Cas9-guide RNA ribonucleoprotein (RNP) with or without the adeno-associated virus serotype 6 (AAV6) as HDR donors in four cell types were explored.
Abstract: Investigations of CRISPR gene knockout editing profiles have contributed to enhanced precision of editing outcomes. However, for homology-directed repair (HDR) in particular, the editing dynamics and patterns in clinically relevant cells, such as human iPSCs and primary T cells, are poorly understood. Here, we explore the editing dynamics and DNA repair profiles after the delivery of Cas9-guide RNA ribonucleoprotein (RNP) with or without the adeno-associated virus serotype 6 (AAV6) as HDR donors in four cell types. We show that editing profiles have distinct differences among cell lines. We also reveal the kinetics of HDR mediated by the AAV6 donor template. Quantification of T50 (time to reach half of the maximum editing frequency) indicates that short indels (especially +A/T) occur faster than longer (>2 bp) deletions, while the kinetics of HDR falls between NHEJ (non-homologous end-joining) and MMEJ (microhomology-mediated end-joining). As such, AAV6-mediated HDR effectively outcompetes the longer MMEJ-mediated deletions but not NHEJ-mediated indels. Notably, a combination of small molecular compounds M3814 and Trichostatin A (TSA), which potently inhibits predominant NHEJ repairs, leads to a 3-fold increase in HDR efficiency.
Cleveland Clinic1, University of the Western Cape2, Cornell University3, Hamad Medical Corporation4, Imperial College London5, Southern Illinois University School of Medicine6, Loma Linda University7, Union Hospital8, The Chinese University of Hong Kong9, Cairo University10, University of Porto11, University of Aveiro12, Harvard University13, Lilavati Hospital and Research Centre14
TL;DR: A systematic review of the available clinical evidence was performed, with articles published on Scopus being manually screened as mentioned in this paper, and 97 articles were included in the study, of which 52 (53.6%) were uncontrolled (open label), 12 (12.4%) unblinded RCTs, and 33 (34.0%) blinded RCT, whereas 44 (45.4%), articles tested individual antioxidants, 31 (32.0%), a combination of several products in variable dosages, and 22 (22.6%), registered antioxidant products.
Abstract: It is widely accepted that oxidative stress plays an important role in the pathophysiology of male infertility and that antioxidants could have a significant role in the treatment of male infertility. The main objectives of this study are: 1) to systematically review the current evidence for the utility of antioxidants in the treatment of male infertility; and 2) propose evidence-based clinical guidelines for the use of antioxidants in the treatment of male infertility. A systematic review of the available clinical evidence was performed, with articles published on Scopus being manually screened. Data extracted included the type of antioxidant used, the clinical conditions under investigation, the evaluation of semen parameters and reproductive outcomes. The adherence to the Cambridge Quality Checklist, Cochrane Risk of Bias for randomized controlled trials (RCTs), CONSORT guidelines and JADAD score were analyzed for each included study. Further, we provided a Strength Weakness Opportunity Threat (SWOT) analysis to analyze the current and future value of antioxidants in male infertility. Of the 1,978 articles identified, 97 articles were included in the study. Of these, 52 (53.6%) were uncontrolled (open label), 12 (12.4%) unblinded RCTs, and 33 (34.0%) blinded RCTs, whereas 44 (45.4%) articles tested individual antioxidants, 31 (32.0%) a combination of several products in variable dosages, and 22 (22.6%) registered antioxidant products. Based on the published evidence, we 1) critically examined the necessity of additional double-blind, randomized, placebo-controlled trials, and 2) proposed updated evidence-based clinical guidelines for antioxidant therapy in male infertility. The current systematic review on antioxidants and male infertility clearly shows that antioxidant supplementation improves semen parameters. In addition, it provides the indications for antioxidant treatment in specific clinical conditions, including varicocele, unexplained and idiopathic male infertility, as well as in cases of altered semen quality.
TL;DR: In this article, the authors compared different single-cell RNA sequencing (scRNA-seq) datasets generated by different technologies and in different laboratories and found that batch-effect correction was by far the most important factor in correctly classifying the cells.
Abstract: Comparing diverse single-cell RNA sequencing (scRNA-seq) datasets generated by different technologies and in different laboratories remains a major challenge. Here we address the need for guidance in choosing algorithms leading to accurate biological interpretations of varied data types acquired with different platforms. Using two well-characterized cellular reference samples (breast cancer cells and B cells), captured either separately or in mixtures, we compared different scRNA-seq platforms and several preprocessing, normalization and batch-effect correction methods at multiple centers. Although preprocessing and normalization contributed to variability in gene detection and cell classification, batch-effect correction was by far the most important factor in correctly classifying the cells. Moreover, scRNA-seq dataset characteristics (for example, sample and cellular heterogeneity and platform used) were critical in determining the optimal bioinformatic method. However, reproducibility across centers and platforms was high when appropriate bioinformatic methods were applied. Our findings offer practical guidance for optimizing platform and software selection when designing an scRNA-seq study. A comprehensive comparison of 20 single-cell RNA-seq datasets derived from the two cell lines analyzed using six preprocessing pipelines, eight normalization methods and seven batch-correction algorithms derived from four different sequencing platforms at different centers.
Center for Nutrition Policy and Promotion1, Wake Forest University2, Purdue University3, Tulane University4, University of Hawaii5, United States Department of Agriculture6, United States Department of Health and Human Services7, University of North Carolina at Chapel Hill8, College of Tropical Agriculture and Human Resources9, Loma Linda University10, University of Iowa11, Northwestern University12, Pennington Biomedical Research Center13
TL;DR: In this article, the authors conducted a systematic review of existing research on diet and health to inform the current Dietary Guidelines for Americans and found that consuming a nutrient-dense dietary pattern was associated with reduced risk of death from all causes.
Abstract: Importance The 2020 Dietary Guidelines Advisory Committee conducted a systematic review of existing research on diet and health to inform the current Dietary Guidelines for Americans. The committee answered this public health question: what is the association between dietary patterns consumed and all-cause mortality (ACM)? Objective To ascertain the association between dietary patterns consumed and ACM. Evidence Review Guided by an analytical framework and predefined inclusion and exclusion criteria developed by the committee, the US Department of Agriculture’s Nutrition Evidence Systematic Review (NESR) team searched PubMed, the Cochrane Central Register of Controlled Trials, and Embase and dual-screened the results to identify articles that were published between January 1, 2000, and October 4, 2019. These studies evaluated dietary patterns and ACM in participants aged 2 years and older. The NESR team extracted data from and assessed risk of bias in included studies. Committee members synthesized the evidence, developed conclusion statements, and graded the strength of the evidence supporting the conclusion statements. Findings A total of 1 randomized clinical trial and 152 observational studies were included in the review. Studies enrolled adults and older adults (aged 17-84 years at baseline) from 28 countries with high or very high Human Development Index; 53 studies originated from the US. Most studies were well designed, used rigorous methods, and had low or moderate risks of bias. Precision, directness, and generalizability were demonstrated across the body of evidence. Results across studies were highly consistent. Evidence suggested that dietary patterns in adults and older adults that involved higher consumption of vegetables, fruits, legumes, nuts, whole grains, unsaturated vegetable oils, fish, and lean meat or poultry (when meat was included) were associated with a decreased risk of ACM. These healthy patterns were also relatively low in red and processed meat, high-fat dairy, and refined carbohydrates or sweets. Some of these dietary patterns also included intake of alcoholic beverages in moderation. Results based on additional analyses with confounding factors generally confirmed the robustness of main findings. Conclusions and Relevance In this systematic review, consuming a nutrient-dense dietary pattern was associated with reduced risk of death from all causes.
Center for Devices and Radiological Health1, Fudan University2, Loma Linda University3, Hoffmann-La Roche4, SAS Institute5, National Institutes of Health6, Illumina7, ATCC8, University of Toledo Medical Center9, Genentech10, Novartis11, University of Helsinki12, Center for Biologics Evaluation and Research13, Science for Life Laboratory14, Palacký University, Olomouc15, University of Western Australia16, Murdoch University17, University of Tartu18, Garvan Institute of Medical Research19, United States Department of Energy Office of Science20, Virginia Tech21, Center for Information Technology22, AstraZeneca23, National Center for Toxicological Research24, Cornell University25, Center for Drug Evaluation and Research26, Silver Spring Networks27
TL;DR: In this article, a systematic interrogation of somatic mutations in paired tumor-normal cell lines to identify factors affecting detection reproducibility and accuracy at six different centers was conducted, using whole-genome sequencing and whole-exome sequencing (WES).
Abstract: Clinical applications of precision oncology require accurate tests that can distinguish true cancer-specific mutations from errors introduced at each step of next-generation sequencing (NGS). To date, no bulk sequencing study has addressed the effects of cross-site reproducibility, nor the biological, technical and computational factors that influence variant identification. Here we report a systematic interrogation of somatic mutations in paired tumor-normal cell lines to identify factors affecting detection reproducibility and accuracy at six different centers. Using whole-genome sequencing (WGS) and whole-exome sequencing (WES), we evaluated the reproducibility of different sample types with varying input amount and tumor purity, and multiple library construction protocols, followed by processing with nine bioinformatics pipelines. We found that read coverage and callers affected both WGS and WES reproducibility, but WES performance was influenced by insert fragment size, genomic copy content and the global imbalance score (GIV; G > T/C > A). Finally, taking into account library preparation protocol, tumor content, read coverage and bioinformatics processes concomitantly, we recommend actionable practices to improve the reproducibility and accuracy of NGS experiments for cancer mutation detection.
TL;DR: Palivizumab, an RSV monoclonal antibody [immunoprophylaxis (IP), has demonstrated effectiveness in disease prevention and is the only licensed IP for RSV disease in specific high-risk pediatric populations as mentioned in this paper.
Abstract: Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, young children, and older or immunocompromised adults. Although aerosolized ribavirin was licensed for RSV treatment on the basis of data demonstrating a reduced need for supplemental oxygen, ribavirin use is limited because of issues with efficacy, safety, and cost. Currently, the treatment of RSV is primarily supportive. New antiviral treatments for RSV are in the early stages of development, but it will be years until any of these may be licensed by the US Food and Drug Administration (FDA). Palivizumab, an RSV monoclonal antibody [immunoprophylaxis (IP)], has demonstrated effectiveness in disease prevention and is the only licensed IP for RSV disease in specific high-risk pediatric populations. Although its efficacy is well established, some challenges that may interfere with its clinical use include cost, need for monthly injections, and changing policy for use by the American Academy of Pediatrics (AAP). Preventing RSV disease would be possible through RSV vaccine development (e.g., live-attenuated, vector-based subunit, or particle-based). Alternatively, new long-acting monoclonal antibodies have demonstrated promising results in early clinical trials. Despite scientific advances, until new agents become available, palivizumab should continue to be used to reduce RSV disease burden in high-risk patients for whom it is indicated.