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  • Choline Plus Working Memory Training Improves Prenatal Alcohol-Induced Deficits in Cognitive Flexibility and Functional Connectivity in Adulthood in Rats.

    Waddell, Jaylyn; Hill, Elizabeth; Tang, Shiyu; Jiang, Li; Xu, Su; Mooney, Sandra M (MDPI AG, 2020-11-14)
    Fetal alcohol spectrum disorder (FASD) is the leading known cause of intellectual disability, and may manifest as deficits in cognitive function, including working memory. Working memory capacity and accuracy increases during adolescence when neurons in the prefrontal cortex undergo refinement. Rats exposed to low doses of ethanol prenatally show deficits in working memory during adolescence, and in cognitive flexibility in young adulthood. The cholinergic system plays a crucial role in learning and memory processes. Here we report that the combination of choline and training on a working memory task during adolescence significantly improved cognitive flexibility (performance on an attentional set shifting task) in young adulthood: 92% of all females and 81% of control males formed an attentional set, but only 36% of ethanol-exposed males did. Resting state functional magnetic resonance imaging showed that functional connectivity among brain regions was different between the sexes, and was altered by prenatal ethanol exposure and by choline + training. Connectivity, particularly between prefrontal cortex and striatum, was also different in males that formed a set compared with those that did not. Together, these findings indicate that prenatal exposure to low doses of ethanol has persistent effects on brain functional connectivity and behavior, that these effects are sex-dependent, and that an adolescent intervention could mitigate some of the effects of prenatal ethanol exposure.
  • Preclinical Metrics Correlate With Drug Activity in Phase II Trials of Targeted Therapies for Non-Small Cell Lung Cancer

    Rybinski, Brad; Hosgood, H. Dean; Wiener, Sara L.; Weiser, Daniel A. (Frontiers Media S.A., 2020-11-05)
    Novel oncology drugs often fail to progress from preclinical experiments to FDA approval. Therefore, determining which preclinical or clinical factors associate with drug activity could accelerate development of effective therapies. We investigated whether preclinical metrics and patient characteristics are associated with objective response rate (ORR) in phase II clinical trials of targeted therapies for non-small cell lung cancer (NSCLC). We developed a reproducible process to select a single phase II trial and supporting preclinical publication for a given drug-indication pair, which we defined as the pairing of a small molecule inhibitor (e.g., crizotinib) with the specific patient population for which it was designed to work (e.g., patients with an ALK aberration). We demonstrated that robust drug activity in mice, as measured by change in tumor size, is independently associated with improved ORR in phase II clinical trials. The number of mice utilized in experiments, the number of publications referencing the drug for NSCLC before the phase II clinical trial, and whether the drug was approved for a cancer other than NSCLC also significantly correlated with ORR. Among clinical characteristics, sex, race, histology, and smoking history were significantly associated with ORR. Further research into metrics that correlate with drug activity has the potential to optimize selection of novel therapies for clinical trials and enrich the drug development pipeline, particularly for patients with targetable genetic aberrations and rare cancers.
  • Bacterial vaginosis and its association with infertility, endometritis, and pelvic inflammatory disease.

    Ravel, Jacques; Moreno, Inmaculada; Simón, Carlos (Elsevier Ltd., 2020-10-19)
    Bacterial vaginosis, pelvic inflammatory disease, and endometritis are infections of the genital tract that can lead to many adverse health outcomes, including infertility. Bacterial vaginosis is characterized by a lower prevalence of lactobacilli and a higher prevalence of anaerobic bacteria, including Gardnerella vaginalis, Megasphaera spp., and Atopobium vaginae. Endometritis and pelvic inflammatory disease are caused by the ascension of pathogenic bacteria to the uterus, although the mechanisms by which they do so are unclear. Bacterial vaginosis, chronic endometritis, and pelvic inflammatory disease have been linked to infertility in retrospective and prospective trials. Similarly, the causes of bacterial vaginosis and endometritis-related infertility are likely multifactorial and stem from inflammation, immune targeting of sperm antigens, the presence of bacterial toxins, and increased risk of sexually transmitted infections. Diagnosis and treatment of bacterial vaginosis, chronic endometritis, and pelvic inflammatory disease before attempting conception may be important components of preconceptional care for symptomatic women to improve outcomes of natural and assisted reproduction.
  • Rapid, Ultrasensitive, and Quantitative Detection of SARS-CoV-2 Using Antisense Oligonucleotides Directed Electrochemical Biosensor Chip.

    Alafeef, Maha; Dighe, Ketan; Moitra, Parikshit; Pan, Dipanjan (American Chemical Society, 2020-10-20)
    A large-scale diagnosis of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is essential to downregulate its spread within as well as across communities and mitigate the current outbreak of the pandemic novel coronavirus disease 2019 (COVID-19). Herein, we report the development of a rapid (less than 5 min), low-cost, easy-to-implement, and quantitative paper-based electrochemical sensor chip to enable the digital detection of SARS-CoV-2 genetic material. The biosensor uses gold nanoparticles (AuNPs), capped with highly specific antisense oligonucleotides (ssDNA) targeting viral nucleocapsid phosphoprotein (N-gene). The sensing probes are immobilized on a paper-based electrochemical platform to yield a nucleic-acid-testing device with a readout that can be recorded with a simple hand-held reader. The biosensor chip has been tested using samples collected from Vero cells infected with SARS-CoV-2 virus and clinical samples. The sensor provides a significant improvement in output signal only in the presence of its target-SARS-CoV-2 RNA-within less than 5 min of incubation time, with a sensitivity of 231 (copies μL-1)-1 and limit of detection of 6.9 copies/μL without the need for any further amplification. The sensor chip performance has been tested using clinical samples from 22 COVID-19 positive patients and 26 healthy asymptomatic subjects confirmed using the FDA-approved RT-PCR COVID-19 diagnostic kit. The sensor successfully distinguishes the positive COVID-19 samples from the negative ones with almost 100% accuracy, sensitivity, and specificity and exhibits an insignificant change in output signal for the samples lacking a SARS-CoV-2 viral target segment (e.g., SARS-CoV, MERS-CoV, or negative COVID-19 samples collected from healthy subjects). The feasibility of the sensor even during the genomic mutation of the virus is also ensured from the design of the ssDNA-conjugated AuNPs that simultaneously target two separate regions of the same SARS-CoV-2 N-gene.
  • Abdominal Wall Transplantation: Indications and Outcomes

    Honeyman, Calum; Dolan, Roisin; Stark, Helen; Fries, Charles Anton; Reddy, Srikanth; Allan, Philip; Vrakas, Giorgios; Vaidya, Anil; Dijkstra, Gerard; Hofker, Sijbrand; et al. (Springer Nature, 2020-11-07)
    Purpose of Review: This article aims to review published outcomes associated with full-thickness vascularized abdominal wall transplantation, with particular emphasis on advances in the field in the last 3 years. Recent Findings: Forty-six full-thickness vascularized abdominal wall transplants have been performed in 44 patients worldwide. Approximately 35% of abdominal wall transplant recipients will experience at least one episode of acute rejection in the first year after transplant, compared with rejection rates of 87.8% and 72.7% for hand and face transplant respectively. Recent evidence suggests that combining a skin containing abdominal wall transplant with an intestinal transplant does not appear to increase sensitization or de novo donor-specific antibody formation. Summary: Published data suggests that abdominal wall transplantation is an effective safe solution to achieve primary closure of the abdomen after intestinal or multivisceral transplant. However, better data is needed to confirm observations made and to determine long-term outcomes, requiring standardized data collection and reporting and collaboration between the small number of active transplant centres around the world.
  • Status Dystonicus, Oculogyric Crisis and Paroxysmal Dyskinesia in a 25 Year-Old Woman with a Novel Variant, K457E.

    Buckley, Cliona; Williams, Jennifer; Munteanu, Tudor; King, Mary; Park, Su Mi; Meredith, Andrea L; Lynch, Timothy (Center for Digital Research and Scholarship, 2020-10-27)
    The diagnosis of a paroxysmal dyskinesia is difficult and status dystonicus is a rare life threatening movement disorder characterised by severe, frequent or continuous episodes of dystonic spasms. A 25 year old woman with chronic ataxia and paroxysmal dyskinesia presented with facial twitching, writhing of arms, oculogyric crisis and visual and auditory hallucinations. She developed respiratory failure and was ventilated. No cause was found so whole exome sequencing was performed and this revealed a novel, non-synonymous heterozygous variant in exon 11 of the KCNMA1 gene, K457E (c 1369A>G) in the patient but not her parents. This variant has not been previously reported in gnomAD or ClinVar. The finding of a de novo variant in a potassium channel gene guided a trial of the potassium channel antagonist 3,4 diaminopyridine resulting in significant improvement, discharge from the intensive care unit and ultimately home.
  • Targeting breast cancer metabolism with a novel inhibitor of mitochondrial ATP synthesis.

    Kim, Myoung Sook; Gernapudi, Ramkishore; Cedeño, Yessenia Cedeño; Polster, Brian M; Martinez, Ramon; Shapiro, Paul; Kesari, Santosh; Nurmemmedov, Elmar; Passaniti, Antonino (Impact Journals LLC, 2020-10-27)
    Inhibitors of mitochondrial respiration and ATP synthesis may promote the selective killing of respiration-competent cancer cells that are critical for tumor progression. We previously reported that CADD522, a small molecule inhibitor of the RUNX2 transcription factor, has potential for breast cancer treatment. In the current study, we show that CADD522 inhibits mitochondrial oxidative phosphorylation by decreasing the mitochondrial oxygen consumption rate (OCR) and ATP production in human breast cancer cells in a RUNX2-independent manner. The enzyme activity of mitochondrial ATP synthase was inhibited by CADD522 treatment. Importantly, results from cellular thermal shift assays that detect drug-induced protein stabilization revealed that CADD522 interacts with both α and β subunits of the F1-ATP synthase complex. Differential scanning fluorimetry also demonstrated interaction of α subunits of the F1-ATP synthase to CADD522. These results suggest that CADD522 might target the enzymatic F1 subunits in the ATP synthase complex. CADD522 increased the levels of intracellular reactive oxygen species (ROS), which was prevented by MitoQ, a mitochondria-targeted antioxidant, suggesting that cancer cells exposed to CADD522 may elevate ROS from mitochondria. CADD522-increased mitochondrial ROS levels were enhanced by exogenously added pro-oxidants such as hydrogen peroxide or tert-butyl hydroperoxide. Conversely, CADD522-mediated cell growth inhibition was blocked by N-acetyl-l-cysteine, a general ROS scavenger. Therefore, CADD522 may exert its antitumor activity by increasing mitochondrial driven cellular ROS levels. Collectively, our data suggest in vitro proof-of-concept that supports inhibition of mitochondrial ATP synthase and ROS generation as contributors to the effectiveness of CADD522 in suppression of tumor growth.
  • Motor Competence and Attainment of Global Physical Activity Guidelines among a Statewide Sample of Preschoolers.

    Slaton, Anthony; Kowalski, Alysse J; Zemanick, Amy; Pulling Kuhn, Ann; Hager, Erin R; Black, Maureen M (MDPI AG, 2020-11-18)
    Global physical activity guidelines for preschoolers include 60 min of moderate-to-vigorous physical activity (MVPA) daily. This study, based on the developmental model of motor skill competence, examines how motor competence relates to preschoolers’ likelihood of meeting global guidelines using ankle accelerometry. We measured physical activity using 24-h ankle-placement accelerometry (Actical) for at least two consecutive days (87% with six-seven days), motor competence using the Test of Gross Motor Development-2 (TGMD-2), and BMI-for-age z-scores (BMIz) using anthropometry and age-and sex-specific CDC norms. Caregivers provided demographic characteristics of children’s age, sex, and race. We used multivariable logistic regression to examine how motor competence, BMIz weight status, and demographic characteristics related to meeting global physical activity guidelines. The sample included 588 preschoolers, age 3–5 years; 55% male; 60% white; and 28% overweight/obese; 75% attained the recommended 60 min of MVPA per day. The odds of meeting MVPA guidelines were associated with higher gross motor quotient, higher object control scores, sex (male), age (older), and race (white), but not with BMIz weight status. Findings support the use of 24-h ankle accelerometry among preschoolers and are consistent with the developmental model of motor competence applied to preschoolers, whereby object control competence relates positively to attaining global physical activity guidelines.
  • Biphasic Packing of DNA and Internal Proteins in Bacteriophage T4 Heads Revealed by Bubblegram Imaging.

    Wu, Weimin; Cheng, Naiqian; Black, Lindsay W; Dietz, Hendrik; Steven, Alasdair C (MDPI AG, 2020-11-10)
    The virions of tailed bacteriophages and the evolutionarily related herpesviruses contain, in addition to highly condensed DNA, substantial quantities of internal proteins. These proteins ("ejection proteins") have roles in scaffolding, maturational proteolysis, and cell-to-cell delivery. Whereas capsids are amenable to analysis at high resolution by cryo-electron microscopy, internal proteins have proved difficult to localize. In this study, we investigated the distribution of internal proteins in T4 by bubblegram imaging. Prior work has shown that at suitably high electron doses, radiation damage generates bubbles of hydrogen gas in nucleoprotein specimens. Using DNA origami as a test specimen, we show that DNA does not bubble under these conditions; it follows that bubbles represent markers for proteins. The interior of the prolate T4 head, ~1000 Å long by ~750 Å wide, has a bubble-free zone that is ~100-110 Å thick, underlying the capsid shell from which proteins are excluded by highly ordered DNA. Inside this zone, which is plausibly occupied by ~4 layers of coaxial spool, bubbles are generated at random locations in a disordered ensemble of internal proteins and the remainder of the genome.
  • An mRNA Vaccine against SARS-CoV-2 - Preliminary Report.

    Jackson, Lisa A; Anderson, Evan J; Rouphael, Nadine G; Roberts, Paul C; Makhene, Mamodikoe; Coler, Rhea N; McCullough, Michele P; Chappell, James D; Denison, Mark R; Stevens, Laura J; et al. (Massachusetts Medical Society, 2020-07-14)
    BACKGROUND The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein. METHODS We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group. RESULTS After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events. CONCLUSIONS The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine.
  • Prediction of hypofibrinogenemia and thrombocytopenia at the point of care with the Quantra® QPlus® System.

    Naik, Bhiken I; Tanaka, Kenichi; Sudhagoni, Ramu G; Viola, Francesco (Elsevier Ltd., 2020-11-10)
    Introduction: Low fibrinogen and platelet counts are associated with bleeding and the need for transfusion. In this study, we investigated whether the Quantra® QPlus® parameters Fibrinogen Contribution (FCS) and Platelet Contribution (PCS) to clot stiffness could predict commonly used fibrinogen and platelet transfusion thresholds in patients undergoing major surgical procedures. Methods: This study used data from a multicenter, prospective observational study of adult patients undergoing cardiac or major orthopedic surgery. Quantra and laboratory assays were performed in parallel at multiple time points. Logistic regression models were used to assess the ability of FCS and PCS to predict fibrinogen and platelet thresholds used to guide transfusions. Receiver operating characteristics (ROC) curves were analyzed to determine the diagnostic accuracy and the optimal FCS and PCS values corresponding to the laboratory-based thresholds. Results: The areas under the ROC curves (AUCs) for FCS at fibrinogen thresholds of <120, 150, and 200 mg/dl ranged from 0.96 to 0.89. Similarly, for PCS at platelet thresholds of <50, 80, 100,000/μl, AUCs ranged from 0.95 to 0.89. The proposed optimal FCS and PCS cutoff values showed high negative predictive value and high sensitivity and specificity (both >86%) at the lowest fibrinogen and platelet threshold levels. Conclusions: This study identifies potential cutoff values for QPlus FCS and PCS proposed for use in place of or in conjunction with laboratory-based assays fibrinogen and platelet thresholds to guide transfusion decisions in surgical patients. These cut-off values will need to be validated in future studies.
  • SARS-CoV-2 and nervous system: From pathogenesis to clinical manifestation.

    Keyhanian, Kiandokht; Umeton, Raffaella Pizzolato; Mohit, Babak; Davoudi, Vahid; Hajighasemi, Fatemeh; Ghasemi, Mehdi (Elsevier Ltd., 2020-11-07)
    Since the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a growing body of evidence indicates that besides common COVID-19 symptoms, patients may develop various neurological manifestations affecting both the central and peripheral nervous systems as well as skeletal muscles. These manifestations can occur prior, during and even after the onset of COVID-19 general symptoms. In this Review, we discuss the possible neuroimmunological mechanisms underlying the nervous system and skeletal muscle involvement, and viral triggered neuroimmunological conditions associated with SARS-CoV-2, as well as therapeutic approaches that have been considered for these specific complications worldwide
  • An antibacterial and injectable calcium phosphate scaffold delivering human periodontal ligament stem cells for bone tissue engineering

    Chen, Hong; Yang, Hui; Weir, Michael D.; Schneider, Abraham; Ren, Ke; Homayounfar, Negar; Oates, Thomas W.; Zhang, Ke; Liu, Jin; Hu, Tao; et al. (Royal Society of Chemistry, 2020-11-01)
    Osteomyelitis and post-operative infections are major problems in orthopedic, dental and craniofacial surgeries. It is highly desirable for a tissue engineering construct to kill bacteria, while simultaneously delivering stem cells and enhancing cell function and tissue regeneration. The objectives of this study were to: (1) develop a novel injectable calcium phosphate cement (CPC) scaffold containing antibiotic ornidazole (ORZ) while encapsulating human periodontal ligament stem cells (hPDLSCs), and (2) investigate the inhibition efficacy against Staphylococcus aureus (S. aureus) and the promotion of hPDLSC function for osteogenesis for the first time. ORZ was incorporated into a CPC-chitosan scaffold. hPDLSCs were encapsulated in alginate microbeads (denoted hPDLSCbeads). The ORZ-loaded CPCC+hPDLSCbeads scaffold was fully injectable, and had a flexural strength of 3.50 ± 0.92 MPa and an elastic modulus of 1.30 ± 0.45 GPa, matching those of natural cancellous bone. With 6 days of sustained ORZ release, the CPCC+10ORZ (10% ORZ) scaffold had strong antibacterial effects on S. aureus, with an inhibition zone of 12.47 ± 1.01 mm. No colonies were observed in the CPCC+10ORZ group from 3 to 7 days. ORZ-containing scaffolds were biocompatible with hPDLSCs. CPCC+10ORZ+hPDLSCbeads scaffold with osteogenic medium had 2.4-fold increase in alkaline phosphatase (ALP) activity and bone mineral synthesis by hPDLSCs, as compared to the control group (p < 0.05). In conclusion, the novel antibacterial construct with stem cell delivery had injectability, good strength, strong antibacterial effects and biocompatibility, supporting osteogenic differentiation and bone mineral synthesis of hPDLSCs. The injectable and mechanically-strong CPCC+10ORZ+hPDLSCbeads construct has great potential for treating bone infections and promoting bone regeneration.
  • A critical appraisal of COVID-19 as a nosocomial infection: An African perspective

    Oladipo, Elijah Kolawole; Ariyo, Olumuyiwa Elijah; Ibukun, Francis Ifedayo; Osasona, Oluwadamilola Gideon; Akinbodewa, Ayodeji Akinwumi; Abejegah, Chukwuyem; Oloke, Julius Kola (African Field Epidemiology Network, 2020-08-20)
    The pandemic of Coronavirus disease 19 is not abating since the outbreak began in December 2019. Africa is currently experiencing a surge after an initial low incidence and nosocomial infections could be contributing to this. A dominant factor responsible for this is a weak healthcare system because of many years of neglect due to abysmal budgetary allocation to the sector. The testing capacity for COVID-19 diagnosis in Africa is grossly inadequate coupled with a severe shortage of personal protective equipment and inadequate infectious diseases expert. These factors exposed the frontline health workers and patients to the hazard of nosocomial infection with the attendants´ morbidity and mortality. Deliberate efforts need to be made toward reducing nosocomial COVID-19 infection.
  • Cryptococcal empyema treated with tube thoracostomy and intrapleural fibrinolysis.

    Kohli, Akshay; Sachdeva, Ashutosh; Pickering, Edward M (Page Press Publications, 2020-11-10)
    A 55-year old woman with a history of relapsed T-cell ALL presented with right pleuritic chest pain and decreased breath sounds over the right hemithorax. Imaging of the chest showed loculated effusions. Tube thoracostomy was performed with intrapleural application of alteplase and dornase alpha over a 3-day period. Repeat imaging demonstrated a marked decrease in the volume of the effusion. In most prior published cases of pleural cryptococcosis, surgical drainage was required in addition to prolonged antifungal agents. More than 50% of patients with cryptococcal infection have severe underlying disease or immunodeficiency state making them high risk for surgery. This is the first case to our knowledge of cryptococcal empyema successfully treated with tube thoracostomy and intrapleural fibrinolysis.
  • A Systematic Review of Community Engagement Outcomes Research in School-Based Health Interventions.

    McMullen, Jaimie M; George, Melissa; Ingman, Benjamin C; Pulling Kuhn, Ann; Graham, Dan J; Carson, Russell L (Blackwell Publishing, 2020-11-12)
    BACKGROUND: Involving communities in school health has been purported as a practice integral to supporting a Whole School, Whole Community, Whole Child (WSCC) approach. Although community collaboration is often included in school-based health initiatives, there is little research considering methods for increasing community engagement. The purpose of this study was to identify effective school-based health interventions documenting changes in community engagement. METHODS: Academic experts and school stakeholders guided procedures for a systematic review of studies published from 1987–2017 and gray literature (ie, best practice documents; policy documents, etc.) on comprehensive school health interventions including community engagement as a targeted outcome. RESULTS: The search identified 9 studies addressing community as an outcome of school-based health interventions; types of partnership mechanisms and partners' roles were classified. CONCLUSIONS: Although involving communities is a WSCC component and commonly recommended as a strategy fundamental to school health, there is little empirical research examining effective strategies for engaging communities and engagement is often not measured as part of intervention studies. Further measurement and research in engaging communities in school health is warranted.
  • Clinical Management of Hyperkalemia

    Palmer, Biff F; Carrero, Juan Jesus; Clegg, Deborah J; Colbert, Gates B; Emmett, Michael; Fishbane, Steven; Hain, Debra J; Lerma, Edgar; Onuigbo, Macaulay; Rastogi, Anjay; et al. (Elsevier Ltd., 2020-11-04)
    Hyperkalemia is an electrolyte abnormality with potentially life-threatening consequences. Despite various guidelines, no universally accepted consensus exists on best practices for hyperkalemia monitoring, with variations in precise potassium (K+) concentration thresholds or for the management of acute or chronic hyperkalemia. Based on the available evidence, this review identifies several critical issues and unmet needs with regard to the management of hyperkalemia. Real-world studies are needed for a better understanding of the prevalence of hyperkalemia outside the clinical trial setting. There is a need to improve effective management of hyperkalemia, including classification and K+ monitoring, when to reinitiate previously discontinued renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, and when to use oral K+-binding agents. Monitoring serum K+ should be individualized; however, increased frequency of monitoring should be considered for patients with chronic kidney disease, diabetes, heart failure, or a history of hyperkalemia and for those receiving RAASi therapy. Recent clinical studies suggest that the newer K+ binders (patiromer sorbitex calcium and sodium zirconium cyclosilicate) may facilitate optimization of RAASi therapy. Enhancing the knowledge of primary care physicians and internists with respect to the safety profiles of these newer K+ binders may increase confidence in managing patients with hyperkalemia. Lastly, the availability of newer K+-binding agents requires further study to establish whether stringent dietary K+ restrictions are needed in patients receiving K+-binder therapy. Individualized monitoring of serum K+ among patients with an increased risk of hyperkalemia and the use of newer K+-binding agents may allow for optimization of RAASi therapy and more effective management of hyperkalemia.
  • Evidence of Structural Protein Damage and Membrane Lipid Remodeling in Red Blood Cells from COVID-19 Patients

    Thomas, Tiffany; Stefanoni, Davide; Dzieciatkowska, Monika; Issaian, Aaron; Nemkov, Travis; Hill, Ryan C; Francis, Richard O; Hudson, Krystalyn E; Buehler, Paul W; Zimring, James C; et al. (American Chemical Society, 2020-10-26)
    The SARS-CoV-2 beta coronavirus is the etiological driver of COVID-19 disease, which is primarily characterized by shortness of breath, persistent dry cough, and fever. Because they transport oxygen, red blood cells (RBCs) may play a role in the severity of hypoxemia in COVID-19 patients. The present study combines state-of-the-art metabolomics, proteomics, and lipidomics approaches to investigate the impact of COVID-19 on RBCs from 23 healthy subjects and 29 molecularly diagnosed COVID-19 patients. RBCs from COVID-19 patients had increased levels of glycolytic intermediates, accompanied by oxidation and fragmentation of ankyrin, spectrin beta, and the N-terminal cytosolic domain of band 3 (AE1). Significantly altered lipid metabolism was also observed, in particular, short- and medium-chain saturated fatty acids, acyl-carnitines, and sphingolipids. Nonetheless, there were no alterations of clinical hematological parameters, such as RBC count, hematocrit, or mean corpuscular hemoglobin concentration, with only minor increases in mean corpuscular volume. Taken together, these results suggest a significant impact of SARS-CoV-2 infection on RBC structural membrane homeostasis at the protein and lipid levels. Increases in RBC glycolytic metabolites are consistent with a theoretically improved capacity of hemoglobin to off-load oxygen as a function of allosteric modulation by high-energy phosphate compounds, perhaps to counteract COVID-19-induced hypoxia. Conversely, because the N-terminus of AE1 stabilizes deoxyhemoglobin and finely tunes oxygen off-loading and metabolic rewiring toward the hexose monophosphate shunt, RBCs from COVID-19 patients may be less capable of responding to environmental variations in hemoglobin oxygen saturation/oxidant stress when traveling from the lungs to peripheral capillaries and vice versa.
  • Comparative analysis of gene expression between Babesia bovis blood stages and kinetes allowed by improved genome annotation

    Ueti, Massaro W; Johnson, Wendell C; Kappmeyer, Lowell S; Herndon, David R; Mousel, Michelle R; Reif, Kathryn E; Taus, Naomi S; Ifeonu, Olukemi O; Silva, Joana C; Suarez, Carlos E; et al. (Elsevier Ltd., 2020-10-15)
    Throughout their life cycle, Babesia parasites alternate between a mammalian host, where they cause babesiosis, and the tick vector. Transition between hosts results in distinct environmental signals that influence patterns of gene expression, consistent with the morphological and functional changes operating in the parasites during their life stages. In addition, comparing differential patterns of gene expression among mammalian and tick parasite stages can provide clues for developing improved methods of control. Hereby, we upgraded the genome assembly of Babesia bovis, a bovine hemoparasite, closing a 139 kbp gap, and used RNA-Seq datasets derived from mammalian blood and tick kinete stages to update the genome annotation. Of the originally annotated genes, 1,254 required structural changes, and 326 new genes were identified, leading to a different predicted proteome compared to the original annotation. Next, the RNA-Seq data was used to identify B. bovis genes that were differentially expressed in the vertebrate and arthropod hosts. In blood stages, 28% of the genes were upregulated up to 300 fold, whereas 26% of the genes in kinetes, a tick stage, were upregulated up to >19,000 fold. We thus discovered differentially expressed genes that may play key biological roles and serve as suitable targets for the development of vaccines to control bovine babesiosis.
  • Complex obstructive lung disease – A diagnostic and management conundrum

    Glick, Danielle R.; Galvin, Jeffrey R.; Deepak, Janaki (Elsevier Ltd., 2020-11-06)
    Rheumatoid arthritis (RA) is a common autoimmune disease most well-known for its inflammatory, destructive polyarthropathy. Extraarticular manifestations of the disease may involve the respiratory system, including interstitial lung disease, pleural disease, pulmonary vascular abnormalities, and airways disease. Smoking is highly prevalent in the RA population, and may even have a synergistic effect in disease development and progression. In the diagnosis of pulmonary disease, this presents a unique diagnostic and therapeutic challenge. We present a case of a woman in her 50s who presented for evaluation of dyspnea and was found to have obstructive lung disease. In addition to RA, she had a significant smoking history and also owned pet birds, making definitive diagnosis difficult. Ultimately, chest imaging was crucial in identifying RA-related lung disease as the root cause of her symptoms, leading to successful treatment and symptom management.

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