Recent Submissions

  • SIRT7 deficiency suppresses inflammation, induces EndoMT, and increases vascular permeability in primary pulmonary endothelial cells

    Wyman, Anne E.; Nguyen, Trang T. T.; Karki, Pratap; Tulapurkar, Mohan E.; Zhang, Chen-Ou; Kim, Junghyun; Feng, Theresa G.; Dabo, Abdoulaye J.; Todd, Nevins W.; Luzina, Irina G.; et al. (Springer Science and Business Media LLC, 2020-07-27)
    Acute lung injury (ALI), a common condition in critically ill patients, has limited treatments and high mortality. Aging is a risk factor for ALI. Sirtuins (SIRTs), central regulators of the aging process, decrease during normal aging and in aging-related diseases. We recently showed decreased SIRT7 expression in lung tissues and fibroblasts from patients with pulmonary fibrosis compared to controls. To gain insight into aging-related mechanisms in ALI, we investigated the effects of SIRT7 depletion on lipopolysaccharide (LPS)-induced inflammatory responses and endothelial barrier permeability in human primary pulmonary endothelial cells. Silencing SIRT7 in pulmonary artery or microvascular endothelial cells attenuated LPS-induced increases in ICAM1, VCAM1, IL8, and IL6 and induced endomesenchymal transition (EndoMT) with decreases in VE-Cadherin and PECAM1 and increases in collagen, alpha-smooth muscle actin, TGFβ receptor 1, and the transcription factor Snail. Loss of endothelial adhesion molecules was accompanied by increased F-actin stress fibers and increased endothelial barrier permeability. Together, these results show that an aging phenotype induced by SIRT7 deficiency promotes EndoMT with impaired inflammatory responses and dysfunction of the lung vascular barrier. © 2020, The Author(s).
  • Changes in the vaginal microbiota across a gradient of urbanization

    Vargas-Robles, Daniela; Morales, Natalia; Rodríguez, Iveth; Nieves, Tahidid; Godoy-Vitorino, Filipa; Alcaraz, Luis David; Pérez, María-Eglée; Ravel, Jacques; Forney, Larry J.; Domínguez-Bello, María Gloria (Springer Science and Business Media LLC, 2020-07-27)
    The vaginal microbiota of healthy women typically has low diversity, which increases after perturbations. Among these, lifestyle associated with certain sexual and antimicrobial practices may be associated with higher diversity. To test this hypothesis, we characterized the vaginal microbiota in the cervicovaginal and introital sites in sexually active Amerindians (N = 82) spanning urbanization, and in urban mestizos (N = 29), in the Venezuelan Amazonas. HPV status was also considered. Sampling was performed in an urban gradient from remote villages to a town, and women were individually classified by the degree of urbanization (low, medium, and high). Amerindian cervicovaginal and introital microbiota diversity were not associated with major changes in urbanization or ethnicity. There was a non-significant trend of increased diversity with urbanization, with a few taxa found overrepresented in urban Amerindians (Brevibacterium linens and Peptoniphilus lacrimalis) or mestizos (Mobiluncus mulieris and Prevotella sp.). Among all women, cervicovaginal and introital samples clustered, respectively, in four and two community state types (CSTs), where most profiles were dominated by Lactobacillus iners, Gardnerella vaginalis or were highly diverse profiles. HPV status did not associate with microbial diversity. In conclusion, no association was found between urban level and the vaginal microbiome in Amerindian women, and little difference was found between ethnicities. L. iners and high diversity profiles, associated with vaginal health outcomes, prevail in these populations. © 2020, The Author(s).
  • Chronic-plus-binge alcohol intake induces production of proinflammatory mtDNA-enriched extracellular vesicles and steatohepatitis via ASK1/p38MAPKα-dependent mechanisms

    Ma, Jing; Cao, Haixia; Rodrigues, Robim M; Xu, Mingjiang; Ren, Tianyi; He, Yong; Hwang, Seonghwan; Feng, Dechun; Ren, Ruixue; Yang, Peixin; et al. (The American Society for Clinical Investigation, 2020-07-23)
    Alcohol-associated liver disease is a spectrum of liver disorders with histopathological changes ranging from simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Recent data suggest that chronic-plus-binge ethanol intake induces steatohepatitis by promoting release by hepatocytes of proinflammatory mitochondrial DNA-enriched (mtDNA-enriched) extracellular vesicles (EVs). The aim of the present study was to investigate the role of the stress kinase apoptosis signal-regulating kinase 1 (ASK1) and p38 mitogen-activated protein kinase (p38) in chronic-plus-binge ethanol-induced steatohepatitis and mtDNA-enriched EV release. Microarray analysis revealed the greatest hepatic upregulation of metallothionein 1 and 2 (Mt1/2), which encode 2 of the most potent antioxidant proteins. Genetic deletion of the Mt1 and Mt2 genes aggravated ethanol-induced liver injury, as evidenced by elevation of serum ALT, neutrophil infiltration, oxidative stress, and ASK1/p38 activation in the liver. Inhibition or genetic deletion of Ask1 or p38 ameliorated ethanol-induced liver injury, inflammation, ROS levels, and expression of phagocytic oxidase and ER stress markers in the liver. In addition, inhibition of ASK1 or p38 also attenuated ethanol-induced mtDNA-enriched EV secretion from hepatocytes. Taken together, these findings indicate that induction of hepatic mtDNA-enriched EVs by ethanol is dependent on ASK1 and p38, thereby promoting alcoholic steatohepatitis.
  • Pretreatment clamping of pulmonary artery during uniportal thoracoscopic lobectomy

    Zhang, Ruijie; Cai, Yixin; Wang, Tiffany; Fu, Xiangning; Zhang, Ni (Springer Nature, 2020-07-22)
    BACKGROUND: Intraoperative pulmonary artery (PA) hemorrhage is one of the leading reasons for conversion from uniportal VATS to open thoracotomy, especially for the small incision (≤3 cm) uniportal VATS performed by our department. So, We designed a technology called pretreatment clamping of the pulmonary artery, which may be helpful to solve the problem. METHODS: A retrospective analysis of 19 patients who had pulmonary artery bleeding during uniportal thoracoscopic lobectomy in which one group had undergone preventive pulmonary artery clamping, the clamping group (n = 11), and one group which did not receive preventive clamping, the non-clamping group (n = 8). We compared the rates of conversion from the uniportal VATS approach to open thoracotomy or multi-incision operation, duration of pulmonary artery repair, blood loss, length of postoperative hospital stay and postoperative complications of the two groups. RESULTS: Compared to the non-clamping group, the clamping group had lower rates of conversion to open thoracotomy (0% vs 62.5%, p < 0.05) and lower rates of conversion to multi-incision operations (18.2% of non-clamping converted to 2-port approach vs 12.5% of clamping converted to 2-port approach and 12.5% converted to 3-port approach, p < 0.05). Duration of pulmonary artery repair was reduced in the clamping group (10.1 ± 3.2 min vs 18.3 ± 5.5 min, p < 0.05). The clamping group also had decreased blood loss (23.6 ± 11.2 ml vs 47.5 ± 14.9 ml, p<0.05). There were no significant differences in postoperative hospital stay and postoperative complications between the two groups. CONCLUSION: Pretreatment clamping of the pulmonary artery in VATS lobectomy can decrease conversion rates, decrease blood loss, shorten repairing time of the pulmonary artery, and feasibly can be applied in uniportal thoracoscopic lobectomy.
  • Association of Influenza Activity and Environmental Conditions With the Risk of Invasive Pneumococcal Disease

    Berry, Isha; Tuite, Ashleigh R; Salomon, Angela; Drews, Steven; Harris, Anthony D; Hatchette, Todd; Johnson, Caroline; Kwong, Jeff; Lojo, Jose; McGeer, Allison; et al. (American Medical Association, 2020-07-01)
    Importance: Streptococcus pneumoniae is the most commonly identified cause of bacterial pneumonia, and invasive pneumococcal disease (IPD) has a high case fatality rate. The wintertime coseasonality of influenza and IPD in temperate countries has suggested that pathogen-pathogen interaction or environmental conditions may contribute to IPD risk. Objectives: To evaluate the short-term associations of influenza activity and environmental exposures with IPD risk in temperate countries and to examine the generalizability of such associations across multiple jurisdictions. Design, Setting, and Participants: This case-crossover analysis of 19 566 individuals with IPD from 1998 to 2011 combined individual-level outcomes of IPD and population-level exposures. Participants lived in 12 jurisdictions in Canada (the province of Alberta and cities of Toronto, Vancouver, and Halifax), Australia (Perth, Sydney, Adelaide, Brisbane, and Melbourne), and the United States (Baltimore, Providence, and Philadelphia). Data were analyzed in 2019. Exposures: Influenza activity, mean temperature, absolute humidity, and UV radiation at delays of 1 to 3 weeks before case occurrence in each jurisdiction. Main Outcomes and Measures: Matched odds ratios (ORs) for IPD associated with changes in exposure variables, estimated using multivariable conditional logistic regression models. Heterogeneity in effects across jurisdictions were evaluated using random-effects meta-analytic models. Results: This study included 19 566 patients: 9629 from Australia (mean [SD] age, 42.8 [30.8] years; 5280 [54.8%] men), 8522 from Canada (only case date reported), and 1415 from the United States (only case date reported). In adjusted models, increased influenza activity was associated with increases in IPD risk 2 weeks later (adjusted OR [aOR] per SD increase, 1.07; 95% CI, 1.01-1.13). Increased humidity was associated with decreased IPD risk 1 week later (aOR per 1 g/m3, 0.98; 95% CI, 0.96-1.00). Other associations were heterogeneous; metaregression suggested that combinations of environmental factors might represent unique local risk signatures. For example, the heterogeneity in effects of UV radiation and humidity at a 2-week lag was partially explained by variation in temperature (UV index: coefficient, 0.0261; 95% CI, 0.0078 to 0.0444; absolute humidity: coefficient, -0.0077; 95% CI, -0.0125 to -0.0030). Conclusions and Relevance: In this study, influenza was associated with increased IPD risk in temperate countries. This association was not explained by coseasonality or case characteristics and appears generalizable. Absolute humidity was associated with decreased IPD risk in the same jurisdictions. The generalizable nature of these associations has important implications for influenza control and advances the understanding of the seasonality of this important disease.
  • The Association of ICU Acuity With Adherence to ICU Evidence-Based Processes of Care.

    Vranas, Kelly C; Scott, Jennifer Y; Badawi, Omar; Harhay, Michael O; Slatore, Christopher G; Sullivan, Donald R; Kerlin, Meeta Prasad (Elsevier Inc, 2020-03-27)
    Background: Admission to high-acuity ICUs has been associated with improved outcomes compared with outcomes in low-acuity ICUs, although the mechanism for these findings is unclear. Research Question: The goal of this study was to determine if high-acuity ICUs more effectively implement evidence-based processes of care that have been associated with improved clinical outcomes. Study Design and Methods: This retrospective cohort study was performed in adult ICU patients admitted to 322 ICUs in 199 hospitals in the Philips ICU telemedicine database between 2010 and 2015. The primary exposure was ICU acuity, defined as the mean Acute Physiology and Chronic Health Evaluation IVa score of all admitted patients in a calendar year, stratified into quartiles. Multivariable logistic regression was used to examine relations of ICU acuity with adherence to evidence-based VTE and stress ulcer prophylaxis, and with the avoidance of potentially harmful events. These events included hypoglycemia, sustained hyperglycemia, and liberal transfusion practices (defined as RBC transfusions prescribed for nonbleeding patients with preceding hemoglobin levels ≥ 7 g/dL). Results: Among 1,058,510 ICU admissions, adherence to VTE and stress ulcer prophylaxis was high across acuity levels. In adjusted analyses, those admitted to low-acuity ICUs compared with the highest acuity ICUs were more likely to experience hypoglycemic events (adjusted OR [aOR], 1.12; 95% CI, 1.04-1.19), sustained hyperglycemia (aOR, 1.07; 95% CI, 1.04-1.10), and liberal transfusion practices (aOR, 1.55; 95% CI, 1.33-1.82). Interpretation: High-acuity ICUs were associated with better adherence to several evidence-based practices, which may be a marker of high-quality care. Future research should investigate how high-acuity ICUs approach ICU organization to identify targets for improving the quality of critical care across all ICU acuity levels.
  • Interactive exploratory data analysis of Integrative Human Microbiome Project data using Metaviz

    Wagner, Justin; Kancherla, Jayaram; Braccia, Domenick; Matsumara, James; Felix, Victor; Crabtree, Jonathan; Mahurkar, Anup; Corrada Bravo, Héctor (F1000 Research Ltd, 2020-06-12)
    The rich data produced by the second phase of the Human Microbiome Project (iHMP) offers a unique opportunity to test hypotheses that interactions between microbial communities and a human host might impact an individual's health or disease status. In this work we describe infrastructure that integrates Metaviz, an interactive microbiome data analysis and visualization tool, with the iHMP Data Coordination Center web portal and the HMP2Data R/Bioconductor package. We describe integrative statistical and visual analyses of two datasets from iHMP using Metaviz along with the metagenomeSeq R/Bioconductor package for statistical analysis of differential abundance analysis. These use cases demonstrate the utility of a combined approach to access and analyze data from this resource. © 2020 Wagner J et al.
  • Safety, reactogenicity, and immunogenicity of a chimpanzee adenovirus vectored Ebola vaccine in adults in Africa: a randomised, observer-blind, placebo-controlled, phase 2 trial

    Tapia, Milagritos D; Sow, Samba O; Ndiaye, Birahim P; Mbaye, Khardiata D; Thiongane, Aliou; Ndour, Cheikh T; Mboup, Souleymane; Ake, Julie A; Keshinro, Babajide; Akintunde, Gideon A; et al. (Elsevier Inc, 2020-06)
    Background: The 2014 Zaire Ebola virus disease epidemic accelerated vaccine development for the virus. We aimed to assess the safety, reactogenicity, and immunogenicity of one dose of monovalent, recombinant, chimpanzee adenovirus type-3 vectored Zaire Ebola glycoprotein vaccine (ChAd3-EBO-Z) in adults. Methods: This phase 2, randomised, observer-blind, controlled trial was done in study centres in Cameroon, Mali, Nigeria, and Senegal. Healthy adults (≥18 years) were randomly assigned with a web-based system (1:1; minimisation procedure accounting for age, gender, centre) to receive ChAd3-EBO-Z (day 0), or saline placebo (day 0) and ChAd3-EBO-Z (month 6). The study was observer-blind until planned interim day 30 analysis, single-blind until month 6, and open-label after month 6 vaccination. Primary outcomes assessed in the total vaccinated cohort, which comprised all participants with at least one study dose administration documented, were serious adverse events (up to study end, month 12); and for a subcohort were solicited local or general adverse events (7 days post-vaccination), unsolicited adverse events (30 days post-vaccination), haematological or biochemical abnormalities, and clinical symptoms of thrombocytopenia (day 0–6). Secondary endpoints (subcohort; per-protocol cohort) evaluated anti-glycoprotein Ebola virus antibody titres (ELISA) pre-vaccination and 30 days post-vaccination. This study is registered with ClinicalTrials.gov, NCT02485301. Findings: Between July 22, 2015, and Dec 10, 2015, 3030 adults were randomly assigned; 3013 were included in the total vaccinated cohort (1509 [50·1%] in the ChAd3-EBO-Z group and 1504 [49·9%] in the placebo/ChAd3-EBO-Z group), 17 were excluded because no vaccine was administered. The most common solicited injection site symptom was pain (356 [48%] of 748 in the ChAd3-EBO-Z group vs 57 [8%] of 751 in the placebo/ChAd3-EBO-Z group); the most common solicited general adverse event was headache (345 [46%] in the ChAd3-EBO-Z group vs 136 [18%] in the placebo/ChAd3-EBO-Z group). Unsolicited adverse events were reported by 123 (16%) of 749 in the ChAd3-EBO-Z group and 119 (16%) of 751 in the placebo/ChAd3-EBO-Z group. Serious adverse events were reported for 11 (1%) of 1509 adults in the ChAd3-EBO-Z group, and 18 (1%) of 1504 in the placebo/ChAd3-EBO-Z group; none were considered vaccination-related. No clinically meaningful thrombocytopenia was reported. At day 30, anti-glycoprotein Ebola virus antibody geometric mean concentration was 900 (95% CI 824–983) in the ChAd3-EBO-Z group. There were no treatment-related deaths. Interpretation: ChAd3-EBO-Z was immunogenic and well tolerated in adults. Our findings provide a strong basis for future development steps, which should concentrate on multivalent approaches (including Sudan and Marburg strains). Additionally, prime-boost approaches should be a focus with a ChAd3-based vaccine for priming and boosted by a modified vaccinia Ankara-based vaccine. Funding: EU's Horizon 2020 research and innovation programme and GlaxoSmithKline Biologicals SA.
  • Quantifying topography-guided actin dynamics across scales using optical flow

    Lee, Rachel M; Campanello, Leonard; Hourwitz, Matt J; Alvarez, Phillip; Omidvar, Ava; Fourkas, John T; Losert, Wolfgang (American Society for Cell Biology, 2020-02-05)
    The dynamic rearrangement of the actin cytoskeleton is an essential component of many mechanotransduction and cellular force generation pathways. Here we use periodic surface topographies with feature sizes comparable to those of in vivo collagen fibers to measure and compare actin dynamics for two representative cell types that have markedly different migratory modes and physiological purposes: slowly migrating epithelial MCF10A cells and polarizing, fast-migrating, neutrophil-like HL60 cells. Both cell types exhibit reproducible guidance of actin waves (esotaxis) on these topographies, enabling quantitative comparisons of actin dynamics. We adapt a computer-vision algorithm, optical flow, to measure the directions of actin waves at the submicron scale. Clustering the optical flow into regions that move in similar directions enables micron-scale measurements of actin-wave speed and direction. Although the speed and morphology of actin waves differ between MCF10A and HL60 cells, the underlying actin guidance by nanotopography is similar in both cell types at the micron and submicron scales.
  • The Envelope Residues E152/156/158 of Zika Virus Influence the Early Stages of Virus Infection in Human Cells

    Bos, Sandra; Viranaicken, Wildriss; Frumence, Etienne; Li, Ge; Desprès, Philippe; Zhao, Richard Y.; Gadea, Gilles (MDPI AG, 2019-11-15)
    Emerging infections of mosquito-borne Zika virus (ZIKV) pose an increasing threat to human health, as documented over the recent years in South Pacific islands and the Americas in recent years. To better understand molecular mechanisms underlying the increase in human cases with severe pathologies, we recently demonstrated the functional roles of structural proteins capsid (C), pre-membrane (prM), and envelop (E) of ZIKV epidemic strains with the initiation of viral infection in human cells. Specifically, we found that the C-prM region contributes to permissiveness of human host cells to ZIKV infection and ZIKV-induced cytopathic effects, whereas the E protein is associated with viral attachment and early infection. In the present study, we further characterize ZIKV E proteins by investigating the roles of residues isoleucine 152 (Ile152), threonine 156 (Thr156), and histidine 158 (His158) (i.e., the E-152/156/158 residues), which surround a unique N-glycosylation site (E-154), in permissiveness of human host cells to epidemic ZIKV infection. For comparison purpose, we generated mutant molecular clones of epidemic BeH819015 (BR15) and historical MR766-NIID (MR766) strains that carry each other's E-152/156/158 residues, respectively. We observed that the BR15 mutant containing the E-152/156/158 residues from MR766 was less infectious in A549-Dual™ cells than parental virus. In contrast, the MR766 mutant containing E-152/156/158 residues from BR15 displayed increased infectivity. The observed differences in infectivity were, however, not correlated with changes in viral binding onto host-cells or cellular responses to viral infection. Instead, the E-152/156/158 residues from BR15 were associated with an increased efficiency of viral membrane fusion inside infected cells due to conformational changes of E protein that enhance exposure of the fusion loop. Our data highlight an important contribution of E-152/156/158 residues to the early steps of ZIKV infection in human cells.
  • Postnatal Guinea Pig Brain Development, as Revealed by Magnetic Resonance and Diffusion Kurtosis Imaging

    Mullins, Roger J.; Xu, Su; Zhuo, Jiachen; Roys, Steve; Pereira, Edna F.R.; Albuquerque, Edson X.; Gullapalli, Rao P. (MDPI AG, 2020-06-12)
    This study used in vivo magnetic resonance imaging (MRI) to identify age dependent brain structural characteristics in Dunkin Hartley guinea pigs. Anatomical T2-weighted images, diffusion kurtosis (DKI) imaging, and T2 relaxometry measures were acquired from a cohort of male guinea pigs from postnatal day (PND) 18–25 (juvenile) to PND 46–51 (adolescent) and PND 118–123 (young adult). Whole-brain diffusion measures revealed the distinct effects of maturation on the microstructural complexity of the male guinea pig brain. Specifically, fractional anisotropy (FA), as well as mean, axial, and radial kurtosis in the corpus callosum, amygdala, dorsal-ventral striatum, and thalamus significantly increased from PND 18–25 to PND 118–123. Age-related alterations in DKI measures within these brain regions paralleled the overall alterations observed in the whole brain. Age-related changes in FA and kurtosis in the gray matter-dominant parietal cerebral cortex and dorsal hippocampus were less pronounced than in the other brain regions. The regional data analysis revealed that between-age changes of diffusion kurtosis metrics were more pronounced than those observed in diffusion tensor metrics. The age-related anatomical differences reported here may be important determinants of the age-dependent neurobehavior of guinea pigs in different tasks. © 2020 by the authors.
  • Intensive care and anesthesia management for HARPOON beating heart mitral valve repair.

    Diprose, Paul; Fogg, Katheryn J; Pittarello, Demetrio; Gammie, James S; D'Ambra, Michael N (Wolters Kluwer Health, 2020-07-01)
    Patients with severe mitral valve regurgitation secondary to degenerative disease are known to benefit from mitral valve repair surgery. Novel techniques for achieving mitral valve repair on the beating heart have been developed and are being introduced into clinical practice. The HARPOON Beating Heart Mitral Valve Repair System (MVRS) in recent studies has demonstrated efficacy and safety for the repair of degenerative mitral valve disease on the beating heart. The device uses transoesophageal echocardiographic guidance to implant artificial expanded polytetrafluoroethylene (ePTFE) cords on prolapsed mitral valve leaflets in the beating heart. It requires general anaesthesia and there are specific intensive care and anaesthesia considerations for the safe management of these cases. This article describes the general principles of intensive care and anaesthesia management employed for the initial patients treated with the HARPOON Beating Heart MVRS, the outcomes for these patients, and the potential challenges for the future management of these cases.
  • Smarter Modeling to Enable a Smarter Insulin

    Taylor, Simeon I.; DiMarchi, Richard D. (American Diabetes Association, 2020-07-20)
  • The Natural History, Pathobiology, and Clinical Manifestations of SARS-CoV-2 Infections

    Machhi, Jatin; Herskovitz, Jonathan; Senan, Ahmed M.; Dutta, Debashis; Nath, Barnali; Oleynikov, Maxim D.; Blomberg, Wilson R.; Meigs, Douglas D.; Hasan, Mahmudul; Patel, Milankumar; et al. (Springer Science and Business Media LLC, 2020-07-21)
    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of coronavirus disease 2019 (COVID-19). SARS-CoV-2, is a positive-sense single-stranded RNA virus with epithelial cell and respiratory system proclivity. Like its predecessor, SARS-CoV, COVID-19 can lead to life-threatening disease. Due to wide geographic impact affecting an extremely high proportion of the world population it was defined by the World Health Organization as a global public health pandemic. The infection is known to readily spread from person-to-person. This occurs through liquid droplets by cough, sneeze, hand-to-mouth-to-eye contact and through contaminated hard surfaces. Close human proximity accelerates SARS-CoV-2 spread. COVID-19 is a systemic disease that can move beyond the lungs by blood-based dissemination to affect multiple organs. These organs include the kidney, liver, muscles, nervous system, and spleen. The primary cause of SARS-CoV-2 mortality is acute respiratory distress syndrome initiated by epithelial infection and alveolar macrophage activation in the lungs. The early cell-based portal for viral entry is through the angiotensin-converting enzyme 2 receptor. Viral origins are zoonotic with genomic linkages to the bat coronaviruses but without an identifiable intermediate animal reservoir. There are currently few therapeutic options, and while many are being tested, although none are effective in curtailing the death rates. There is no available vaccine yet. Intense global efforts have targeted research into a better understanding of the epidemiology, molecular biology, pharmacology, and pathobiology of SARS-CoV-2. These fields of study will provide the insights directed to curtailing this disease outbreak with intense international impact.
  • Extracorporeal Membrane Oxygenation for COVID-19

    Sanford, Zachary; Madathil, Ronson J.; Deatrick, Kristopher B.; Tabatabai, Ali; Menaker, Jay; Galvagno, Samuel M.; Mazzeffi, Michael A.; Rabin, Joseph; Ghoreishi, Mehrdad; Rector, Raymond; et al. (SAGE Publications, 2020-07-21)
  • Innovations—The COVID-19 Pandemic

    Ad, Niv (SAGE Publications, 2020-07-20)
  • Current State of Research About Chinese Herbal Medicines (CHM) for the Treatment of Coronavirus Disease 2019 (COVID-19): A Scoping Review

    López-Alcalde, Jesús; Yan, Yuqian; Witt, Claudia M.; Barth, Jürgen (Mary Ann Liebert Inc, 2020-07-01)
    Background: There is currently no effective treatment against coronavirus disease 2019 (COVID-19). The optimal selection of interventions targeting the virus is unknown. Therefore, evidence from randomized controlled trials (RCTs) to support specific treatment against COVID-19 is urgently needed. The use of Chinese herbal medicines (CHMs) might have a role in the treatment and symptomatic management of patients with COVID-19. It was aimed at providing an overview of the available evidence and ongoing trials concerning the effects of CHMs for the treatment of COVID-19. Methods: This is a narrative review of relevant studies. Searches were conducted to identify documents published till April 22, 2020. Electronic databases, evidence-based collections, websites of relevant organizations, and trial registries were consulted. Results: A total of 25 guidelines on the treatment of patients with COVID-19 were identified. Four guidelines provided recommendations on the use of CHMs; these guidelines were developed in China and South Korea and were based on the consensus of experts exclusively. The remaining 21 guidelines provided no guidance on CHMs. No finished RCTs of CHMs for the treatment of patients with COVID-19 was found. According to the evidence evaluated in this review, a Cochrane review of CHMs for severe acute respiratory syndrome and five uncontrolled observational studies of the effects of CHMs in patients with COVID-19, the effects of CHMs for COVID-19 are unknown. A total of 52 ongoing clinical trials of CHM interventions for the treatment of COVID-19 were found. These trials will be carried out mostly in China (n = 51). Forty (77%) of the ongoing trials will be randomized, whereas 12 (23%) have an unclear sequence generation procedure. Forty-seven trials (90%) will have a sample size <400 participants. Conclusions: To the authors' knowledge, only the Chinese and the South Korean guidelines recommend CHMs as a treatment option for patients with COVID-19. These guidelines base their recommendations on the consensus of experts. Clinical guidelines or health authorities from other countries do not provide advice on CHMs. Due to the absence of RCT, there is currently no reliable evidence on the effects of any specific CHM intervention for the treatment of patients with COVID-19. A high number of clinical trials of different herbal products are being currently conducted in China.
  • Frontline Blinatumomab in Older Adults with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

    Niyongere, Sandrine; Sanchez-Petitto, Gabriela; Masur, Jack; Baer, Maria R.; Duong, Vu H.; Emadi, Ashkan (MDPI AG, 2020-06-16)
    Outcomes of acute lymphoblastic leukemia (ALL) in older adults treated with chemotherapy are poor. The CD19/CD3 bispecific T-cell engager (BiTE) antibody blinatumomab is approved for refractory, relapsed or minimal/measurable residual disease (MRD)-positive B-cell ALL, but there is little experience in the upfront setting, including in older patients. We retrospectively analyzed outcomes of blinatumomab monotherapy in five newly diagnosed Philadelphia chromosome-negative B-cell ALL patients over 70 years. Three had cytokine release syndrome, treated with dexamethasone and/or tocilizumab, and four patients had neurotoxicity, treated with dexamethasone, without blinatumomab interruption. All five achieved complete remission (CR) after cycle one, three with undetectable MRD. All five were alive at 8 to 15 months. Three remained in MRD-negative CR. Two relapsed after cycle 3, one with extramedullary disease. In our small cohort of patients over 70 years, blinatumomab was safe initial therapy and produced a high response rate.
  • GDNF drives rapid tubule morphogenesis in a novel 3D in vitro model for ADPKD

    Dixon, Eryn E.; Maxim, Demetrios S.; Halperin Kuhns, Victoria L.; Lane-Harris, Allison C.; Outeda, Patricia; Ewald, Andrew J.; Watnick, Terry J.; Welling, Paul A.; Woodward, Owen M. (The Company of Biologists, 2020-06-08)
    Cystogenesis is a morphological consequence of numerous genetic diseases of the epithelium. In the kidney, the pathogenic mechanisms underlying the program of altered cell and tubule morphology are obscured by secondary effects of cyst expansion. Here, we developed a new 3D tubuloid system to isolate the rapid changes in protein localization and gene expression that correlate with altered cell and tubule morphology during cyst initiation. Mouse renal tubule fragments were pulsed with a cell differentiation cocktail including glial-derived neurotrophic factor (GDNF) to yield collecting duct-like tubuloid structures with appropriate polarity, primary cilia, and gene expression. Using the 3D tubuloid model with an inducible Pkd2 knockout system allowed the tracking of morphological, protein, and genetic changes during cyst formation. Within hours of inactivation of Pkd2 and loss of polycystin-2, we observed significant progression in tubuloid to cyst morphology that correlated with 35 differentially expressed genes, many related to cell junctions, matrix interactions, and cell morphology previously implicated in cystogenesis. This article has an associated First Person interview with the first author of the paper.
  • The Differential Diagnosis of Reparative Changes and Malignancy: Performance in the College of American Pathologists Pap Education and Proficiency Testing Programs

    Staats, Paul N.; Souers, Rhona J.; Nunez, Amberly Lindau; Li, Zaibo; Kurtycz, Daniel F. I.; Goodrich, Kelly; Witt, Benjamin Lloyd; Davey, Diane Davis; Booth, Christine Noga (College of American Pathologists, 2020-07)
    Context.-Repair is a challenging diagnosis and a significant source of false-positive (FP) interpretations in cervical cytology. No large-scale study of performance of repair in the liquid-based era has been performed. Objective.-To evaluate the performance of repair in the College of American Pathologists Pap Education and Proficiency Testing (PT) programs. Design.-The FP rate for slides classified as repair was evaluated by preparation type, participant type (cytotechnologist, pathologist, or laboratory), and program. The specific misdiagnosis category and individual slide performance were also evaluated. The rate of misclassification of slides as repair by participants for other diagnostic categories in the Pap Education program was assessed. Results.-The overall FP rate was 1700 of 12 715 (13.4%). There was no significant difference by program or preparation type. Within the Education program there was no difference by participant type, but pathologists' FP rate in the PT program (47 of 514, 9.1%) was significantly better than cytotechnologists in the PT program (51 of 380, 13.4%) and pathologists in the Education program (690 of 4900, 14.1%). High-grade squamous intraepithelial lesions/cancers (HSILþ) accounted for 1380 of 1602 FP interpretations (86%) in Education, but 43 of 98 (43.9%) in PT. Most slides had a low rate of misclassification, but a small number were poor performers. False-negative diagnosis of HSILþ as repair was less common, ranging from 0.7% to 1.8%. Conclusions.-Despite initial indications that liquid-based cytology might reduce the rate of misclassification of repair, FP interpretations remain common and are no different by preparation type. Misclassification is most commonly as HSIL or carcinoma, potentially resulting in significant patient harm.

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