Publications by authors named "Jennifer Yu"

171 Publications

Electronic forms for patient reported outcome measures (PROMs) are an effective, time-efficient, and cost-minimizing alternative to paper forms.

Pediatr Rheumatol Online J 2021 May 3;19(1):67. Epub 2021 May 3.

The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.

Background: Patient reported outcome measures (PROMs) provide valuable insight on patients' well-being and facilitates communication between healthcare providers and their patients. The increased integration of the technology within the healthcare setting presents the opportunity to collect PROMs electronically, rather than on paper. The Childhood Health Assessment Questionnaire (CHAQ) and Quality of My Life (QoML) are common PROMs collected from pediatric rheumatology patients. The objectives of this study are to (a) determine the equivalence of the paper and electronic forms (e-form) of CHAQ and QoML questionnaires; (b) identify potential benefits and barriers associated with using an e-form to capture PROMs; and (c) gather feedback on user experience.

Methods: Participants completed both a paper and an e-form of the questionnaires in a randomized order, following which they completed a feedback survey. Agreement of the scores between the forms were statistically analyzed using the intraclass correlation coefficient (ICC) (95 % Confidence Interval (CI)) and bias was assessed using a Bland-Altman plot. Completion and processing times of the forms were compared using mean and median measures. Quantitative analysis was performed to assess user experience ratings, while comments were qualitatively analyzed to identify important themes.

Results: 196 patients participated in this project. Scores on the forms had high ICC agreement > 0.9. New patients took longer than returning patients to complete the forms. Overall, the e-form was completed and processed in a shorter amount of time than the paper form. 83 % of survey respondents indicated that they either preferred the e-form or had no preference. Approximately 10 % of respondents suggested improvements to improve the user interface.

Conclusions: E-forms collect comparable information in an efficient manner to paper forms. Given that patients and caregivers indicated they preferred completing PROMs in this manner, we will implement their suggested changes and incorporate e-forms as standard practice for PROMs collection in our pediatric rheumatology clinic.
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http://dx.doi.org/10.1186/s12969-021-00551-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091685PMC
May 2021

Trials and Tribulations: mHealth Clinical Trials in the COVID-19 Pandemic.

Yearb Med Inform 2021 Apr 21. Epub 2021 Apr 21.

Graduate School of Biomedical Engineering, The University of New South Wales, Sydney, Australia.

Introduction: Mobile phone-based interventions in cardiovascular disease are growing in popularity. A randomised control trial (RCT) for a novel smartphone app-based model of care, named TeleClinical Care - Cardiac (TCC-Cardiac), commenced in February 2019, targeted at patients being discharged after care for an acute coronary syndrome or episode of decompensated heart failure. The app was paired to a digital sphygmomanometer, weighing scale and a wearable fitness band, all loaned to the patient, and allowed clinicians to respond to abnormal readings. The onset of the COVID-19 pandemic necessitated several modifications to the trial in order to protect participants from potential exposure to infection. The use of TCC-Cardiac during the pandemic inspired the development of a similar model of care (TCC-COVID), targeted at patients being managed at home with a diagnosis of COVID-19.

Methods: Recruitment for the TCC-Cardiac trial was terminated shortly after the World Health Organization announced COVID-19 as a global pandemic. Telephone follow-up was commenced, in order to protect patients from unnecessary exposure to hospital staff and patients. Equipment was returned or collected by a 'no-contact' method. The TCC-COVID app and model of care had similar functionality to the original TCC-Cardiac app. Participants were enrolled exclusively by remote methods. Oxygen saturation and pulse rate were measured by a pulse oximeter, and symptomatology measured by questionnaire. Measurement results were manually entered into the app and transmitted to an online server for medical staff to review.

Results: A total of 164 patients were involved in the TCC-Cardiac trial, with 102 patients involved after the onset of the pandemic. There were no hospitalisations due to COVID-19 in this cohort. The study was successfully completed, with only three participants lost to follow-up. During the pandemic, 5 of 49 (10%) of patients in the intervention arm were readmitted compared to 12 of 53 (23%) in the control arm. Also, in this period, 28 of 29 (97%) of all clinically significant alerts received by the monitoring team were managed successfully in the outpatient setting, avoiding hospitalisation. Patients found the user experience largely positive, with the average rating for the app being 4.56 out of 5. 26 patients have currently been enrolled for TCC-COVID. Recruitment is ongoing. All patients have been safely and effectively monitored, with no major adverse clinical events or technical malfunctions. Patient satisfaction has been high.

Conclusion: The TCC-Cardiac RCT was successfully completed despite the challenges posed by COVID-19. Use of the app had an added benefit during the pandemic as participants could be monitored safely from home. The model of care inspired the development of an app with similar functionality designed for use with patients diagnosed with COVID-19.
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http://dx.doi.org/10.1055/s-0041-1726487DOI Listing
April 2021

Re-evaluating Biopsy for Recurrent Glioblastoma: A Position Statement by the Christopher Davidson Forum Investigators.

Neurosurgery 2021 Apr 16. Epub 2021 Apr 16.

Department of Neurological Surgery, Washington University School of Medicine, St Louis, Missouri, USA.

Patients with glioblastoma (GBM) need bold new approaches to their treatment, yet progress has been hindered by a relative inability to dynamically track treatment response, mechanisms of resistance, evolution of targetable mutations, and changes in mutational burden. We are writing on behalf of a multidisciplinary group of academic neuro-oncology professionals who met at the collaborative Christopher Davidson Forum at Washington University in St Louis in the fall of 2019. We propose a dramatic but necessary change to the routine management of patients with GBM to advance the field: to routinely biopsy recurrent GBM at the time of presumed recurrence. Data derived from these samples will identify true recurrence vs treatment effect, avoid treatments with little chance of success, enable clinical trial access, and aid in the scientific advancement of our understanding of GBM.
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http://dx.doi.org/10.1093/neuros/nyab063DOI Listing
April 2021

Novel Method of Evaluating Liver Transplant Surgery Fellows Using Objective Measures of Operative Efficiency and Surgical Outcomes.

J Am Coll Surg 2021 Apr 6. Epub 2021 Apr 6.

Section of Abdominal Transplant Surgery, Washington University School of Medicine, St Louis, MO. Electronic address:

Background: The majority of liver transplantations (LTs) in North America are performed by transplant surgery fellows with attending surgeon supervision. Although a strict case volume requirement is mandatory for graduating fellows, no guidelines exist on providing constructive feedback to trainees during fellowship.

Study Design: A retrospective review of all adult LTs performed by abdominal transplant surgery fellows at a single American Society of Transplant Surgeons-accredited academic institution from 2005 to 2019 was conducted. Data from the most recent 5 fellows were averaged to generate reference learning curves for 8 variables representing operative efficiency (ie total operative time, warm ischemia time, and cold ischemia time) and surgical outcomes (ie intraoperative blood loss, unplanned return to the operating room, biliary complication, vascular complication, and patient/graft loss). Data for newer fellows were plotted against the reference curves at 3-month intervals to provide an objective assessment measure.

Results: Three hundred and fifty-two adult LTs were performed by 5 fellows during the study period. Mean patient age was 56 years; 67% were male; and mean Model for End-Stage Liver Disease score at transplantation was 22. For the 8 primary variables, mean values included the following: total operative time 330 minutes, warm ischemia time 28 minutes, cold ischemia time 288 minutes, intraoperative blood loss 1.59 L, biliary complication 19.6%, unplanned return to operating room 19.3%, and vascular complication 2.3%. A structure for feedback to fellows was developed using a printed report card and through in-person meetings with faculty at 3-month intervals.

Conclusions: Comparative feedback using institution-specific reference curves can provide valuable objective data on progression of individual fellows. It can aid in the timely identification of areas in need of improvement, which enhances the quality of training and has the potential to improve patient care and transplantation outcomes.
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http://dx.doi.org/10.1016/j.jamcollsurg.2021.03.029DOI Listing
April 2021

SERUM BIOCHEMISTRY AND SELECT MINERAL PARAMETERS OF PRE-RELEASE SUNDA PANGOLINS () FOLLOWING REHABILITATION IN VIETNAM.

J Zoo Wildl Med 2021 Apr;52(1):241-252

Global Health Program, Smithsonian's National Zoological Park and Conservation Biology Institute, Washington, DC 20008, USA.

Native to Southeast Asia, the Sunda pangolin () is critically endangered largely because of poorly regulated wildlife trade, consumptive practices, and use in traditional Chinese medicine. Efforts to rescue and rehabilitate animals confiscated from the illegal trade are complicated by a general lack of knowledge surrounding the normal health and disease processes unique to the species. To provide clinical reference intervals for normal health states of Sunda pangolins, biochemical parameters were determined from rescued individuals in Vietnam that had undergone a 14-day observation period and met a set of criteria for release back into the wild. Blood samples were collected from 42 apparently healthy Sunda pangolins while anesthetized or awake. Packed cell volume (PCV) and total solids (TS) were determined manually, and serum biochemistry values were determined in-house with a benchtop analyzer. Additional biochemical and mineral parameters not included in the primary panel were determined from a subset of 10 pangolins through an external diagnostic laboratory. Overall reference intervals were calculated for PCV and TS ( = 29) and for standard serum biochemistry parameters ( = 42). Females and males demonstrated significant variation with respect to body mass, potassium (K+), and phosphorus, whereas age was a significant source of variation in alkaline phosphatase. Seasonal variation in glucose (GLU), creatinine (CRE), total proteins, sodium, calcium, and K+ was also observed. Comparisons between anesthetized and awake pangolins demonstrated significant variation in GLU, CRE, and K+. The parameters determined in this study can serve as a clinical reference for ex situ Sunda pangolin conservation efforts. In the context of wildlife rehabilitation, serial bloodwork allows for continued monitoring of patient health and should inform decision making regarding release readiness and timing.
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http://dx.doi.org/10.1638/2020-0124DOI Listing
April 2021

Cefovecin pharmacokinetics after single-dose intramuscular administration in cheetahs (Acinonyx jubatus).

J Vet Pharmacol Ther 2021 Mar 28. Epub 2021 Mar 28.

Global Health Program, Smithsonian's National Zoo and Conservation Biology Institute, Washington, DC, USA.

Cefovecin is a third-generation cephalosporin with potential value for use in exotic felids due to its long duration of action. A sparse sampling protocol was implemented with 18 zoo-housed cheetahs (Acinonyx jubatus) to evaluate the pharmacokinetics of cefovecin (Convenia ) after a single 8 mg/kg intramuscular injection. Blood was collected serially for 15 days following administration, and plasma cefovecin concentrations were determined using high-pressure liquid chromatography with ultraviolet detection. Pharmacokinetic parameters were estimated using population pharmacokinetic methods and non-linear mixed effects modeling (NLME). Cefovecin was well tolerated by all cats, with no adverse effects observed. Peak plasma cefovecin concentration was 84.75 µg/ml, with a mean residence time of 207.9 h and an elimination half-life of 144.1 h (6.00 days). Plasma concentrations of cefovecin were maintained >7 µg/ml in all individuals for the entire study duration (15 days). These concentrations are lower, and the half-life slightly shorter, than the values reported for domestic cats. Cefovecin was highly protein-bound (approximately 99.9%) in cheetah plasma, which is nearly identical to domestic cats. These results indicate that cefovecin is potentially useful as a long-acting antibiotic in cheetahs.
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http://dx.doi.org/10.1111/jvp.12969DOI Listing
March 2021

Characterization of the GBoV1 Capsid and Its Antibody Interactions.

Viruses 2021 02 20;13(2). Epub 2021 Feb 20.

Department of Biochemistry and Molecular Biology, Center for Structural Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.

Human bocavirus 1 (HBoV1) has gained attention as a gene delivery vector with its ability to infect polarized human airway epithelia and 5.5 kb genome packaging capacity. Gorilla bocavirus 1 (GBoV1) VP3 shares 86% amino acid sequence identity with HBoV1 but has better transduction efficiency in several human cell types. Here, we report the capsid structure of GBoV1 determined to 2.76 Å resolution using cryo-electron microscopy (cryo-EM) and its interaction with mouse monoclonal antibodies (mAbs) and human sera. GBoV1 shares capsid surface morphologies with other parvoviruses, with a channel at the 5-fold symmetry axis, protrusions surrounding the 3-fold axis and a depression at the 2-fold axis. A 2/5-fold wall separates the 2-fold and 5-fold axes. Compared to HBoV1, differences are localized to the 3-fold protrusions. Consistently, native dot immunoblots and cryo-EM showed cross-reactivity and binding, respectively, by a 5-fold targeted HBoV1 mAb, 15C6. Surprisingly, recognition was observed for one out of three 3-fold targeted mAbs, 12C1, indicating some structural similarity at this region. In addition, GBoV1, tested against 40 human sera, showed the similar rates of seropositivity as HBoV1. Immunogenic reactivity against parvoviral vectors is a significant barrier to efficient gene delivery. This study is a step towards optimizing bocaparvovirus vectors with antibody escape properties.
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http://dx.doi.org/10.3390/v13020330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924616PMC
February 2021

Use of a Portable Analyzer for Venous Blood Gas and Biochemistry Analysis in Free-Ranging Indian Flying Foxes (Pteropus giganteus) in Myanmar.

J Wildl Dis 2021 Jan;57(1):242-245

Global Health Program, Smithsonian's National Zoological Park and Conservation Biology Institute, 3001 Connecticut Avenue, NW, MRC 5526, Suite 205A, Washington, DC 20008, USA.

We determined venous blood gas, acid-base, and biochemical parameters for thirteen free-ranging Indian flying foxes (Pteropus giganteus) in Myanmar, using a handheld i-STAT analyzer with CG8+ and CHEM8 cartridges. For field-based projects, portable blood analyzers enable identification and management of electrolyte and acid-base imbalances and collection of physiologic data, but present logistical challenges.
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http://dx.doi.org/10.7589/JWD-D-20-00095DOI Listing
January 2021

The intersection of land use and human behavior as risk factors for zoonotic pathogen exposure in Laikipia County, Kenya.

PLoS Negl Trop Dis 2021 Feb 19;15(2):e0009143. Epub 2021 Feb 19.

Global Health Program, Smithsonian Conservation Biology Institute, Smithsonian Institution, Washington, DC, United States of America.

A majority of emerging infectious diseases (EIDs) are zoonotic, mainly caused through spillover events linked to human-animal interactions. We conducted a survey-based human behavioral study in Laikipia County, Kenya, which is characterized by a dynamic human-wildlife-livestock interface. Questionnaires that assessed human-animal interactions, sanitation, and illnesses experienced within the past year were distributed to 327 participants among five communities in Laikipia. This study aimed to 1) describe variation in reported high-risk behaviors by community type and 2) assess the relationship between specific behaviors and self-reported illnesses. Behavioral trends were assessed in R via Fisher's exact tests. A generalized linear mixed model with Lasso penalization (GLMMLasso) was used to assess correlations between behaviors and participants' self-reported illness within the past year, with reported behaviors as independent variables and reported priority symptoms as the outcome. Reported behaviors varied significantly among the study communities. Participants from one community (Pastoralist-1) were significantly more likely to report eating a sick animal in the past year (p< 0.001), collecting an animal found dead to sell in the past year (p<0.0001), and not having a designated location for human waste (p<0.0001) when compared to participants from other communities. The GLMMLasso revealed that reports of an ill person in the household in the past year was significantly associated with self-reported illness. Sixty-eight percent of participants reported that bushmeat is available within the communities. Our study demonstrates community-level variation in behaviors that may influence zoonotic pathogen exposure. We further recommend development of targeted studies that explore behavioral variations among land use systems in animal production contexts.
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http://dx.doi.org/10.1371/journal.pntd.0009143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894889PMC
February 2021

Piwil1 Regulates Glioma Stem Cell Maintenance and Glioblastoma Progression.

Cell Rep 2021 Jan;34(1):108522

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NE60, Cleveland, OH 44195, USA; Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, CA50, Cleveland, OH 44195, USA. Electronic address:

Piwi proteins are a subfamily of Argonaute proteins that maintain germ cells in eukaryotes. However, the role of their human homologs in cancer stem cells, and more broadly in cancer, is poorly understood. Here, we report that Piwi-like family members are overexpressed in glioblastoma (GBM), with Piwil1 (Hiwi) most frequently overexpressed (88%). Piwil1 is enriched in glioma stem-like cells (GSCs) to maintain self-renewal. Silencing Piwil1 in GSCs leads to global changes in gene expression resulting in cell-cycle arrest, senescence, or apoptosis. Piwil1 knockdown increases expression of the transcriptional co-regulator BTG2 and the E3-ubiquitin ligase FBXW7, leading to reduced c-Myc expression, as well as loss of expression of stem cell factors Olig2 and Nestin. Piwil1 regulates mRNA stability of BTG2, FBXW7, and CDKN1B. In animal models of GBM, Piwil1 knockdown suppresses tumor growth and promotes mouse survival. These findings support a role of Piwil1 in GSC maintenance and glioblastoma progression.
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http://dx.doi.org/10.1016/j.celrep.2020.108522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837390PMC
January 2021

Effects of Lupron and surgical castration on fecal androgen metabolite concentrations and intermale aggression in capybaras (Hydrochoerus hydrochaeris).

Zoo Biol 2021 Mar 18;40(2):135-141. Epub 2020 Dec 18.

Global Health Program, Smithsonian's National Zoo and Conservation Biology Institute, Washington, District of Columbia, USA.

To curb agonistic interactions in a bachelor group of three male capybaras (Hydrochoerus hydrochaeris), a single dose of leuprolide acetate (Lupron®) was used in an attempt to chemically sterilize the males. Concurrently, fecal androgen metabolite (FAM) concentrations were quantified via enzyme immunoassay to monitor changes in testosterone production after injection of the gonadotropin-releasing hormone agonist. When Lupron proved ineffective in suppressing intraspecific aggression, surgical castration was performed on two males, with continued noninvasive endocrine monitoring. In all three capybaras, FAM concentrations increased initially as a result of the luteinizing hormone surge, but then decreased significantly following chemical sterilization. Surgical castration resulted in further, persistent declines in FAM concentrations in two males, while the third, intact male demonstrated a rise in FAM to pre-Lupron concentrations at 8.5 and 9.5-month postadministration. Despite successful suppression of sperm and testosterone production, intermale aggression continued, ultimately necessitating separation of the animals and transfer to other holding institutions. Under this set of conditions, a single Lupron dose was inadequate for suppressing intraspecific aggression in a group of three males with a pre-established history of aggression.
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http://dx.doi.org/10.1002/zoo.21586DOI Listing
March 2021

Timely Intervention and Control of a Novel Coronavirus (COVID-19) Outbreak at a Large Skilled Nursing Facility - San Francisco, California, 2020.

Infect Control Hosp Epidemiol 2020 Dec 14:1-20. Epub 2020 Dec 14.

California Department of Public Health, Richmond, California.

Objective: To describe epidemiologic and genomic characteristics of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in a large skilled nursing facility (SNF), and the strategies that controlled transmission.

Design, Setting, And Participants: Cohort study during March 22-May 4, 2020 of all staff and residents at a 780-bed SNF in San Francisco, California.

Methods: Contact tracing and symptom screening guided targeted testing of staff and residents; respiratory specimens were also collected through serial point prevalence surveys (PPS) in units with confirmed cases. Cases were confirmed by real-time reverse transcription-polymerase chain reaction testing for SARS-CoV-2; whole genome sequencing (WGS) characterized viral isolate lineages and relatedness. Infection prevention and control (IPC) interventions included restricting from work any staff who had close contact to a confirmed case; restricting movements between units; implementing surgical face masking facility-wide; and recommended PPE (isolation gown, gloves, N95 respirator and eye protection) for clinical interactions in units with confirmed cases.

Results: Of 725 staff and residents tested through targeted testing and serial PPS, twenty-one (3%) were SARS-CoV-2-positive; sixteen (76%) staff and 5 (24%) residents. Fifteen (71%) were linked to a single unit. Targeted testing identified 17 (81%) cases; PPS identified 4 (19%). Most (71%) cases were identified prior to IPC intervention. WGS was performed on SARS-CoV-2 isolates from four staff and four residents; five were of Santa Clara County lineage and the three others were distinct lineages.

Conclusions: Early implementation of targeted testing, serial PPS, and multimodal IPC interventions limited SARS-CoV-2 transmission within the SNF.
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http://dx.doi.org/10.1017/ice.2020.1375DOI Listing
December 2020

Cisplatin-Mediated Upregulation of APE2 Binding to MYH9 Provokes Mitochondrial Fragmentation and Acute Kidney Injury.

Cancer Res 2021 02 7;81(3):713-723. Epub 2020 Dec 7.

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.

Cisplatin chemotherapy is standard care for many cancers but is toxic to the kidneys. How this toxicity occurs is uncertain. In this study, we identified apurinic/apyrimidinic endonuclease 2 (APE2) as a critical molecule upregulated in the proximal tubule cells (PTC) following cisplatin-induced nuclear DNA and mitochondrial DNA damage in cisplatin-treated C57B6J mice. The APE2 transgenic mouse phenotype recapitulated the pathophysiological features of C-AKI (acute kidney injury, AKI) in the absence of cisplatin treatment. APE2 pulldown-MS analysis revealed that APE2 binds myosin heavy-Chain 9 (MYH9) protein in mitochondria after cisplatin treatment. Human MYH9-related disorder is caused by mutations in MYH9 that eventually lead to nephritis, macrothrombocytopenia, and deafness, a constellation of symptoms similar to the toxicity profile of cisplatin. Moreover, cisplatin-induced C-AKI was attenuated in APE2-knockout mice. Taken together, these findings suggest that cisplatin promotes AKI development by upregulating APE2, which leads to subsequent MYH9 dysfunction in PTC mitochondria due to an unrelated role of APE2 in DNA damage repair. This postulated mechanism and the availability of an engineered transgenic mouse model based on the mechanism of C-AKI provides an opportunity to identify novel targets for prophylactic treatment of this serious disease. SIGNIFICANCE: These results reveal and highlight an unexpected role of APE2 via its interaction with MYH9 and suggest that APE2 has the potential to prevent acute kidney injury in patients with cisplatin-treated cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/3/713/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869671PMC
February 2021

Diagnostic and Treatment Challenges for Acquired Hemophilia A in Pediatrics: Report of 2 Cases.

J Pediatr Hematol Oncol 2020 Nov 11. Epub 2020 Nov 11.

Department of Pediatrics, University of California-San Diego School of Medicine, La Jolla.

Acquired hemophilia A (AHA) occurs rarely in children. We report 2 cases of adolescent females with AHA. The first case underwent bone marrow aspiration/biopsy during workup, which was complicated by bleeding. Bleeding resolved after initiation of therapy with cyclophosphamide and glucocorticoid, but despite the addition of rituximab, she did not achieve complete remission until treatment with intravenous immunoglobulin. In the second case, we observed that a mixing study without incubation will not detect an acquired factor VIII inhibitor, but further workup based on suspicion for AHA led to the correct diagnosis. Both had significant medication toxicity which required treatment modification.
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http://dx.doi.org/10.1097/MPH.0000000000002007DOI Listing
November 2020

Results of Treatment of a Biliary Cystadenoma by Unroofing and Fulguration in a Female.

Am Surg 2020 Nov 6:3134820956313. Epub 2020 Nov 6.

Section of Hepato-Pancreato-Biliary Surgery, Siteman Cancer Center, Barnes-Jewish Hospital, Washington University School of Medicine in St. Louis, MO, USA.

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http://dx.doi.org/10.1177/0003134820956313DOI Listing
November 2020

Characterization of AAV-Specific Affinity Ligands: Consequences for Vector Purification and Development Strategies.

Mol Ther Methods Clin Dev 2020 Dec 4;19:362-373. Epub 2020 Oct 4.

Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.

Affinity-based purification of adeno-associated virus (AAV) vectors has replaced density-based methods for vectors used in clinical settings. This method utilizes camelid single-domain antibodies recognizing AAV capsids. These include AVB Sepharose (AVB) and POROS CaptureSelect affinity ligand for AAV8 (CSAL8) and AAV9 (CSAL9). In this study, we utilized cryo-electron microscopy and 3D image reconstruction to map the binding sites of these affinity ligands on the capsids of several AAV serotypes, including AAV1, AAV2, AAV5, AAV8, and AAV9, representing the range of sequence and structure diversity among AAVs. The AAV-ligand complex structures showed that AVB and CSAL9 bound to the 5-fold capsid region, although in different orientations, and CSAL8 bound to the side of the 3-fold protrusion. The AAV contact residues required for ligand binding, and thus AAV purification, and the ability of the ligands to neutralize infection were analyzed. The data show that only a few residues within the epitopes served to block affinity ligand binding. Neutralization was observed for AAV1 and AAV5 with AVB, for AAV1 with CSAL8, and for AAV9 with CSAL9, associated with regions that overlap with epitopes for neutralizing monoclonal antibodies against these capsids. This information is critical and could be generally applicable in the development of novel AAV vectors amenable to affinity column purification.
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http://dx.doi.org/10.1016/j.omtm.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591348PMC
December 2020

SATB2 drives glioblastoma growth by recruiting CBP to promote FOXM1 expression in glioma stem cells.

EMBO Mol Med 2020 12 30;12(12):e12291. Epub 2020 Oct 30.

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Nuclear matrix-associated proteins (NMPs) play critical roles in regulating chromatin organization and gene transcription by binding to the matrix attachment regions (MARs) of DNA. However, the functional significance of NMPs in glioblastoma (GBM) progression remains unclear. Here, we show that the Special AT-rich Binding Protein-2 (SATB2), one of crucial NMPs, recruits histone acetyltransferase CBP to promote the FOXM1-mediated cell proliferation and tumor growth of GBM. SATB2 is preferentially expressed by glioma stem cells (GSCs) in GBM. Disrupting SATB2 markedly inhibited GSC proliferation and GBM malignant growth by down-regulating expression of key genes involved in cell proliferation program. SATB2 activates FOXM1 expression to promote GSC proliferation through binding to the MAR sequence of FOXM1 gene locus and recruiting CBP to the MAR. Importantly, pharmacological inhibition of SATB2/CBP transcriptional activity by the CBP inhibitor C646 suppressed GSC proliferation in vitro and GBM growth in vivo. Our study uncovers a crucial role of the SATB2/CBP-mediated transcriptional regulation in GBM growth, indicating that targeting SATB2/CBP may effectively improve GBM treatment.
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http://dx.doi.org/10.15252/emmm.202012291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721366PMC
December 2020

Chronic neural activity recorded within breast tumors.

Sci Rep 2020 09 9;10(1):14824. Epub 2020 Sep 9.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.

Nerve fibers are known to reside within malignant tumors and the greater the neuronal density the worse prognosis for the patient. Recent discoveries using tumor bearing animal models have eluded to the autonomic nervous system having a direct effect on tumor growth and metastasis. We report the first direct and chronic in vivo measurements of neural activity within tumors. Using a triple-negative mammary cancer mouse model and chronic neural interface techniques, we have recorded neural activity directly within the tumor mass while the tumor grows and metastasizes. The results indicate that there is a strong connection between the autonomic nervous system and the tumor and could help uncover the mechanisms of tumor growth and metastasis.
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http://dx.doi.org/10.1038/s41598-020-71670-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481786PMC
September 2020

HIIT for post-COVID patients within cardiac rehabilitation: Response to letter to the editor.

Int J Cardiol 2021 Jan 31;322:291-292. Epub 2020 Aug 31.

Department of Cardiology, Prince of Wales Hospital and the Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.

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http://dx.doi.org/10.1016/j.ijcard.2020.08.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456951PMC
January 2021

Indications for readmission following mastectomy for breast cancer: An assessment of patient and operative factors.

Breast J 2020 10 26;26(10):1966-1972. Epub 2020 Aug 26.

Section of Endocrine and Oncologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.

We investigated the impact of patient and operative factors on 30-day hospital readmission following mastectomy for breast cancer. Using the 2011 HCUP California State Inpatient Database, we evaluated readmissions in adult women undergoing mastectomy for invasive, in situ, or history of breast cancer. Clinical data assessment was performed using ICD-9-CM codes and the Elixhauser comorbidity index. Chi-square tests and logistic regression were used to analyze patient and operative factors and associations with 30-day hospital readmission. Of 6214 women undergoing mastectomy, 306 (4.9%) were readmitted within 30 days postoperatively, most commonly for surgical site infection (130, 42.5%) and hematoma (29, 9.5%). 30-day readmission was associated with increasing index length of stay (LOS), comorbidities, and non-private insurance (P < .05). Age, mastectomy type (unilateral vs bilateral, with vs without lymph node assessment), immediate reconstruction, and port placement during the index procedure did not significantly influence the odds of 30-day readmission. Multivariable logistic regression showed increased odds of readmission with index LOS > 2 days (OR 1.81, P < .01), metastatic disease (OR 2.16, P = .01), and Medicare insurance (OR 1.72, P < .01). Index LOS > 2 days, metastatic disease, and Medicare insurance are significant predictors of 30-day readmission following mastectomy for breast cancer. Surgical site infection and wound complications were the most common diagnoses requiring readmission and resulted in over half of readmissions in our study population at 30 days.
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http://dx.doi.org/10.1111/tbj.14029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722119PMC
October 2020

Introduction to laser thermal therapy for brain disorders.

Int J Hyperthermia 2020 07;37(2):1-2

Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.

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http://dx.doi.org/10.1080/02656736.2020.1789764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673657PMC
July 2020

Feasibility and Utility of a Cardiovascular Risk Screening Tool in Women Undergoing Routine Gynecology Evaluation.

J Womens Health (Larchmt) 2020 09 13;29(9):1150-1159. Epub 2020 Jul 13.

Mount Sinai School of Medicine, New York, New York, USA.

Background: The goals of this multicenter survey were to examine the prevalence and patient awareness of cardiovascular risk factors, and the association between history of adverse pregnancy outcomes (APO—including gestational hypertension, gestational diabetes, and preeclampsia) and prevalence of cardiovascular risks among women presenting to outpatient obstetrics/gynecology (OB/GYN) clinics.

Materials And Methods: We surveyed 2,946 female patients attending 16 outpatient OB/GYN clinics across the United States between January 2010 and January 2012. Main outcome measures were self-reported cardiovascular risk factors and symptoms such as angina and dyspnea.

Results: Mean age of the patients was 51 ± 13.6 years. Cardiovascular risks and symptoms were highly prevalent (86.0% and 40.1%, respectively). Many patients did not know if they had common risk factors such as hypertension, hypercholesterolemia, or diabetes (18.4%, 32.0%, and 17.9%, respectively). Women with a history of APO were slightly more likely to be aware of common risk factors, including abnormal blood pressure (17% vs. 18.6%), high cholesterol (31.7% vs. 32%), and obesity/elevated body mass index (43.9% vs. 49.7%). Compared with patients with no history of APO, patients with APO (n = 380, 12.9%) were more likely to have risk factors (89.5% vs. 83.9%, p = 0.002) and symptoms (45.5% vs. 39.3%, p = 0.02).

Conclusions: Awareness of cardiovascular risk factors and symptoms among all women surveyed in this study was poor, although awareness for some risk factors was relatively higher among patients with APO. This study demonstrates the feasibility of cardiovascular assessment in OB/GYN clinics using a simple questionnaire and its potential role for early recognition and timely intervention.
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http://dx.doi.org/10.1089/jwh.2019.8074DOI Listing
September 2020

Cost-effectiveness analyses demonstrate that observation is superior to sentinel lymph node biopsy for postmenopausal women with HR + breast cancer and negative axillary ultrasound.

Breast Cancer Res Treat 2020 Sep 10;183(2):251-262. Epub 2020 Jul 10.

Department of Surgery, Section of Endocrine and Oncologic Surgery, Washington University St. Louis, St. Louis, MO, USA.

Purpose: To evaluate the cost-effectiveness of axillary observation versus sentinel lymph node biopsy (SLNB) after negative axillary ultrasound (AUS). In patients with clinical T1-T2 N0 breast cancer and negative AUS, SLNB is the current standard of care for axillary staging. However, SLNB is costly, invasive, decreasing in importance for medical decision-making, and is not considered therapeutic. Observation alone is currently being evaluated in randomized clinical trials, and is thought to be non-inferior to SLNB for patients with negative AUS.

Methods: We performed cost-effectiveness analyses of observation versus SLNB after negative AUS in postmenopausal women with clinical T1-T2 N0, HR/HER2 breast cancer. Costs at the 2016 price level were evaluated from a third-party commercial payer perspective using the MarketScan® Database. We compared cost, quality-adjusted life years (QALYs), and net monetary benefit (NMB). Multiple sensitivity analyses varying baseline probabilities, costs, utilities, and willingness-to-pay thresholds were performed.

Results: Observation was superior to SLNB for patients with N0 and N1 disease, and for the entire patient population (NMB in US$: $655,659 for observation versus $641,778 for SLNB for the entire patient population). In the N0 and N1 groups, observation incurred lower cost and was associated with greater QALYs. SLNB was superior for patients with > 3 positive lymph nodes, representing approximately 5% of the population. Sensitivity analyses consistently demonstrated that observation is the optimal strategy for AUS-negative patients.

Conclusion: Considering both cost and effectiveness, observation is superior to SLNB in postmenopausal women with cT1-T2 N0, HR/HER2 breast cancer and negative AUS.
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http://dx.doi.org/10.1007/s10549-020-05768-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607839PMC
September 2020

Mobile Phone Technologies in the Management of Ischemic Heart Disease, Heart Failure, and Hypertension: Systematic Review and Meta-Analysis.

JMIR Mhealth Uhealth 2020 07 6;8(7):e16695. Epub 2020 Jul 6.

Department of Cardiology, Prince of Wales Hospital, Sydney, Australia.

Background: Cardiovascular disease (CVD) remains the leading cause of death worldwide. Mobile phones have become ubiquitous in most developed societies. Smartphone apps, telemonitoring, and clinician-driven SMS allow for novel opportunities and methods in managing chronic CVD, such as ischemic heart disease, heart failure, and hypertension, and in the conduct and support of cardiac rehabilitation.

Objective: A systematic review was conducted using seven electronic databases, identifying all relevant randomized control trials (RCTs) featuring a mobile phone intervention (MPI) used in the management of chronic CVD. Outcomes assessed included mortality, hospitalizations, blood pressure (BP), and BMI.

Methods: Electronic data searches were performed using seven databases from January 2000 to June 2019. Relevant articles were reviewed and analyzed. Meta-analysis was performed using standard techniques. The odds ratio (OR) was used as a summary statistic for dichotomous variables. A random effect model was used.

Results: A total of 26 RCTs including 6713 patients were identified and are described in this review, and 12 RCTs were included in the meta-analysis. In patients with heart failure, MPIs were associated with a significantly lower rate of hospitalizations (244/792, 30.8% vs 287/803, 35.7%; n=1595; OR 0.77, 95% CI 0.62 to 0.97; P=.03; I=0%). In patients with hypertension, patients exposed to MPIs had a significantly lower systolic BP (mean difference 4.3 mm Hg; 95% CI -7.8 to -0.78 mm Hg; n=2023; P=.02).

Conclusions: The available data suggest that MPIs may have a role as a valuable adjunct in the management of chronic CVD.
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http://dx.doi.org/10.2196/16695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381017PMC
July 2020

Protein sumoylation with SUMO1 promoted by Pin1 in glioma stem cells augments glioblastoma malignancy.

Neuro Oncol 2020 12;22(12):1809-1821

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Background: The tumorigenic potential of glioma stem cells (GSCs) is associated with multiple reversible molecular alternations, but the role of posttranslational protein sumoylation in GSCs has not been elucidated. The development of GSC-targeting drugs relies on the discovery of GSC-preferential molecular modifications and the relevant signaling pathways. In this work, we investigated the protein sumoylation status, the major sumoylated substrate, and the key regulatory enzyme in GSCs to explore the therapeutic potential of disrupting protein sumoylation for glioblastoma (GBM) treatment.

Methods: Patient-derived GSCs, primary GBM sections, and intracranial GBM xenografts were used to determine protein sumoylation and the related molecular mechanisms by immunoblot, quantitative PCR, immunoprecipitation, immunofluorescence, and immunohistochemistry. Orthotopic GBM xenograft models were applied to investigate the inhibition of tumor growth by disrupting protein sumoylation with short hairpin (sh)RNAs or molecular inhibitors.

Results: We show that high levels of small ubiquitin-related modifier 1 (SUMO1)-but not SUMO2/3-modified sumoylation are preferentially present in GSCs. The promyelocytic leukemia (PML) protein is a major SUMO1-sumoylated substrate in GSCs, whose sumoylation facilitates its interaction with c-Myc to stabilize c-Myc proteins. The prolyl-isomerase Pin1 is preferentially expressed in GSCs and functions as the key enzyme to promote SUMO1 sumoylation. Disruption of SUMO1 sumoylation by Pin1 silencing with shRNAs or inhibition with its inhibitor Juglone markedly abrogated GSC maintenance and mitigated GSC-driven tumor growth.

Conclusions: Our findings indicate that high SUMO1-modified protein sumoylation as a feature of GSCs is critical for GSC maintenance, suggesting that targeting SUMO1 sumoylation may effectively improve GBM treatment.
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http://dx.doi.org/10.1093/neuonc/noaa150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746948PMC
December 2020

Structural Characterization of Cuta- and Tusavirus: Insight into Protoparvoviruses Capsid Morphology.

Viruses 2020 06 17;12(6). Epub 2020 Jun 17.

Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA.

Several members of the genus, capable of infecting humans, have been recently discovered, including cutavirus (CuV) and tusavirus (TuV). To begin the characterization of these viruses, we have used cryo-electron microscopy and image reconstruction to determine their capsid structures to ~2.9 Å resolution, and glycan array and cell-based assays to identify glycans utilized for cellular entry. Structural comparisons show that the CuV and TuV capsids share common features with other parvoviruses, including an eight-stranded anti-parallel β-barrel, depressions at the icosahedral 2-fold and surrounding the 5-fold axes, and a channel at the 5-fold axes. However, the viruses exhibit significant topological differences in their viral protein surface loops. These result in three separated 3-fold protrusions, similar to the bufaviruses also infecting humans, suggesting a host-driven structure evolution. The surface loops contain residues involved in receptor binding, cellular trafficking, and antigenic reactivity in other parvoviruses. In addition, terminal sialic acid was identified as the glycan potentially utilized by both CuV and TuV for cellular entry, with TuV showing additional recognition of poly-sialic acid and sialylated Lewis X (sLeXLeXLeX) motifs reported to be upregulated in neurotropic and cancer cells, respectively. These structures provide a platform for annotating the cellular interactions of these human pathogens.
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http://dx.doi.org/10.3390/v12060653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354515PMC
June 2020

Dual Role of WISP1 in maintaining glioma stem cells and tumor-supportive macrophages in glioblastoma.

Nat Commun 2020 06 15;11(1):3015. Epub 2020 Jun 15.

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.

The interplay between glioma stem cells (GSCs) and the tumor microenvironment plays crucial roles in promoting malignant growth of glioblastoma (GBM), the most lethal brain tumor. However, the molecular mechanisms underlying this crosstalk are incompletely understood. Here, we show that GSCs secrete the Wnt-induced signaling protein 1 (WISP1) to facilitate a pro-tumor microenvironment by promoting the survival of both GSCs and tumor-associated macrophages (TAMs). WISP1 is preferentially expressed and secreted by GSCs. Silencing WISP1 markedly disrupts GSC maintenance, reduces tumor-supportive TAMs (M2), and potently inhibits GBM growth. WISP1 signals through Integrin α6β1-Akt to maintain GSCs by an autocrine mechanism and M2 TAMs through a paracrine manner. Importantly, inhibition of Wnt/β-catenin-WISP1 signaling by carnosic acid (CA) suppresses GBM tumor growth. Collectively, these data demonstrate that WISP1 plays critical roles in maintaining GSCs and tumor-supportive TAMs in GBM, indicating that targeting Wnt/β-catenin-WISP1 signaling may effectively improve GBM treatment and the patient survival.
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http://dx.doi.org/10.1038/s41467-020-16827-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295765PMC
June 2020

Mouse models of neutropenia reveal progenitor-stage-specific defects.

Nature 2020 06 22;582(7810):109-114. Epub 2020 Apr 22.

Division of Immunobiology and Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required; however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes, aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.
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http://dx.doi.org/10.1038/s41586-020-2227-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041154PMC
June 2020

Detection of novel coronaviruses in bats in Myanmar.

PLoS One 2020 9;15(4):e0230802. Epub 2020 Apr 9.

One Health Institute, School of Veterinary Medicine, University of California, Davis, California, United States of America.

The recent emergence of bat-borne zoonotic viruses warrants vigilant surveillance in their natural hosts. Of particular concern is the family of coronaviruses, which includes the causative agents of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and most recently, Coronavirus Disease 2019 (COVID-19), an epidemic of acute respiratory illness originating from Wuhan, China in December 2019. Viral detection, discovery, and surveillance activities were undertaken in Myanmar to identify viruses in animals at high risk contact interfaces with people. Free-ranging bats were captured, and rectal and oral swabs and guano samples collected for coronaviral screening using broadly reactive consensus conventional polymerase chain reaction. Sequences from positives were compared to known coronaviruses. Three novel alphacoronaviruses, three novel betacoronaviruses, and one known alphacoronavirus previously identified in other southeast Asian countries were detected for the first time in bats in Myanmar. Ongoing land use change remains a prominent driver of zoonotic disease emergence in Myanmar, bringing humans into ever closer contact with wildlife, and justifying continued surveillance and vigilance at broad scales.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230802PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144984PMC
April 2020

Development of Corneal Sensation With Remodeling of the Epithelium and the Palisades of Vogt After Corneal Neurotization.

Cornea 2020 May;39(5):657-660

Department of Ophthalmology, University of Pittsburgh Schools of Medicine and Engineering, Pittsburgh, PA.

Purpose: Neurotrophic keratopathy (NK) produces persistent epithelial erosion which is hard to treat effectively. Recently, corneal neurotization surgery has produced reinnervation of the cornea with resolving neurotrophic keratopathy. We hypothesized that the generation of corneal epithelial nerves after neurotization surgery would not only restore the integrity of corneal epithelium but also produce a change in the configuration of the palisades of Vogt (POV), which houses the corneal epithelial stem cells.

Methods: We assessed a patient with unilateral congenital corneal anesthesia with optical coherence tomography pre-neurotization and post-neurotization.

Results: Over the course of 2 years, the patient gained corneal epithelial sensation and corneal and limbal epithelium was restored to normal thickness with corresponding changes in the POV.

Conclusions: The intimate relationship between epithelium and sensory nerves of the cornea has been well documented; however, changes in the corneal epithelial stem cell niche in conjunction with development of innervation have not previously been reported. Considering the architecture of the corneal nerves in conjunction with the architecture of the POV may assist in developing treatments that can support the regeneration and maintenance of epithelium during nerve regeneration.
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http://dx.doi.org/10.1097/ICO.0000000000002269DOI Listing
May 2020