Recent Submissions

  • Variation of Human Neural Stem Cells Generating Organizer States In Vitro before Committing to Cortical Excitatory or Inhibitory Neuronal Fates

    Micali, N.; Kim, S.-K.; Colantuoni, C. (Cell Press, 2020)
    Better understanding of the progression of neural stem cells (NSCs) in the developing cerebral cortex isimportant for modeling neurogenesis and defining the pathogenesis of neuropsychiatric disorders. Here,we use RNA sequencing, cell imaging, and lineage tracing of mouse and humanin vitroNSCs and monkeybrain sections to model the generation of cortical neuronal fates. We show that conserved signaling mech-anisms regulate the acute transition from proliferative NSCs to committed glutamatergic excitatory neurons.As human telencephalic NSCs develop from pluripotencyin vitro, they transition through organizer states thatspatially pattern the cortex before generating glutamatergic precursor fates. NSCs derived from multiple hu-man pluripotent lines vary in these early patterning states, leading differentially to dorsal or ventral telence-phalic fates. This work furthers systematic analyses of the earliest patterning events that generate the majorneuronal trajectories of the human telencephalon. Copyright 2020 The Authors
  • The SENIEUR protocol and the efficacy of hepatitis B vaccination in healthy elderly persons by age, gender, and vaccine route

    Edelman, R.; Deming, M.E.; Toapanta, F.R.; Heuser, M.D.; Chrisley, L.; Barnes, R.S.; Wasserman, S.S.; Handwerger, B.S.; Pasetti, M.; Sztein, M.B. (BioMed Central Ltd., 2020)
    Background: Reduced response to hepatitis B vaccines is associated with aging, confounding and comorbid conditions, as well as inadvertent subcutaneous (SC) inoculation. We hypothesized that the antibody and T cell-mediated immune responses (T-CMI) of elderly adults to a vaccine intended for intramuscular (IM) administration would be attenuated when deposited into SC fat, independent of confounding conditions. Results: Fifty-two healthy, community dwelling elderly adults (65-82 years), seronegative for HBV, were enrolled in the SENIEUR protocol as a strictly healthy population. These seniors were randomized to receive a licensed alum-adjuvanted recombinant HBV vaccine either SC or IM, with the inoculum site verified by imaging. The response rates, defined as hepatitis B surface antibodies (HBsAb) ?10 IU/L, were significantly lower in the elderly than in young adults, a group of 12, healthy, 21-34-year-old volunteers. Moreover, elderly participants who received the vaccine IM were significantly more likely to be responders than those immunized SC (54% versus 16%, p = 0.008). The low seroconversion rate in the IM group progressively declined with increasing age, and responders had significantly lower HBsAb titers and limited isotype responses. Moreover, T-CMI (proliferation and cytokine production) were significantly reduced in both percentage of responders and intensity of the response for both Th1 and Th2 subsets in the elderly. Conclusions: Our data demonstrate the blunted immunogenicity of SC inoculation as measured by peak titers and response rates. Further, the qualitative and quantitative deficits in B- A nd T-CMI responses to primary alum adjuvanted protein antigens persisted even in strictly healthy elderly populations with verified IM placement compared to younger populations. Clinical trial registration:, NCT04162223. Registered 14 November 2019. Retrospectively registered. Copyright 2020 The Author(s).
  • Successful Treatment of Acute Limb Ischemia Secondary to Iatrogenic Distal Embolization Using Catheter Directed Aspiration Thrombectomy

    Farhat-Sabet, A.A.; Tolaymat, B.; Drucker, C.B.; Ucuzian, A.A.; Toursavadkohi, S.A.; Nagarsheth, K.H. (Frontiers Media S.A., 2020)
    Objective: Acute limb ischemia (ALI) due to thromboembolism is a limb- and life-threatening condition regularly encountered by vascular surgeons. Iatrogenic distal embolization is occasionally seen as a complication of various endovascular procedures. We present a series of four patients who developed ALI due to arterial embolization during cardiovascular procedures that were successfully treated via catheter directed aspiration embolectomy. Methods: Retrospective review of demographics, risk factors, and procedural outcomes was completed for 4 patients who presented with ALI due to distal embolization following cardiovascular procedures. All patients were successfully treated with catheter directed aspiration embolectomy using the Penumbra Indigo System (Penumbra Inc., Alameda, California). All patients had high-quality angiography demonstrating successful embolectomy and end-procedure patency. Results: Three patients presented with Rutherford 2A and one with Rutherford 2B ALI secondary to intraoperative distal embolization. Three patients presented with ALI secondary to distal embolization during peripheral vascular interventions, and one following emergent intra-aortic balloon pump (IABP) placement for myocardial infarction. All emboli were located in the infra-inguinal vasculature. Median post-operative ABIs were 0.94 (n = 4). Median length of stay was 2 days. There were no mortalities and no need for adjunctive fasciotomy, amputation, or bypass for limb salvage. All patients improved clinically after intervention, and returned to their reported pre-hospitalization functional status. Conclusion: All procedures achieved technical success with catheter-directed aspiration thrombectomy with or without adjunctive lysis. Catheter-directed aspiration embolectomy with the Penumbra Indigo System for ALI following an iatrogenic embolic event is a safe, less-invasive treatment option. The use of this technology may reduce the need for traditional open thrombectomy or thrombolytic therapy to address ALI. Copyright 2020 Farhat-Sabet, et. al.
  • Potential of pembrolizumab in metastatic or recurrent head and neck cancer: Evidence to date

    McCusker, M.G.; Orkoulas-Razis, D.; Mehra, R. (Dove Medical Press Ltd., 2020)
    Relapsed and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a heterogeneous disease previously associated with poor prognosis and limited treatment options until the advent and implementation of immune checkpoint inhibitors (ICIs). The fully humanized monoclonal antibody pembrolizumab alone, or in combination with chemotherapy, was shown to have significantly improved overall survival (OS) when compared to the standard of care (SOC) EXTREME regimen consisting of the monoclonal antibody cetuximab combined with a platinum and 5-fluorouracil. Pembrolizumab with or without chemotherapy will soon supplant the EXTREME regimen that has been in use for over a decade. Given the fast-approaching significant change in the treatment algorithm for R/M HNSCC and the novelty of ICIs in general, it is important to review the literature to date to understand how this rapidly growing treatment class has come about and explore potential areas of research for the plethora of questions that remain unanswered in selecting patients appropriate for treatment with ICIs in the R/M setting. In this review, we explore the landmark trials leading to the use of ICIs for R/M HNSCC with a particular focus on pembrolizumab, the most well-studied ICI in this setting. We also provide an overview of the rationale behind the use of ICIs in relation to the immune system and challenges surrounding tumor heterogeneity and PD-L1 expression status, human papilloma virus (HPV) and the efficacy of ICI, potential of radiation therapy for enhancement of ICI response, and complications of immune-related adverse events (irAEs). Copyright 2020 McCusker et al.
  • Spontaneous Streptococcus pyogenes pelvic inflammatory disease; Case report and review of the literature

    Snyder, A.; Schmalzle, S.A. (Elsevier Ltd, 2020)
    Streptococcus pyogenes gynecological infections generally occur in association with childbirth, intra-uterine devices, and other invasive gynecologic procedures, but rarely cause spontaneous pelvic inflammatory disease. We describe a case of a healthy young woman with spontaneous S. pyogenes pelvic inflammatory disease, bacteremia, and shock, and summarize an additional 13 cases found in the literature. The majority were bacteremic and a significant number were also hypotensive. The same proportion had presenting gastrointestinal symptoms as had genitourinary symptoms, masking the diagnosis in many. Many prior case reports postulate a connection with S. pyogenes pharyngitis in a close contact, and an oro-genital route of transmission has been proposed given the exceedingly low rates of genital colonization with S. pyogenes. A high index of suspicion is needed for an accurate and timely diagnosis of this rare but potentially fatal condition. Copyright 2020 The Author(s)
  • The lymph node stromal laminin α5 shapes alloimmunity

    Li, L.; Shirkey, M.W.; Zhang, T.; Xiong, Y.; Piao, W.; Saxena, V.; Paluskievicz, C.; Lee, Y.; Toney, N.; Cerel, B.M.; et al. (American Society for Clinical Investigation, 2020)
    Lymph node stromal cells (LNSCs) regulate immunity through constructing lymphocyte niches. LNSC-produced laminin α5 (Lama5) regulates CD4+ T cells but the underlying mechanisms of its functions are poorly understood. Here we show that depleting Lama5 in LNSCs resulted in decreased Lama5 protein in the LN cortical ridge (CR) and around high endothelial venules (HEVs). Lama5 depletion affected LN structure with increased HEVs, upregulated chemokines, and cell adhesion molecules, and led to greater numbers of Tregs in the T cell zone. Mouse and human T cell transendothelial migration and T cell entry into LNs were suppressed by Lama5 through the receptors α6 integrin and α-dystroglycan. During immune responses and allograft transplantation, depleting Lama5 promoted antigen-specific CD4+ T cell entry into the CR through HEVs, suppressed T cell activation, and altered T cell differentiation to suppressive regulatory phenotypes. Enhanced allograft acceptance resulted from depleting Lama5 or blockade of T cell Lama5 receptors. Lama5 and Lama4/Lama5 ratios in allografts were associated with the rejection severity. Overall, our results demonstrated that stromal Lama5 regulated immune responses through altering LN structures and T cell behaviors. This study delineated a stromal Lama5–T cell receptor axis that can be targeted for immune tolerance modulation.
  • Return of Individual Research Results: A Guide for Biomedical Researchers Utilizing Human Biospecimens

    Sobel, M.E.; Dreyfus, J.C.; O'Leary, T.J. (Elsevier Inc., 2020)
    The recent movement toward returning individual research results to study subjects/participants generates ethical and legal challenges for laboratories performing research on human biospecimens. The concept of an individual's interest in knowing the results of testing on their tissue is pitted against individual and systemic risks and an established legal framework regulating the performance of laboratory testing for medical care purposes. This article discusses the rationale for returning individual research results to subjects, the potential risks associated with returning these results, and the legal framework in the United States that governs testing of identifiable human biospecimens. On the basis of these considerations, this article provides recommendations for investigators to consider when planning and executing human biospecimen research, with the objective of appropriately balancing the interests of research subjects, the need for ensuring integrity of the research process, and compliance with US laws and regulations. Copyright 2020 American Society for Investigative Pathology
  • Lipid-Mediated Insertion of Toll-Like Receptor (TLR) Ligands for Facile Immune Cell Engineering

    Zhang, M.H.; Slaby, E.M.; Szeto, G.L. (Frontiers Media S.A., 2020)
    Cell-based immunotherapies have tremendous potential to treat many diseases, such as activating immunity in cancer or suppressing it in autoimmune diseases. Most cell-based cancer immunotherapies in the clinic provide adjuvant signals through genetic engineering to enhance T cell functions. However, genetically encoded signals have minimal control over dosing and persist for the life of a cell lineage. These properties make it difficult to balance increasing therapeutic efficacy with reducing toxicities. Here, we demonstrated the potential of phospholipid-coupled ligands as a non-genetic system for immune cell engineering. This system provides simple, controlled, non-genetic adjuvant delivery to immune cells via lipid-mediated insertion into plasma membranes. Lipid-mediated insertion (termed depoting) successfully delivered Toll-like receptor (TLR) ligands intracellularly and onto cell surfaces of diverse immune cells. These ligands depoted into immune cells in a dose-controlled fashion and did not compete during multiplex pairwise loading. Immune cell activation could be enhanced by autocrine and paracrine mechanisms depending on the biology of the TLR ligand tested. Depoted ligands functionally persisted on plasma membranes for up to 4 days in naïve and activated T cells, enhancing their activation, proliferation, and skewing cytokine secretion. Our data showed that depoted ligands provided a persistent yet non-permanent adjuvant signal to immune cells that may minimize the intensity and duration of toxicities compared to permanent genetic delivery. Altogether, these findings demonstrate potential for lipid-mediated depoting as a universal cell engineering approach with unique, complementary advantages to other cell engineering methods. Copyright 2020 Zhang, et. al.
  • Non-operative management of blunt abdominal solid organ trauma in adult patients

    Ibrahim, W.; Hirshon, J.M.; El-Shinawi, M. (African Federation for Emergency Medicine, 2020)
    Introduction Despite agreement in the literature that “stable” blunt trauma patients may be managed conservatively, in Egypt many such patients receive operative management. This paper presents the results of a pragmatic, prospective, observational study to evaluate outcomes of non-operative (NOP) versus operative (OP) management of blunt abdominal solid organ trauma in hemodynamically stable adults admitted to Tanta University Emergency Hospital (TUH) in Egypt. Methods A prospective observational study enrolled adult blunt abdominal trauma patients with solid organ injury at TUH over a 3-year period (June 2014–June 2017). Inclusion criteria were age ≥18 yr, mean arterial pressure >65 mm Hg, heart rate <110 bpm, hematocrit ≥7 mg/dl, and abdominal organ injury diagnosed by ultrasound or computed tomography (CT). Excluded patients were those with pelvis and femur fractures; patients with penetrating abdominal trauma; predominate burn injuries, children and pregnant women. All patients were assigned to non-operative or operative management based on clinician preference. Outcomes of interest were 30-day mortality, blood transfusion volume, and length of stay. Descriptive statistics and χ2 were used to compare outcomes. Results During the study period, 4254 trauma patients presented to TUH. Of these, 790 had blunt abdominal trauma and 111 (14.1%) met inclusion criteria. Injury severity scores for each group were comparable (24 ± 10 – NOP vs. 28 ± 11 – OP, p = 0.126). NOP received less transfused blood (213.41 ± 360.3 ml [NOP] vs.1155.17 ± 380.4 ml [OP] (p < 0.0001)) but had a longer length of stay (8.29 ± 2.8 [NOP] vs. 6.45 ± 1.97 days [OP] (p = 0.012)). There was no difference in mortality between groups (p = 0.091). Conclusion Our study demonstrated that non-operative management in Egypt of blunt abdominal trauma was safe and resulted in fewer procedures, fewer units of blood transfused, and no increase in mortality. Longer length of stay for non-operative patients might reflect treating physician caution in their management.
  • Phosphodiesterase 5 (PDE5) restricts intracellular cGMP accumulation during enterotoxigenic Escherichia coli infection

    Foulke-Abel, J.; Yu, H.; Kaper, J.B.; Donowitz, M. (Taylor and Francis Inc., 2020)
    Diarrhea caused by enterotoxigenic Escherichia coli (ETEC) has a continuing impact on residents and travelers in underdeveloped countries. Both heat-labile (LT) and heat-stable (ST) enterotoxins contribute to pathophysiology via induction of cyclic nucleotide synthesis, and previous investigations focused on intracellular signal transduction rather than possible intercellular second messenger signaling. We modeled ETEC infection in human jejunal enteroid/organoid monolayers (HEM) and evaluated cyclic nucleotide pools, finding that intracellular cAMP was significantly increased but also underwent apical export, whereas cGMP was minimally retained intracellularly and predominantly effluxed into the basolateral space. LT and virulence factors including EatA, EtpA, and CfaE promoted ST release and enhanced ST-stimulated cGMP production. Intracellular cGMP was regulated by MK-571-sensitive export in addition to degradation by phosphodiesterase 5. HEMs had limited ST-induced intracellular cGMP accumulation compared to T84 or Caco-2 models. Cyclic nucleotide export/degradation demonstrates additional complexity in the mechanism of ETEC infection and may redirect understanding of diarrheal onset. Copyright 2020, The Author(s).
  • Mothers' satisfaction with health extension services and the associated factors in Gamo Goffa zone, Southern Ethiopia

    Mergia, M.; Shegaze, M.; Memiah, P. (Public Library of Science, 2020)
    Background Providing compassionate and respectful maternity services in order to bring satisfaction to service users is one of the health extension services packages in Ethiopia. Though the service utilization and its associated factors have been well documented so far, yet there is a dearth of information on client satisfaction; particularly among rural women who are mostly the target groups of health extension services within the Ethiopia. Thus, this study aimed to assess mothers' satisfaction with health extension services and the associated factors in the Gamo Goffa Zone, of Southern Ethiopia. Methods A community based cross sectional study was conducted among 478 women from February 1st to February 28th of 2018. A pre-tested and interviewer administered questionnaire was used to collect the data. The study participants were selected using a systematic random sampling technique by allocating a proportion to each rural kebeles. Both bivariate and multivariate logistic regression analysis were performed to identify associated factors. Odds ratio with its 95% confidence interval was used to determine the degree of association. Level of statistical significance was set at a p-value of less than 0.05. Result The overall proportion of mothers who were satisfied with health extension services was 37.4% with 95% CI (33-44%). Mothers who had good family monthly income [AOR = 4.66 (95% CI: 1.1, 20.6)], whose husbands participated in the health extension program [AOR = 4.02 (95% CI: 2.0, 8.1)], who had recent participation in planning of health extension programs [AOR = 5.75 (95% CI: 2.0, 16.5)], who were recognized as a model family [AOR = 2.23 (95% CI: 1.1, 4.6)] had higher odds of satisfaction with health extension services. Conclusion Satisfaction with the health extension services was low among women in the study area. A better household monthly income, women's and their husbands' participation in health extension services and being a member of a model family were positively associated with their satisfaction. Interventions to enhance women's satisfaction in the health extension service need to focus on household-based involvement of them and their husbands in planning and implementing the services. Likewise, expansion of experiences of model families in the community would raise satisfaction levels. Copyright 2020 Mergia et al.
  • Imaging hydroxyapatite in sub-retinal pigment epithelial deposits by fluorescence lifetime imaging microscopy with tetracycline staining

    Szmacinski, H.; Zeng, H.-H.; Eslami, K.; Puche, A.C.; Thompson, R.B. (SPIE, 2020)
    SIGNIFICANCE: Recent evidence suggests that hydroxyapatite (HAP) in sub-retinal pigment epithelial (sub-RPE) deposits in aged human eyes may act to nucleate and contribute to their growth to clinically detectable size. Sub-RPE deposits such as drusen are clinical hallmarks of age-related macular degeneration (AMD), therefore enhanced and earlier detection is a clinical need. We found that tetracycline-family antibiotics, long known to stain HAP in teeth and bones, can also label the HAP in sub-RPE deposits. However, HAP-bound tetracycline fluorescence excitation and emission spectra overlap with the well-known autofluorescence of outer retinal tissues, making them difficult to resolve. AIM: In this initial study, we sought to determine if the HAP-bound tetracyclines also exhibit enhanced fluorescence lifetimes, providing a useful difference in lifetime compared with the short lifetimes observed in vivo in the human retina by the pioneering work of Schweitzer, Zinkernagel, Hammer, and their colleagues, and thus a large enough effect size to resolve the HAP from background by fluorescence lifetime imaging. APPROACH: We stained authentic HAP with tetracyclines and measured the lifetime(s) by phase fluorometry, and stained aged, fixed human cadaver retinas with drusen with selected tetracyclines and imaged them by fluorescence lifetime imaging microscopy (FLIM). RESULTS: We found that chlortetracycline and doxycycline exhibited substantial increase in fluorescence lifetime compared to the free antibiotics and the retinal background, and the drusen were easily resolvable from the retinal background in these specimens by FLIM. CONCLUSIONS: These findings suggest that FLIM imaging of tetracycline (and potentially other molecules) binding to HAP could become a diagnostic tool for the development and progression of AMD.
  • Knowledge of and attitudes towards cardiopulmonary resuscitation among junior doctors and medical students in Upper Egypt: Cross-sectional study

    Mohammed, Z.; Arafa, A.; Hirshon, J.M. (BioMed Central Ltd., 2020)
    Background: Cardiopulmonary resuscitation (CPR) is a fundamental skill that should be acquired by all medical community members. This study aims to evaluate the knowledge and attitudes of junior doctors and medical students towards CPR and CPR training at Beni-Suef University Hospital in Upper Egypt, a representative region with conditions common to LMIC settings. Participants and methods: In this cross-sectional study, a total of 205 participants (60 junior doctors and 145 medical students) responded to a self-administered questionnaire assessing their knowledge regarding basic life support (BLS) and CPR techniques in neonates, children, and adults, in addition to attitudes towards the importance and necessity of CPR and CPR training. Results: Of the 60 junior doctors that participated in the study, only 31.7% had adequate knowledge of CPR, but up to 95% reported positive attitudes towards CPR training. Among the 145 medical student participants, only 6.2% had adequate knowledge of CPR, while 91% reported positive attitudes towards training. Deficiencies in CPR knowledge were more apparent in questions related to CPR in children and neonates. Junior doctors and medical students with previous CPR training demonstrated significantly better CPR knowledge than their counterparts without prior training. A statistically significant positive correlation was detected between CPR knowledge and attitude towards CPR training among medical students (r = 0.41, p < 0.001). Conclusion: The results of this study demonstrate suboptimal and inadequate CPR knowledge among junior doctors and medical students in a representative hospital in Upper Egypt. However, participants reported overwhelmingly positive attitudes and eagerness towards the implementation of CPR training. Further research needs to be done to establish CPR skill proficiency as well as to investigate barriers to CPR training, effectiveness of available programs, and the potential implementation of such a program in Egypt and other LMICs. Copyright 2020 The Author(s).
  • Histone Deacetylase SIRT1 Mediates C5b-9-Induced Cell Cycle in Oligodendrocytes

    Tatomir, A.; Rao, G.; Boodhoo, D.; Vlaicu, S.I.; Beltrand, A.; Anselmo, F.; Rus, V.; Rus, H. (Frontiers Media S.A., 2020)
    Sublytic levels of C5b-9 increase the survival of oligodendrocytes (OLGs) and induce the cell cycle. We have previously observed that SIRT1 co-localizes with surviving OLGs in multiple sclerosis (MS) plaques, but it is not yet known whether SIRT1 is involved in OLGs survival after exposure to sublytic C5b-9. We have now investigated the role of SIRT1 in OLGs differentiation and the effect of sublytic levels of C5b-9 on SIRT1 and phosphorylated-SIRT1 (Ser27) expression. We also examined the downstream effects of SIRT1 by measuring histone H3 lysine 9 trimethylation (H3K9me3) and the expression of cyclin D1 as a marker of cell cycle activation. OLG progenitor cells (OPCs) purified from the brain of rat pups were differentiated in vitro and treated with sublytic C5b-9 or C5b6. To investigate the signaling pathway activated by C5b-9 and required for SIRT1 expression, we pretreated OLGs with a c-jun antisense oligonucleotide, a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002), and a protein kinase C (PKC) inhibitor (H7). Our data show a significant reduction in phospho-SIRT1 and SIRT1 expression during OPCs differentiation, associated with a decrease in H3K9me3 and a peak of cyclin D1 expression in the first 24 h. Stimulation of OLGs with sublytic C5b-9 resulted in an increase in the expression of SIRT1 and phospho-SIRT1, H3K9me3, cyclin D1 and decreased expression of myelin-specific genes. C5b-9-stimulated SIRT1 expression was significantly reduced after pretreatment with c-jun antisense oligonucleotide, H7 or LY294002. Inhibition of SIRT1 with sirtinol also abolished C5b-9-induced DNA synthesis. Taken together, these data show that induction of SIRT1 expression by C5b-9 is required for cell cycle activation and is mediated through multiple signaling pathways. Copyright 2020 Tatomir, et. al.
  • H3Africa partnerships to empower clinical research sites to generate high-quality biological samples

    Croxton, T.; Agala, N.; Abimiku, A. (AOSIS OpenJournals Publishing AOSIS (Pty) Ltd, 2020)
    Background: The Institute of Human Virology Nigeria (IHVN) - Human Heredity and Health in Africa (H3Africa) Biorepository (I-HAB) seeks to provide high-quality biospecimens for research. This depends on the ability of clinical research sites (CRS) - who provide biospecimens - to operate according to well-established industry standards. Yet, standards are often neglected at CRSs located in Africa. Here, I-HAB reports on its four-pronged approach to empower CRSs to prepare high-quality biospecimens for research. Objectives: I-HAB sought (1) to assess a four-pronged approach to improve biobanking practices and sample quality among CRSs, and (2) to build human capacity. Methods: I-HAB partnered with two H3Africa principal investigators located in Nigeria and Ghana from August 2013 through to May 2017 to debut its four-pronged approach (needs assessment, training and mentorship, pilot, and continuous quality improvement) to empower CRSs to attain high-quality biospecimens. Results: Close collaborations were instrumental in establishing mutually beneficial and lasting relationships. Improvements during the 12 months of engagement with CRSs involved personnel, procedural, and supply upgrades. In total, 51 staff were trained in over 20 topics. During the pilot, CRSs extracted 50 DNA biospecimens from whole blood and performed quality control. The CRSs shipped extracted DNA to I-HAB and I-HAB that comparatively analysed the DNA. Remediation was achieved via recommendations, training, and mentorship. Preanalytical, analytical and post-analytical processes, standard operating procedures, and workflows were systematically developed. Conclusion: Partnerships between I-HAB and H3Africa CRSs enabled research sites to produce high-quality biospecimens through needs assessment, training and mentorship, pilot, and continuous monitoring and improvement. Copyright: 2020. The Authors.
  • Genomics of Otitis Media (OM) Molecular Genetics Approaches to Characterize Disease Pathophysiology

    Giese, A.P.J.; Isaiah, A.; Riazuddin, S.; Ahmed, Z.M. (Frontiers Media S.A., 2020)
    Otitis media (OM) is an infective and inflammatory disorder known to be a major cause of hearing impairment across all age groups. Both acute and chronic OM result in substantial healthcare utilization related to antibiotic prescription and surgical procedures necessary for its management. Although several studies provided evidence of genetics playing a significant role in the susceptibility to OM, we had limited knowledge about the genes associated with OM until recently. Here we have summarized the known genetic factors that confer susceptibility to various forms of OM in mice and in humans and their genetic load, along with associated cellular signaling pathways. Spotlighted in this review are fucosyltransferase (FUT) enzymes, which have been implicated in the pathogenesis of OM. A comprehensive understanding of the functions of OM-associated genes may provide potential opportunities for its diagnosis and treatment. Copyright 2020 The Authors.
  • Hypofractionated Proton Therapy with Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Phase 1 Trial from the University of Florida and Proton Collaborative Group

    Hoppe, B.S.; Nichols, R.C.; Mohindra, P. (Elsevier Inc., 2020)
    Purpose: We report the safety data from the first multicenter phase 1 trial investigating the use of hypofractionated proton therapy with concurrent chemotherapy for patients with stage II or III non-small cell lung cancer. Methods and Materials: From 2013 through 2018, patients with newly diagnosed stage II or III non-small cell lung cancer were enrolled in a multicenter phase 1 clinical trial evaluating concurrent chemotherapy with increasing dose-per-fraction proton therapy. This was a stepwise 5 + 2 dose-intensification protocol with the following dose arms: (1) 2.5 GyRBE per fraction to 60 GyRBE; (2) 3.0 GyRBE per fraction to 60 GyRBE; (3) 3.53 GyRBE per fraction to 60.01 GyRBE; and (4) 4.0 GyRBE per fraction to 60 GyRBE. A dose arm was considered tolerable if no radiation therapy-attributable severe adverse event (SAE) occurred within 90 days of treatment among 5 patients enrolled on the arm or if 1 SAE occurred among 7 patients enrolled. Dose constraints to the heart, brachial plexus, and spinal cord were more conservative at higher doses per fraction. Results: The study closed early because of slow accrual and competing enrollment in NRG 1308 before accrual was met, with no maximum tolerated dose identified. Eighteen patients were treated, including 5 patients on arms 1 and 2, 7 patients on arm 3, and 1 patient on arm 4. Two SAEs occurred among 7 patients treated at 3.53 GyRBE per fraction; however, per outside expert review, both were attributed to chemotherapy and unrelated to radiation therapy. Conclusions: Hypofractionated proton therapy delivered at 2.5 to 3.53 GyRBE per fraction to a dose of 60 GyRBE with concurrent chemotherapy has an acceptable toxicity profile. Further exploration of this regimen is warranted on a phase 2 clinical trial. 2020 The Author(s)
  • Extraperitoneal packing in unstable blunt pelvic trauma: A single-center study

    Frassini, S.; Gupta, S.; Granieri, S.; Cimbanassi, S.; Sammartano, F.; Scalea, T.M.; Chiara, O. (Wolters Kluwer Health, 2020)
    BACKGROUND: Hemodynamically unstable pelvic fractures often require a multi-modal approach including both operative and endovascular management. While an important adjunct in hemorrhage control, time to angioembolization even at the most advanced trauma centers may take hours. Extraperitoneal packing (EPP) is a fast and effective procedure that can immediately address pelvic hemorrhage from the retroperitoneal space in severe pelvic injuries. The aim of this study was to evaluate the efficacy of early EPP, looking at 24 hours and overall mortality, and the hemodynamic impact of EPP in unstable blunt pelvic trauma. METHODS: All trauma patients admitted to an urban Level I trauma center were evaluated from 2002 to 2018 in a retrospective single-center comparative study. Inclusion criteria were patients 14 years or older who sustained blunt trauma with pelvic fractures and hemodynamic instability. Exclusion criteria were a concomitant head injury (Abbreviated Injury Scale >3) and patients who underwent resuscitative thoracotomy. The patient population was divided into two groups: an EPP group and a no-EPP group. Propensity score matching was used to adjust for differences in baseline characteristics in the two groups: a one-to-one matched analysis using nearest-neighbor matching was performed based on the estimated propensity score of each patient. RESULTS: Two hundred forty-four patients presented hemodynamically unstable, with a pelvic fracture (180 no-EPP, 64 EPP). With propensity score matching, 37 patients in each group were analyzed. Survival within the first 24 hours was significantly improved in the EPP group (81.1% vs. 59.5%, p = 0.042) and we registered similar results in overall survival rate (78.4% EPP group vs. 56.8% no-EPP group, p = 0.047). Those patients who underwent early EPP (n = 64) were associated with a significant improvement in hemodynamic stability, with a pre-EPP mean arterial pressure of 49.9 mm Hg and post-EPP mean arterial pressure of 70.1 mm Hg (p < 0.01). CONCLUSION: Extraperitoneal pelvic packing is an effective procedure that can be performed immediately, even within the trauma bay, to improve hemodynamic stability and overall survival in patients who sustain severe blunt pelvic trauma. The early use of EPP can be lifesaving. LEVEL OF EVIDENCE: Therapeutic, Level III.

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