Recent Submissions

  • Trends in Moral Injury, Distress, and Resilience Factors among Healthcare Workers at the Beginning of the COVID-19 Pandemic.

    Hines, Stella E; Chin, Katherine H; Glick, Danielle R; Wickwire, Emerson M (MDPI AG, 2021-01-09)
    The coronavirus severe acute respiratory syndrome (COVID-19) pandemic has placed increased stress on healthcare workers (HCWs). While anxiety and post-traumatic stress have been evaluated in HCWs during previous pandemics, moral injury, a construct historically evaluated in military populations, has not. We hypothesized that the experience of moral injury and psychiatric distress among HCWs would increase over time during the pandemic and vary with resiliency factors. From a convenience sample, we performed an email-based, longitudinal survey of HCWs at a tertiary care hospital between March and July 2020. Surveys measured occupational and resilience factors and psychiatric distress and moral injury, assessed by the Impact of Events Scale-Revised and the Moral Injury Events Scale, respectively. Responses were assessed at baseline, 1-month, and 3-month time points. Moral injury remained stable over three months, while distress declined. A supportive workplace environment was related to lower moral injury whereas a stressful, less supportive environment was associated with increased moral injury. Distress was not affected by any baseline occupational or resiliency factors, though poor sleep at baseline predicted more distress. Overall, our data suggest that attention to improving workplace support and lowering workplace stress may protect HCWs from adverse emotional outcomes. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
  • Tampering of Viruses and Bacteria with Host DNA Repair: Implications for Cellular Transformation.

    Benedetti, Francesca; Curreli, Sabrina; Gallo, Robert C; Zella, Davide (MDPI AG, 2021-01-11)
    A reduced ability to properly repair DNA is linked to a variety of human diseases, which in almost all cases is associated with an increased probability of the development of cellular transformation and cancer. DNA damage, that ultimately can lead to mutations and genomic instability, is due to many factors, such as oxidative stress, metabolic disorders, viral and microbial pathogens, excess cellular proliferation and chemical factors. In this review, we examine the evidence connecting DNA damage and the mechanisms that viruses and bacteria have evolved to hamper the pathways dedicated to maintaining the integrity of genetic information, thus affecting the ability of their hosts to repair the damage(s). Uncovering new links between these important aspects of cancer biology might lead to the development of new targeted therapies in DNA-repair deficient cancers and improving the efficacy of existing therapies. Here we provide a comprehensive summary detailing the major mechanisms that viruses and bacteria associated with cancer employ to interfere with mechanisms of DNA repair. Comparing these mechanisms could ultimately help provide a common framework to better understand how certain microorganisms are involved in cellular transformation. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
  • Oral sedation for pain with cervical dilator placement: a randomized controlled trial

    Lee, Jessica K.; Burke, Anne E.; Thaler, Katrina; Robinson, Jennifer A.; Sufrin, Carolyn (Elsevier Ltd., 2021-01-01)
    Objective: Assess oral sedation versus placebo for pain control with cervical dilator placement. Study design: We randomized participants presenting for dilation and evacuation to lorazepam 1 mg/oxycodone 5 mg or placebo 45 min before cervical dilator placement. Our primary outcome was median visual analog scale (VAS) pain score after dilator placement using a 100-mm VAS. We used our outcome data to calculate median pain score changes from baseline to better reflect pain score differences between study groups. Planned sample size was 30 participants per group, for a total of 60. Results: We randomized 27 participants; 9 received sedation and 11 placebo. Median pain score increase from baseline to last dilator placement was 20 [interquartile range (IQR) 8–29] and 31 (IQR 15–81) in the oral sedation and placebo groups, p =.16. Conclusion: We were unable to enroll our desired sample size, and our sample is underpowered to make any conclusions. Our results suggest that oral sedation may provide some benefit for pain relief with dilator insertion and indicate that further research might be worthwhile especially in settings that do not routinely provide these analgesics. Implications: We had difficulty with study recruitment because many patients desired oral sedation for pain management for cervical dilator placement and declined randomization. Randomized trials of pain management with a placebo arm may find recruitment challenging especially if default clinical care already includes a pain management option that patients would have to opt out of. © 2021 The Authors
  • B and T Cell Immunity in Tissues and Across the Ages.

    Booth, Jayaum S; Toapanta, Franklin R (MDPI AG, 2021-01-06)
    B and T cells are key components of the adaptive immune system and coordinate multiple facets of immunity including responses to infection, vaccines, allergens, and the environment. In humans, B- and T-cell immunity has been determined using primarily peripheral blood specimens. Conversely, human tissues have scarcely been studied but they host multiple adaptive immune cells capable of mounting immune responses to pathogens and participate in tissue homeostasis. Mucosal tissues, such as the intestines and respiratory track, are constantly bombarded by foreign antigens and contain tissue-resident memory T (TRM) cells that exhibit superior protective capacity to pathogens. Also, tissue-resident memory B (BRM) cells have been identified in mice but whether humans have a similar population remains to be confirmed. Moreover, the immune system evolves throughout the lifespan of humans and undergoes multiple changes in its immunobiology. Recent studies have shown that age-related changes in tissues are not necessarily reflected in peripheral blood specimens, highlighting the importance of tissue localization and subset delineation as essential determinants of functional B and T cells at different life stages. This review describes our current knowledge of the main B- and T-cell subsets in peripheral blood and tissues across age groups.
  • Overcoming Obstacles to Targeting Muscarinic Receptor Signaling in Colorectal Cancer.

    Ali, Osman; Tolaymat, Mazen; Hu, Shien; Xie, Guofeng; Raufman, Jean-Pierre (MDPI AG, 2021-01-13)
    Despite great advances in our understanding of the pathobiology of colorectal cancer and the genetic and environmental factors that mitigate its onset and progression, a paucity of effective treatments persists. The five-year survival for advanced, stage IV disease remains substantially less than 20%. This review examines a relatively untapped reservoir of potential therapies to target muscarinic receptor expression, activation, and signaling in colorectal cancer. Most colorectal cancers overexpress M3 muscarinic receptors (M3R), and both in vitro and in vivo studies have shown that activating these receptors stimulates cellular programs that result in colon cancer growth, survival, and spread. In vivo studies using mouse models of intestinal neoplasia have shown that using either genetic or pharmacological approaches to block M3R expression and activation, respectively, attenuates the development and progression of colon cancer. Moreover, both in vitro and in vivo studies have shown that blocking the activity of matrix metalloproteinases (MMPs) that are induced selectively by M3R activation, i.e., MMP1 and MMP7, also impedes colon cancer growth and progression. Nonetheless, the widespread expression of muscarinic receptors and MMPs and their importance for many cellular functions raises important concerns about off-target effects and the safety of employing similar strategies in humans. As we highlight in this review, highly selective approaches can overcome these obstacles and permit clinicians to exploit the reliance of colon cancer cells on muscarinic receptors and their downstream signal transduction pathways for therapeutic purposes.
  • Near-Complete Sequence of a Highly Divergent Reovirus Genome Recovered from Callinectes sapidus.

    Zhao, Mingli; Flowers, Emily M; Schott, Eric J (American Society for Microbiology, 2021-01-07)
    This report describes the sequence of a reovirus genome, discovered in Callinectes sapidus in Brazil. The genome sequence of Callinectes sapidus reovirus 2 (CsRV2) consists of 12 segments that encode 13 putative proteins. The predicted RNA-dependent RNA polymerase is highly similar to that of Eriocheir sinensis reovirus 905, suggesting that CsRV2 also belongs to the genus Cardoreovirus.
  • Discovery of beta-lactamase CMY-10 inhibitors for combination therapy against multi-drug resistant Enterobacteriaceae

    Parvaiz, Nousheen; Ahmad, Faisal; Yu, Wenbo; MacKerell, Alexander D; Azam, Syed Sikander (Public Library of Science, 2021-01-15)
    β-lactam antibiotics are the most widely used antimicrobial agents since the discovery of benzylpenicillin in the 1920s. Unfortunately, these life-saving antibiotics are vulnerable to inactivation by continuously evolving β-lactamase enzymes that are primary resistance determinants in multi-drug resistant pathogens. The current study exploits the strategy of combination therapeutics and aims at identifying novel β-lactamase inhibitors that can inactivate the β-lactamase enzyme of the pathogen while allowing the β-lactam antibiotic to act against its penicillin-binding protein target. Inhibitor discovery applied the Site-Identification by Ligand Competitive Saturation (SILCS) technology to map the functional group requirements of the β-lactamase CMY-10 and generate pharmacophore models of active site. SILCS-MC, Ligand-grid Free Energy (LGFE) analysis and Machine-learning based random-forest (RF) scoring methods were then used to screen and filter a library of 700,000 compounds. From the computational screens 74 compounds were subjected to experimental validation in which β-lactamase activity assay, in vitro susceptibility testing, and Scanning Electron Microscope (SEM) analysis were conducted to explore their antibacterial potential. Eleven compounds were identified as enhancers while 7 compounds were recognized as inhibitors of CMY-10. Of these, compound 11 showed promising activity in β-lactamase activity assay, in vitro susceptibility testing against ATCC strains (E. coli, E. cloacae, E. agglomerans, E. alvei) and MDR clinical isolates (E. cloacae, E. alvei and E. agglomerans), with synergistic assay indicating its potential as a β-lactam enhancer and β-lactamase inhibitor. Structural similarity search against the active compound 11 yielded 28 more compounds. The majority of these compounds also exhibited β-lactamase inhibition potential and antibacterial activity. The non-β-lactam-based β-lactamase inhibitors identified in the current study have the potential to be used in combination therapy with lactam-based antibiotics against MDR clinical isolates that have been found resistant against last-line antibiotics.
  • Identifying intracellular signaling modules and exploring pathways associated with breast cancer recurrence

    Chen, Xi; Gu, Jinghua; Neuwald, Andrew F; Hilakivi-Clarke, Leena; Clarke, Robert; Xuan, Jianhua (Springer Nature, 2021-01-11)
    Exploring complex modularization of intracellular signal transduction pathways is critical to understanding aberrant cellular responses during disease development and drug treatment. IMPALA (Inferred Modularization of PAthway LAndscapes) integrates information from high throughput gene expression experiments and genome-scale knowledge databases to identify aberrant pathway modules, thereby providing a powerful sampling strategy to reconstruct and explore pathway landscapes. Here IMPALA identifies pathway modules associated with breast cancer recurrence and Tamoxifen resistance. Focusing on estrogen-receptor (ER) signaling, IMPALA identifies alternative pathways from gene expression data of Tamoxifen treated ER positive breast cancer patient samples. These pathways were often interconnected through cytoplasmic genes such as IRS1/2, JAK1, YWHAZ, CSNK2A1, MAPK1 and HSP90AA1 and significantly enriched with ErbB, MAPK, and JAK-STAT signaling components. Characterization of the pathway landscape revealed key modules associated with ER signaling and with cell cycle and apoptosis signaling. We validated IMPALA-identified pathway modules using data from four different breast cancer cell lines including sensitive and resistant models to Tamoxifen. Results showed that a majority of genes in cell cycle/apoptosis modules that were up-regulated in breast cancer patients with short survivals (< 5 years) were also over-expressed in drug resistant cell lines, whereas the transcription factors JUN, FOS, and STAT3 were down-regulated in both patient and drug resistant cell lines. Hence, IMPALA identified pathways were associated with Tamoxifen resistance and an increased risk of breast cancer recurrence. The IMPALA package is available at © 2021, The Author(s).
  • Listeria Meningitis: An Inconsistent Organism Causing an Inconsistent Disease.

    Hauser, Naomi; Luethy, Paul M; Stamatos, Nicholas (Elsevier Inc., 2020-07-24)
  • Opinion: Standardizing gene product nomenclature-a call to action.

    Fujiyoshi, Kenji; Bruford, Elspeth A; Mroz, Pawel; Sims, Cynthe L; O'Leary, Timothy J; Lo, Anthony W I; Chen, Neng; Patel, Nimesh R; Patel, Keyur Pravinchandra; Seliger, Barbara; et al. (National Academy of Sciences of the United States of America, 2021-01-19)
  • Contemporary incidence and risk factors of post transplant Erythrocytosis in deceased donor kidney transplantation.

    Alasfar, Sami; Hall, Isaac E; Mansour, Sherry G; Jia, Yaqi; Thiessen-Philbrook, Heather R; Weng, Francis L; Singh, Pooja; Schröppel, Bernd; Muthukumar, Thangamani; Mohan, Sumit; et al. (Springer Nature, 2021-01-12)
    Background: Post-Transplant erythrocytosis (PTE) has not been studied in large recent cohorts. In this study, we evaluated the incidence, risk factors, and outcome of PTE with current transplant practices using the present World Health Organization criteria to define erythrocytosis. We also tested the hypothesis that the risk of PTE is greater with higher-quality kidneys. Methods: We utilized the Deceased Donor Study which is an ongoing, multicenter, observational study of deceased donors and their kidney recipients that were transplanted between 2010 and 2013 across 13 centers. Eryrthocytosis is defined by hemoglobin> 16.5 g/dL in men and> 16 g/dL in women. Kidney quality is measured by Kidney Donor Profile Index (KDPI). Results: Of the 1123 recipients qualified to be in this study, PTE was observed at a median of 18 months in 75 (6.6%) recipients. Compared to recipients without PTE, those with PTE were younger [mean 48±11 vs 54±13 years, p < 0.001], more likely to have polycystic kidney disease [17% vs 6%, p < 0.001], have received kidneys from younger donors [36 ±13 vs 41±15 years], and be on RAAS inhibitors [35% vs 22%, p < 0.001]. Recipients with PTE were less likely to have received kidneys from donors with hypertension [16% vs 32%, p = 0.004], diabetes [1% vs 11%, p = 0.008], and cerebrovascular event (24% vs 36%, p = 0.036). Higher KDPI was associated with decreased PTE risk [HR 0.98 (95% CI: 0.97–0.99)]. Over 60 months of follow-up, only 17 (36%) recipients had sustained PTE. There was no association between PTE and graft failure or mortality, Conclusions: The incidence of PTE was low in our study and PTE resolved in majority of patients. Lower KDPI increases risk of PTE. The underutilization of RAAS inhibitors in PTE patients raises the possibility of under-recognition of this phenomenon and should be explored in future studies. © 2021, The Author(s).
  • Control of synaptic transmission and neuronal excitability in the parabrachial nucleus.

    Cramer, Nathan; Silva-Cardoso, Gleice; Masri, Radi; Keller, Asaf (Elsevier B.V., 2020-12-14)
    The parabrachial nucleus (PB) is a hub for aversive behaviors, including those related to pain. We have shown that the expression of chronic pain is causally related to amplified activity of PB neurons, and to changes in synaptic inhibition of these neurons. These findings indicate that regulation of synaptic activity in PB may modulate pain perception and be involved in the pathophysiology of chronic pain. Here, we identify the roles in PB of signaling pathways that modulate synaptic functions. In pharmacologically isolated lateral PB neurons in acute mouse slices we find that baclofen, a GABAB receptor agonist, suppresses the frequency of miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSC). Activation of µ-opioid peptide receptors with DAMGO had similar suppressive effects on excitatory and inhibitory synapses, while the κ-opioid peptide receptor agonist U-69593 suppressed mIPSC release but had no consistent effects on mEPSCs. Activation of cannabinoid type 1 receptors with WIN 55,212-2 reduced the frequency of both inhibitory and excitatory synaptic events, while the CB1 receptor inverse agonist AM251 had opposite effects on mIPSC and mEPSC frequencies. AM251 increased the frequency of inhibitory events but led to a reduction in excitatory events through a GABAB mediated mechanism. Although none of the treatments produced a consistent effect on mIPSC or mEPSC amplitudes, baclofen and DAMGO both reliably activated a postsynaptic conductance. These results demonstrate that multiple signaling pathways can alter synaptic transmission and neuronal excitability in PB and provide a basis for investigating the contributions of these systems to the development and maintenance of chronic pain.
  • Reduction in Revascularization With Icosapent Ethyl: Insights From REDUCE-IT Revascularization Analyses.

    Peterson, Benjamin E; Bhatt, Deepak L; Steg, Ph Gabriel; Miller, Michael; Brinton, Eliot A; Jacobson, Terry A; Ketchum, Steven B; Juliano, Rebecca A; Jiao, Lixia; Doyle, Ralph T; et al. (Wolters Kluwer Health, 2020-11-05)
    A total of 8179 randomly assigned patients were followed for 4.9 years (median). First revascularizations were reduced to 9.2% (22.5/1000 patient-years) with icosapent ethyl versus 13.3% (33.7/1000 patient-years) with placebo (hazard ratio, 0.66 [95% CI, 0.58-0.76]; P<0.0001; number needed to treat for 4.9 years=24); similar reductions were observed in total (first and subsequent) revascularizations (negative binomial rate ratio, 0.64 [95% CI, 0.56-0.74]; P<0.0001), and across elective, urgent, and emergent revascularizations. Icosapent ethyl significantly reduced percutaneous coronary intervention (hazard ratio, 0.68 [95% CI, 0.59-0.79]; P<0.0001) and coronary artery bypass grafting (hazard ratio, 0.61 [95% CI, 0.45-0.81]; P=0.0005).
  • Comparison of the effectiveness of single- and multiple-sessions disinfection protocols against endotoxins in root canal infections: systematic review and meta-analysis.

    Nascimento, Gustavo G; Rabello, Diego G D; Corazza, Bruna J M; Gomes, Ana P M; Silva, Eduardo G; Martinho, Frederico C (Springer Nature, 2021-01-13)
    This systematic review (SR) addressed the following common clinical question: What is more effective in reducing or eliminating endotoxin in endodontic infections-single or multiple-session treatments using calcium hydroxide medications? Literature searches of Medline/PubMed, Embase, Cochrane Library, Scielo, Science Direct, Web of Knowledge, Scopus, and Google Scholar databases. Two reviewers independently assessed the eligibility for inclusion, extracted data, and evaluated the quality of the studies using the risk of bias tools. Electronic searches resulted in 358 articles, of which 32 studies were included for full-text assessment, and nine were included in this review. Meta-analysis pooling all the nine studies revealed lower levels of endotoxin for multiple-session treatment (P < 0.001). The sub-group analysis indicated no difference between single-session and 7 days of Ca(OH)2 medication (SMD - 0.32; P = 0.22). However, 14-days (I2 = 80.5%, P < 0.001) and 30-days (I2 = 78.9%, P < 0.01) of Ca(OH)2 medication was more effective than single-session treatment (both, p < 0.001). Overall, Overall, this SR provides evidence to support that multiple-session disinfection protocols with the placement of Ca(OH)2 medications are more effective in reducing the levels of endotoxin from root canal infections compared to single-session when applied for 14 and 30 days.
  • Improving Uptake of a National Web-Based Psychoeducational Workshop for Informal Caregivers of Veterans: Mixed Methods Implementation Evaluation.

    Yank, Veronica; Gale, Randall C; Nevedal, Andrea; Okwara, Leonore; Koenig, Christopher J; Trivedi, Ranak B; Dupke, Nancy J; Kabat, Margaret; Asch, Steven M (JMIR Publications Inc., 2021-01-07)
    Background: Although web-based psychoeducational programs may be an efficient, accessible, and scalable option for improving participant well-being, they seldom are sustained beyond trial publication. Implementation evaluations may help optimize program uptake, but few are performed. When the US Department of Veterans Affairs (VA) launched the web-based psychoeducational workshop Building Better Caregivers (BBC) for informal caregivers of veterans nationwide in 2013, the workshop did not enroll as many caregivers as anticipated. Objective: This study aims to identify the strengths and weaknesses of initial implementation, strategies likely to improve workshop uptake, whether the VA adopted these strategies, and whether workshop enrollment changed. Methods: We used mixed methods and the Promoting Action on Research Implementation in Health Services (PARIHS) implementation evaluation framework. In stage 1, we conducted semistructured interviews with caregivers, local staff, and regional and national VA leaders and surveys with caregivers and staff. We collected and analyzed survey and interview data concurrently and integrated the results to identify implementation strengths and weaknesses, and strategies likely to improve workshop uptake. In stage 2, we reinterviewed national leaders to determine whether the VA adopted recommended strategies and used national data to determine whether workshop enrollment changed over time. Results: A total of 54 caregivers (n=32, 59%), staff (n=13, 24%), and regional (n=5, 9%) and national (n=4, 7%) leaders were interviewed. We received survey responses from 72% (23/32) of caregivers and 77% (10/13) of local staff. In stage 1, survey and interview results were consistent across multiple PARIHS constructs. Although participants from low-enrollment centers reported fewer implementation strengths and more weaknesses, qualitative themes were consistent across high- and low-enrollment centers, and across caregiver, staff, and leadership respondent groups. Identified strengths included belief in a positive workshop impact and the use of some successful outreach approaches. Implementation weaknesses included missed opportunities to improve outreach and to better support local staff. From these, we identified and recommended new and enhanced implementation strategies-increased investment in outreach and marketing capabilities; tailoring outreach strategies to multiple stakeholder groups; use of campaigns that are personal, repeated, and detailed, and have diverse delivery options; recurrent training and mentoring for new staff; and comprehensive data management and reporting capabilities. In stage 2, we determined that the VA had adopted several of these strategies in 2016. In the 3 years before and after adoption, cumulative BBC enrollment increased from 2139 (2013-2015) to 4030 (2016-2018) caregivers. Conclusions: This study expands the limited implementation science literature on best practices to use when implementing web-based psychoeducational programs. We found that robust outreach and marketing strategies and support for local staff were critical to the implementation success of the BBC workshop. Other health systems may want to deploy these strategies when implementing their web-based programs.
  • A virtual emergency: learning lessons from remote medical student education during the COVID-19 pandemic.

    Smith, Elana; Boscak, Alexis (Springer Science and Business Media Deutschland GmbH, 2021-01-08)
    Purpose: The COVID-19 pandemic resulted in the cancelation of traditional on-site clinical rotations for medical students across the country. Radiology educators have had to rapidly adapt to a new, virtual educational landscape. We describe our experience restructuring a Trauma and Emergency Radiology Elective to an online format and present survey data obtained from students who completed the course. Methods: This elective is a 4-week course offered to third and fourth year medical students at a large Level 1 Trauma Center. Changes to the traditional rotation included assigning an increased number of self-study educational resources, independent review of unknown cases using a virtual workstation, and online interactive conferences. At the conclusion of each block, students were asked to complete post-course feedback surveys. Results: Thirteen students enrolled in this online course; 92% submitted post-course surveys. Students strongly agreed that the course was clinically relevant, with accessible, engaging material (average score, 4.92/5), and 91.7% of students were very likely to recommend this rotation to others. Students reported improved post-course confidence in ordering and interpreting imaging studies. A majority (60%) of students who had previously taken an on-site course would have preferred a course that combined traditional and online learning elements. Conclusions: The success of our online rotation highlights the merits of self-directed learning and flipped-classroom techniques. Many of the principles incorporated into this course could be applied and/or modified to increase medical student engagement when students return to the hospital. © 2021, American Society of Emergency Radiology.
  • Durability of Responses after SARS-CoV-2 mRNA-1273 Vaccination.

    Widge, Alicia T; Rouphael, Nadine G; Jackson, Lisa A; Anderson, Evan J; Roberts, Paul C; Makhene, Mamodikoe; Chappell, James D; Denison, Mark R; Stevens, Laura J; Pruijssers, Andrea J; et al. (Massachusetts Medical Society, 2020-12-03)
  • Pharmacotherapeutics of SARS-CoV-2 Infections

    Kevadiya, Bhavesh D; Machhi, Jatin; Herskovitz, Jonathan; Oleynikov, Maxim D; Blomberg, Wilson R; Bajwa, Neha; Soni, Dhruvkumar; Das, Srijanee; Hasan, Mahmudul; Patel, Milankumar; et al. (Springer Nature, 2021-01-06)
    The COVID-19 pandemic has affected more than 38 million people world-wide by person to person transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therapeutic and preventative strategies for SARS-CoV-2 remains a significant challenge. Within the past several months, effective treatment options have emerged and now include repurposed antivirals, corticosteroids and virus-specific antibodies. The latter has included convalescence plasma and monoclonal antibodies. Complete viral eradication will be achieved through an effective, safe and preventative vaccine. To now provide a comprehensive summary for each of the pharmacotherapeutics and preventative strategies being offered or soon to be developed for SARS-CoV-2. Graphical abstract: [Figure not available: see fulltext.].

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