SHOCK

Mechanical Ventilation With Moderate Tidal Volume Exacerbates Extrapulmonary Sepsis-Induced Lung Injury via IL33-WISP1 Signaling Pathway IL-33 and WISP1 play central roles in acute lung injury (ALI) induced by mechanical ventilation with moderate tidal volume (MTV) in the setting of sepsis. Here, we sought to determine the inter-relationship between IL-33 and WISP1 and the associated signaling pathways in this process. We used a two hit model of cecal ligation puncture (CLP) followed by MTV ventilation (4 h 10 ml/kg) in wildtype, IL-33-/- or ST2-/- mice or wildtype mice treated with intratracheal antibodies to WISP1. Macrophages (Raw 264.7 and alveolar macrophages from wildtype or ST2-/- mice) were used to identify specific signaling components. CLP + MTV resulted in ALI that was partially sensitive to genetic ablation of IL-33 or ST2 or antibody neutralization of WISP1. Genetic ablation of IL-33 or ST2 significantly prevented ALI after CLP + MTV and reduced levels of WISP1 in the circulation and BALF. rIL-33 increased WISP1 in alveolar macrophages in an ST2, PI3K/AKT and ERK dependent manner. This WISP1 upregulation and WNT β-catenin activation were sensitive to inhibition of the β-catenin/TCF/CBP/P300 nuclear pathway. We show that IL-33 drives WISP1 upregulation and ALI during MTV in CLP sepsis. The identification of this relationship and the associated signaling pathways reveals a number of possible therapeutic targets to prevent ALI in ventilated sepsis patients. Address reprint requests to Li-Ming Zhang, MD, Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, 200 Lothrop Street, UPMC MUH N467, Pittsburgh 15213, PA, USA. E-mail: zhangl1@anes.upmc.edu. Received 22 September, 2020 Revised 13 October, 2020 Accepted 14 December, 2020 Competing interests: The authors declare that they have no competing interest. Funding: This work was supported by National Institute of Health grants [R01-GM-108639, (LMZ)] for the design of the study, collection for analysis and interpretation of data, and writing the manuscript; National Institute of Health grants [R01-HL-22489, (HRT)] for his salary support. Ethics approval and consent to participate: Animal protocols were approved by the Animal Care and Use Committee of the University of Pittsburgh and experiments were performed in strict adherence to the National Institutes of Health Guidelines for the Use of Laboratory Animals. Consent for publication: Not applicable Availability of data and materials: The datasets generated and/or analyzed during the current study are available in the Dr. Billiar Lab of University of Pittsburgh, and the datasets are available from the corresponding author on reasonable request. Authors' contributions: Study concepts and design: SL, MHD, HRT, TRB, BRP, BHP, LMZ; data collection: SL, MHD.; writing up of the first of the paper: SL, TRB, BRP, LMZ; data analysis and interpretation: SL, MHD, HRT, BHP, TRB, BRP, LMZ; statistical analysis: SL, LMZ; manuscript preparation: SL, LMZ; manuscript revision: SL, MHD, HRT, BHP, TRB, BRP, LMZ; manuscript final version approval: SL, MHD, HRT, BHP, TRB, BRP, LMZ. All authors read and approved the final manuscript. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). © 2020 by the Shock Society

Hypobaria Exposure Worsens Cardiac Function and Endothelial Injury in an Animal Model of Polytrauma: Implications for Aeromedical Evacuation Background: Aeromedical evacuation can expose traumatically injured patients to low pressure (hypobaria) and hypoxia. Here we sought to assess the impact of hypobaria on inflammation, organ injury, and mortality in a mouse model of polytrauma. Methods: Eight to 12 week-old male C57BL/6J mice were subjected to sham or polytrauma consisting of bowel ischemia by superior mesenteric artery (SMA) occlusion, hindlimb muscle crush, and tibia fracture. Two hours after injury, animals were randomized to undergo either 6 hours of hypobaria or sea-level, room air conditions. At 8 or 24 hours after injury, transthoracic echocardiography was performed. Acute kidney injury (AKI) biomarkers were measured by qRT-PCR. Plasma cytokine and endothelial injury markers were determined by ELISA. Results: Eight hours after traumatic injury, mice exhibited a marked increase in plasma IL-6 (57 vs. 1216 pg/ml), AKI with increased Ngal and Kim-1, and endothelial injury as evidenced by significantly increased plasma hyaluronic acid (96 vs.199 ng/ml), thrombomodulin (23.2 vs. 58.9 ng/ml), syndecan-1 (0.99 vs. 4.34 ng/ml), and E-selectin (38.6 vs. 62.7 ng/ml). The trauma mice also developed cardiac dysfunction with decreased cardiac output and stroke volume at 8 hours post-injury. Hypobaric exposure after polytrauma led to decreased ejection fraction (81.0 vs. 74.2%, p < 0.01) and increased plasma hyaluronic acid (199 vs. 260 ng/ml, p < 0.05), thrombomodulin (58.9 vs. 75.4 ng/ml, p < 0.05), and syndecan-1 (4.34 vs. 8.33 ng/ml, p < 0.001) at 8 hours post-injury. Conclusions: Hypobaria exposure appeared to worsen cardiac dysfunction and endothelial injury following polytrauma and thus may represent a physiological "second hit" following traumatic injury. Address reprint requests to Wei Chao, MD, PhD, Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, 660 W. Redwood St. Howard Hall #598A, Baltimore, MD, 21201, USA. E-mail: wchao@som.umaryland.edu Received 18 October, 2020 Revised 12 November, 2020 Accepted 17 December, 2020 Conflict of interest: All authors have declared no conflict of interest. Disclosures: This work was supported in part by the grants from the US Air Force Research (FA8650-17-2-6H12 and FA8650-18-2-6H17) and the National Institutes of Health (R01GM122908, R01GM117233, R35GM124775, R01NS110567, and T32HL007698). The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Air Force, the Department of Defense, or the U.S. Government. Author contribution: K.L. performed the majority of experiments, data analysis and interpretation, and wrote manuscript draft. A.S. contributed to study design, hypobaria chamber assembly, and polytrauma model creation. Y.Y. performed all echocardiography and data analysis. B.W. contributed to study design and direction. J.H. performed BAL collection and analysis. J.Z. assisted with animal husbandry, organ collection, and sample processing. S.W. contributed to technique supervision, data analysis, and figure preparation. G.F., A.C., R.K., and C.M. contributed to data interpretation and manuscript editing. W.C. designed the study, provided direction throughout the experiments, advised on data analysis and interpretation, and finalized the manuscript. © 2020 by the Shock Society

Low Microcirculatory Perfused Vessel Density and High Heterogeneity are Associated with Increased Intensity and Duration of Lactic Acidosis After Cardiac Surgery with Cardiopulmonary Bypass Introduction: Lactic acidosis after cardiac surgery with cardiopulmonary bypass is common and associated with an increase in postoperative morbidity and mortality. A number of potential causes for an elevated lactate after cardiopulmonary bypass including cellular hypoxia, impaired tissue perfusion, ischemic-reperfusion injury, aerobic glycolysis, catecholamine infusions, and systemic inflammatory response after exposure to the artificial cardiopulmonary bypass circuit. Our goal was to examine the relationship between early abnormalities in microcirculatory convective blood flow and diffusive capacity and lactate kinetics during early resuscitation in the intensive care unit. We hypothesized that patients with impaired microcirculation after cardiac surgery would have a more severe postoperative hyperlactatemia, represented by the lactate time-integral of an arterial blood lactate concentration greater than 2.0 mmol/L. Methods: We measured sublingual microcirculation using incident darkfield video microscopy in 50 subjects on ICU admission after cardiac surgery. Serial measurements of systemic hemodynamics, blood gas, lactate, and catecholamine infusions were recorded each hour for the first 6 hours after surgery. Lactate area under the curve (AUC) was calculated over the first 6 hours. The lactate AUC was compared between subjects with normal and low perfused vessel density (PVD < 18 mm/mm2), high heterogeneity index (MHI > 0.4), and low vessel-by-vessel microvascular flow index (MFIv < 2.6). Results: Thirteen (26%) patients had a low postoperative PVD, 20 patients (40%) had a high MHI, and 26 (52%) patients had a low MFIv. Patients with low perfused vessel density had higher lactate AUC compared to subjects with a normal PVD (22.3 [9.4–31.0] vs. 2.6 [0–8.8]; p < 0.0001). Patients with high microcirculatory heterogeneity had a higher lactate AUC compared to those with a normal MHI (2.5 [0.1–8.2] vs. 13.1 [3.7–31.1]; p < 0.001). We did not find a difference in lactate AUC when comparing high and low MFIv. Conclusion: Low perfused vessel density and high microcirculatory heterogeneity are associated with an increased intensity and duration of lactic acidosis after cardiac surgery with cardiopulmonary bypass. Address reprint requests to John C. Greenwood, MD, Department of Emergency Medicine, Hospital of the University of Pennsylvania. 3400 Spruce Street, Philadelphia, PA 19104, USA. E-mail: john.greenwood@pennmedicine.upenn.edu Received 28 October, 2020 Revised 13 November, 2020 Accepted 14 December, 2020 Ethics approval and consent to participate: This study was approved by our institutional review board (IRB # 829765) and informed consent was obtained prior to enrollment. All consent forms were copied in triplicate, one given to the subject, the second placed in the official medical record, the third kept in a secured location within the PI's office. Consent for publication: John C. Greenwood, MD (Corresponding author) consent to the publication of this work if accepted by the journal. Availability of data and materials: All original data and materials are kept in a locally managed REDCap database at the University of Pennsylvania. Deidentified microcirculation data is available online, uploaded to open access Zenodo database found here: https://doi.org/10.5281/zenodo.4106205. Competing interests: None. None of the authors have received any financial support or have a conflict of interest related to Cytocam or Braedius, BV. Funding: Not applicable Authors' contributions: JCG made substantial contributions to the conception or design of the work; the acquisition, analysis, or interpretation of data; drafted the work or substantively revised the manuscript. DHJ made substantial contributions to the conception or design of the work; the analysis and interpretation of data; substantively revised the manuscript. AES made substantial contributions to the acquisition, analysis, or interpretation of data; drafted the work or substantively revised the manuscript. JTG made substantial contributions to the conception or design of the work; drafted the work or substantively revised the manuscript. JH made substantial contributions to the conception or design of the work; drafted the work or substantively revised the manuscript. JH made substantial contributions to the conception or design of the work; drafted the work or substantively revised the manuscript. JH made substantial contributions to the conception or design of the work; drafted the work or substantively revised the manuscript. MAA made substantial contributions to the conception or design of the work; drafted the work or substantively revised the manuscript. TJK made substantial contributions to the conception or design of the work; the analysis, or interpretation of data; drafted the work or substantively revised the manuscript. FSS made substantial contributions to the conception or design of the work; the analysis, or interpretation of data; drafted the work or substantively revised the manuscript. JGTA made substantial contributions to the conception or design of the work; the analysis, or interpretation of data; drafted the work or substantively revised the manuscript. JB made substantial contributions to the conception or design of the work; the analysis, or interpretation of data; drafted the work or substantively revised the manuscript. BSA made substantial contributions to the conception or design of the work; the analysis, or interpretation of data; drafted the work or substantively revised the manuscript. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). © 2020 by the Shock Society

Targeting Uric Acid Prevents Brain Injury and Anxiety in a Rat Model of Hemorrhagic Shock Secondary brain injury following hemorrhagic shock (HS) is a frequent complication in patients, even in absence of direct brain trauma, leading to behavioral changes and more specifically anxiety and depression. Despite pre-clinical studies showing inflammation and apoptosis in the brain after HS, none have addressed the impact of circulating mediators. Our group demonstrated an increased uric acid (UA) circulation in rats following HS. Since UA is implicated in endothelial dysfunction and inflammatory response, we hypothesized UA could alter the blood-brain barrier (BBB) and impact the brain. Male Wistar rats were randomly assigned to: SHAM, HS (hemorrhagic shock) and HS + U (hemorrhagic shock + 1.5 mg/kg of uricase). The uricase intervention, specifically targeting UA, was administered during fluid resuscitation. It prevented BBB dysfunction (fluorescein sodium salt permeability and expression of ICAM-1) following HS. As for neuroinflammation, all of the results obtained (MPO activity; Iba1 and GFAP expression) showed a significant increase after HS, also prevented by the uricase. The same pattern was observed after quantification of apoptosis (caspase-3 activity and TUNEL) and neurodegeneration (Fluoro-Jade). Finally, the forced swim, elevated plus maze and social interaction tests detected anxiety-like behavior after HS, which was blunted in rats treated with the uricase. In conclusion, we have identified UA as a new circulatory inflammatory mediator, responsible for brain alterations and anxious behavior after HS in a murine model. The ability to target UA holds the potential of an adjunctive therapeutic solution to reduce brain dysfunction related to hemorrhagic shock in human. Address reprint requests to Emmanuel Charbonney, MD, PhD, Centre de Recherche du Centre Hospitalier de, l'Université de Montréal (CRCHUM), Pavillon R 900, Rue Saint-Denis, Montréal Qc H2X 0A9, Canada. E-mail: emmanuel.charbonney@umontreal.ca Received 7 October, 2020 Revised 23 October, 2020 Accepted 7 December, 2020 Funding and Disclosures Part of the present work has been funded thanks to the Fondation NeuroTrauma Marie-Robert Dr. Emmanuel Charbonney had received financial support for his program of research from Sanofi Genzyme Canada The preliminary data of the present work have been presented as an abstract, at the International 2019 Brain Injury Association's 13th World Congress on Brain Injury, in Toronto AUTHOR CONTRIBUTION STATEMENT SLE, KG, GR and EC, designed the study, supervised and conducted the experiments, analyzed the data and drafted the manuscript. SLE, KG, BB, JB, CL, CB, MAG conducted the animal experiments, processed the molecular and IF experiments, with their analysis. SLE, JB and GR conducted the behavior experiment and their analysis. SLE, KG, FB, GR and EC conducted the analysis, verified the reproducibility of the results and reviewed the final version of the manuscript. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.shockjournal.com). © 2020 by the Shock Society

Circulating Syndecan-1 and Tissue Factor Pathway Inhibitor, Biomarkers of Endothelial Dysfunction, Predict Mortality in Burn Patients Objective: The aim of this study is to evaluate the association between burn injury and admission plasma levels of Syndecan-1 (SDC-1) and Tissue Factor Pathway Inhibitor (TFPI), and their ability to predict 30-day mortality. Background: SDC-1 and TFPI are expressed by vascular endothelium and shed into the plasma as biomarkers of endothelial damage. Admission plasma biomarker levels have been associated with morbidity and mortality in trauma patients, but this has not been well characterized in burn patients. Methods: This cohort study enrolled burn patients admitted to a regional burn center between 2013 and 2017. Blood samples were collected within 4 hours of admission and plasma SDC-1 and TFPI were quantified by ELISA. Demographics and injury characteristics were collected prospectively. The primary outcome was 30-day in-hospital mortality Results: Of 158 patients, 74 met inclusion criteria. Most patients were male with median age of 41.5 years and burn TBSA of 20.5%. The overall mortality rate was 20.3%. Admission SDC-1 and TFPI were significantly higher among deceased patients. Plasma SDC-1 >34 ng/mL was associated with a 32-times higher likelihood of mortality [OR: 32.65 (95% CI, 2.67–399.78); P = 0.006] and a strong predictor of mortality (AUROC 0.92). TFPI was associated with a 9-times higher likelihood of mortality [OR: 9.59 (95% CI, 1.02–89.75); P = 0.002] and a fair predictor of mortality (AUROC 0.68). Conclusions: SDC-1 and TFPI are associated with a higher risk of 30-day mortality. We propose the measurement of SDC-1 on admission to identify burn patients at high risk of mortality. However, further investigation with a larger sample size is warranted. Address reprint requests to Jeffrey W. Shupp, MD, MedStar Washington Hospital Center, The Burn Center, Department of Surgery, 110 Irving St. NW Suite 3B-55, Washington, DC 20010. E-mail: Jeffrey.w.shupp@medstar.net Received 5 October, 2020 Revised 27 October, 2020 Accepted 8 December, 2020 Disclosure of funding: This work was funded by the U.S. Department of Defense (DOD) (W911QY-15-C-0025, and W911NF-17-1-0594). This project was done in partnership with the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority and funding, in part, was provided through Interagency Agreement (750119PR2100075). SYSCOT Study Group Authorship: Melissa M. McLawhorn, RN BSN, Lauren T. Moffatt, PhD, Jeffrey W Shupp, MD, Rachael A Callcut, MD, MSPH, Mitchell J Cohen, MD, Linda R. Petzold, PhD, Jeffrey D. Varner, PhD, Maria Cristina Bravo, PhD, Kathleen E. Brummel-Ziedins, PhD, Kalev Freeman, MD, PhD, Kenneth G. Mann, PhD, Thomas Orfeo, PhD, Aarti Gautam, PhD, Rasha Hammamieh, PhD, Marti Jett, PhD, Anthony E. Pusateri, PhD Disclosure: This project was done in partnership with the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority and funding, in part, was provided through Interagency Agreement (750119PR2100075). The authors report no conflicts of interest. Research protocols were developed as part of the Systems Biology for Biological Responses to Severe Hemorrhage, conducted and supported by the Department of Defense. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 © 2020 by the Shock Society

Toll-Like Receptors, Associated Biochemical Signaling Networks, and S100 Ligands Host cells recognize molecules that signal danger using pattern recognition receptors (PRRs). Toll-Like Receptors (TLRs) are the most studied class of PRRs and detect pathogen associated molecular patterns and danger associated molecular patterns. Cellular TLR activation and signal transduction can therefore contain, combat and clear danger by enabling appropriate gene transcription. Here we review the expression, regulation and function of different TLRs, with an emphasis on TLR-4, and how TLR adaptor protein binding directs intracellular signaling resulting in activation or termination of an innate immune response. Finally, we highlight the recent progress of research on the involvement of S100 proteins as ligands for TLR-4 in inflammatory disease. Address reprint requests to John C. Marshall, MD, St. Michael's Hospital, 4th Floor Bond Wing, Room 4-007, 30 Bond Street, Toronto, Ontario, M5B 1W8, Canada. E-mail: john.marshall@unityhealth.to Received 25 October, 2020 Revised 12 November, 2020 Accepted 30 November, 2020 Conflicts of Interest: The authors have no conflicts of interest to declare. Grant Funding Source: Canadian Institutes of Health Research (MOP 129493) © 2020 by the Shock Society

Bone Marrow-Derived Mononuclear Cell Transplantation can Reduce Systemic Inflammation and Endothelial Glycocalyx Damage in Sepsis Bone marrow-derived mononuclear cells (BMMNCs) secrete anti-inflammatory mediators that protect against acute inflammation. Current evidence suggests that BMMNC transplantation can reduce acute tissue injury caused by systemic inflammation and lung dysfunction. This study evaluated the role of BMMNCs in reducing systemic inflammatory responses to vascular endothelial injury in sepsis. Bone marrow cells were harvested from the tibias and femurs of twelve-week-old male Wistar rats; BMMNCs were separated by density centrifugation. Additional rats underwent cecal ligation and puncture (CLP) or similar sham surgery. BMMNCs were injected intravenously 30 min after CLP. The Sham and CLP Control groups were administered PBS. The seven-day survival rate improved markedly in the CLP-BMMNC group compared with that in the Control group. BMMNCs markedly suppressed the serum levels of pro-inflammatory mediators such as tumor necrosis factor-alpha, interleukin-6, and histone H3 at 3, 6, and 12 h after CLP. In the CLP-BMMNC group, the serum levels of syndecan-1, the main component of the vascular endothelial glycocalyx layer, were notably lower than those in the Control group 6 h after CLP. Histological analysis revealed improvement of morphological damages in the CLP-BMMNC group. Ultrastructural analysis revealed that the glycocalyx structure was maintained and the continuity of the vascular endothelial glycocalyx layer was preserved in the BMMNC group, compared to the case for the Control group at 6 and 12 h. Therefore, BMMNC transplantation may provide reduced systemic inflammation and endothelial glycocalyx damage, dramatically improving the survival of rats. These findings provide insights into formulating potential therapeutic strategies against sepsis. Address reprint requests to Tsunehiro Matsubara, MD, Osaka University Graduate School of Medicine Department of Traumatology and Acute Critical Care Center, 2-15 Yamadaoka, Suita-city, Osaka 565-0871, Japan. E-mail: tsunehiro1231@live.jp Received 1 August, 2020 Revised 10 September, 2020 Accepted 9 December, 2020 Conflicts of Interest and Source of Funding: This study received a Grant-in-Aid for Young Scientists from The Ministry of Education, Culture, Sports, Science and Technology, Japan. The authors declare no conflicts of interest. © 2020 by the Shock Society

Neutrophil-To-Lymphocyte Ratio And Covid-19 No abstract available

Pharmacological and Genetic Inhibition of Translocator Protein 18 kDa Ameliorated Neuroinflammation in Murine Endotoxemia Model Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction associated with sepsis. The development of an effective strategy for early diagnosis and therapeutic intervention is essential for the prevention of poor prognosis of SAE. Translocator protein 18 kDa (TSPO) is a mitochondrial protein implicated in steroidogenesis and inflammatory responses. Despite accumulating evidence that implicates TSPO in the neuroinflammatory response of the central nervous system, the possible role of TSPO in SAE remains unclear. Aim of this study is to address a role of TSPO in neuroinflammation using mice 24 h after systemic injection of lipopolysaccharide (LPS), which consistently demonstrated microglial activation and behavioral inhibition. Quantitative polymerase chain reaction analysis revealed that hippocampal TSPO expression was induced following the systemic LPS injection, associated with an increase in pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-1β. Interestingly, pretreatment with the TSPO antagonist, ONO-2952, or germ-line deletion of the TSPO gene exhibited an anti-inflammatory effect with significant suppression of LPS-induced production of those cytokines. These effects demonstrated by the ONO-2952 or TSPO knockout were associated with significant recovery from behavioral inhibition, as shown by improved locomotor activity in the open field analysis. Histological analysis revealed that ONO-2952 pretreatment suppressed the LPS-induced activation of TSPO-expressing microglia in the hippocampus of mice. Collectively, these results suggest that TSPO plays a critical role in the SAE mouse model. Based on this finding, monitoring TSPO activity, as well as the progress of endotoxemia and its sequelae in the animal model, would deepen our understanding of the underlying molecular mechanism of SAE. Address reprint requests to Hidenori Aizawa, MD, PhD, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553 Japan. E-mail: haizawa@hiroshima-u.ac.jp Received 24 September, 2020 Revised 12 October, 2020 Accepted 23 November, 2020 Disclosure: The authors declare that they have no conflicts of interest. Funding: This research was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (JP19H05723) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to HA; a Grant-in-Aid for 'Integrated Research on Depression, Dementia and Development Disorders (20dm0107093)' carried out under the Strategic Research Program for Brain Sciences by AMED to SY and a Grant-in-Aid for Scientific Research C (18K08888) to KH. © 2020 by the Shock Society

HIF-1α and Hypoxia Responsive Genes are Differentially Expressed in Leukocytes from Survivors and Non-Survivors Patients during Clinical Sepsis Hypoxia inducible factor 1 alpha (HIF-1α) is linked to the metabolic and immune alterations in septic patients. Stabilization of HIF-1α by hypoxia or inflammation promotes the expression of several genes related to glycolytic metabolism, angiogenesis, coagulation, cell proliferation and apoptosis. Here we analyzed public available blood transcriptome datasets from septic patients and evaluated by PCR array the expression of HIF-1α and other hypoxia responsive genes in peripheral blood mononuclear cells (PBMC) from patients with sepsis secondary to community acquired infections. Samples were collected at ICU admission (D0, n=29) and after 7 days follow-up (D7, n = 18); healthy volunteers (n = 10) were included as controls. Hypoxia and glycolysis were among the top scored molecular signatures in the transcriptome datasets. PCR array showed that 24 out of 78 analyzed genes were modulated in septic patients compared to healthy volunteers; most of them (23/24) were downregulated at admission. This same pattern was observed in surviving patients, while non-survivors presented more upregulated genes. EGLN1, EGLN2 and HIF1AN, inhibitors of HIF-1α activation were downregulated in patients, regardless of the outcome, while HIF-1α and other target genes, such as PDK1 and HMOX1, expression were higher in non-survivors than in survivors, mainly at D7. Non-survivor patients also presented a higher SOFA score and lower PaO2/FiO2 ratio. Our results indicate a differential modulation of hypoxia pathway in leukocytes between septic patients who survived and those who did not survive with an increased intensity at D7, which is possibly influenced by disease severity and may affect the immune response in sepsis. Address reprint requests to Reinaldo Salomao, MD, PhD, Division of Infectious Diseases, Escola Paulista de Medicina, Hospital São Paulo, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669, 10th Floor, Sao Paulo, SP, 04039-032, Brazil. E-mail: rsalomao@unifesp.br Received 25 September, 2020 Revised 19 October, 2020 Accepted 6 November, 2020 Funding: This work was supported by FAPESP (Grant 2017/21052-0). RS is the recipient of a Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) fellowship. BLF has a scholarship from FAPESP (2016/13855-2). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.shockjournal.com). © 2020 by the Shock Society

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

Telephone consultation 11855 int 1193,

Advanced Medical and Health Research

Scientific writing for residents – A dialog across the divide Vikram Kate, AR Pranavi, Sathasivam Sureshkumar International Journal of Advanced Medical and Health Research 2020 7(2):39-41

Quagmire of esophageal replacement in infants and children Rajendra Govind Saoji, Avanti Rajendra Saoji International Journal of Advanced Medical and Health Research 2020 7(2):42-49 A normally functioning esophagus is a specialized functioning organ, and it functions in concert with other derivatives of foregut origin. Unlike adults, esophageal replacement (OR) in infants and children is uniformly done for benign conditions. The complexity of esophageal substitution techniques and its sequelae are not experienced only during childhood, but they spill over into adult life as well making life-long commitment and follow-up necessary. Although multiple technical approaches and their modifications are being practiced for OR over the past century, there is no clear consensus regarding the best one. In recent years, realizing that patient's own esophagus suits him/her best, esophageal lengthening and tissue engineering techniques are challenging the replacement techniques. There are no randomized controlled pediatric studies to compare different types of OR.

Emerging concepts in enhanced recovery after surgery: Potential functional adaptations to existing principles Balakrishnan Gurushankari, Kanchan Bilgi, Raja Kalayarasan, Sathasivam Sureshkumar, Pankaj Kundra, Vikram Kate, Ananthakrishnan Nilakantan International Journal of Advanced Medical and Health Research 2020 7(2):50-60 The revolutionary concept of enhanced recovery after surgery (ERAS), recognized and proven in colonic surgery, soon caught on as an attractive proposition that translated into better and faster patient recovery after various types of surgery. As an evolving concept, it is being widely accepted, with various surgical specialties suitably adapting the guidelines for use in the perioperative setting. Identification and mitigation of risk factors in special groups of patients such as patients presenting for emergency surgery, those in the extremes of age and weight, and those with various comorbidities require additional care and investigations. The use of ERAS in emergency setting has been remarkably difficult to implement, owing to a short preoperative period, altered physiology, and unexpected postoperative outcomes. There is reluctance in the application of ERAS in emergency due to difficulty in implementing all its components, especially the preoperative components. The rapid advancements in technology and increased availability of point of care diagnostics, such as ultrasound and intraoperative electroencephalogram, and the increasing number of anesthesiologists getting trained in their usage are important factors that are positively influencing perioperative patient care in the last decade. This has led to significant developments in noninvasive and rapid methods of monitoring hemodynamics and postoperative care. This review aims to highlight the influence of newer perioperative practices that are already included or are likely to have positive impact when included in an ERAS program and provide comprehensive review on the application of ERAS in emergency setting and in various surgical specialties.

Oral health-related quality of life of children with repaired cleft lip and palate in Yaounde, Cameroon: A cross-sectional study Atanga Léonel Christophe, Ngaba Mambo Olive Nicole, Edouma Bohimbo Jacques Gérard, Ndjolo Alexis International Journal of Advanced Medical and Health Research 2020 7(2):61-66 Background: Further care needs and impact of repaired cleft lip and palate (CLP) on the daily life of children are unknown in our setting, since many of them are lost to follow-up after surgery. Aim: To assess the oral health-related quality of life (OHRQoL) of children with repaired CLP and to identify the main issues that deserve additional care. Methods: We carried out a single-center, cross-sectional study of 27 children (mean age: 7.74 ± 0.7 years; 16 girls) operated for CLP and 30 healthy controls (mean age: 8.03 ± 0.7 years; 15 girls). Self and proxy-rated OHRQoL was assessed by the child oral health impact profile, a reliable and valid questionnaire designed for use with children and teenagers. Results: Patients had lower quality of life scores than controls for functional well-being (22.1 ± 1.2 vs. 27.9 ± 0.74;P< 0.001), emotional well-being (32.3 ± 1.4 vs. 37.3 ± 0.6; P = 0.002), and self-esteem (24.4 ± 0.9 vs. 29.2 ± 0.4;P< 0.001). Redo surgeries (n = 10) and a visible facial difference (n = 17) were the main depreciative determinants of the OHRQoL, particularly for emotional well-being (30.2 ± 1.7 vs. 35.2 ± 1.4;P= 0.003 and 29.6 ± 1.8 vs. 36.8 ± 1.3; P = 0.003; respectively). Conclusion: Children with repaired CLP have a lower OHRQoL than their healthy peers. Psychosocial care, orthodontics, and speech therapy are the main needs for further care aimed at improving their quality of life.

Prevalence of vitamin D deficiency and associated risk factors among adults in Chandigarh Divesh Dik, Maninder Kaur International Journal of Advanced Medical and Health Research 2020 7(2):67-73 Background: Vitamin D deficiency is a global health concern affecting individuals across all the age groups in both the genders. Aims and Objectives: The present study intends to assess the prevalence of Vitamin D deficiency and associated risk factors in adult males and females of Chandigarh. Materials and Methods: The sample included 332 males and 295 females of the age ranging between 30 and 70 years. Vitamin D level of all the participants was estimated by employing chemiluminescence immunoassay method. All the subjects were divided into three categories of Vitamin D level, i.e., normal range (>30–100 ng/ml), insufficiency (21–29 ng/ml), and deficiency (0–20 ng/ml) as per the Endocrine Society Guidelines (2011). Results: The overall prevalence of Vitamin D deficiency was found to be 28.5% in males and 63.4% in females of Chandigarh. The prevalence of Vitamin D deficiency exhibited an age-associated increment in both the males and females. Conclusion: Lesser physical activity and no intake of calcium, Vitamin D, and multivitamin supplements were possible determinants of Vitamin D deficiency.

Prevalence and patterns of journal use among undergraduate medical students in a tertiary care teaching hospital – A cross-sectional analytical study Siddhartha Das, Sitanshu Sekhar Kar, Parthibane Sivanantham, Vaibhav Shukla, Noopura Ramavarman International Journal of Advanced Medical and Health Research 2020 7(2):74-79 Background: Medical students are expected to be self-directed learners and constantly update their knowledge. Apart from the books, journals also help in this knowledge gathering exercise. This study was conducted with an objective to assess the journal usage pattern among undergraduate medical students and to consider implementing a training program on journal use based on the survey findings. Materials and Methods: This was a cross-sectional study conducted among the undergraduate medical students using anonymous self-administered online questionnaire. The e-mail address and WhatsApp number of the students were initially collected with the help of student volunteers from each batch, and then, an online link to the survey was sent to all of them by these volunteers. Results: Around 37% (190/505) of the respondents reported having used journals, and nearly three-fourths of them were introduced to journals by their faculties. Research articles were the most sought after article type among the students. The Medline database was very commonly used by the students. Around 80% of the respondents opined that journal usage may be included as a training program at the undergraduate level. Conclusion: Perception regarding including journal usage as a training program at the undergraduate level was significantly associated (P < 0.05) with journal use among students.

Frequency of systemic involvement in patients with acute dengue fever - the expanded dengue syndrome: A retrospective review from a tertiary care hospital in Karachi Ayesha Khalil, Sadia Ishaque, Adeel Khatri, Asif J Muhammad International Journal of Advanced Medical and Health Research 2020 7(2):80-84 Background: Dengue is globally the most common arboviral disease. As the primary immunopathological target in dengue is the endothelium, presentations beyond the typical triad of fever, myalgias, and thrombocytopenia are increasingly encountered. Severe systemic organ involvement can occur even without evidence of dengue hemorrhagic fever (DHF). These manifestations of dengue have been termed the “expanded dengue syndrome” by WHO. Aim: To observe the types and frequency of organ involvement in patients admitted with acute dengue fever. Methods: This is a retrospective cross-sectional study. Records of patients above 18 years admitted with acute dengue fever from December 2016 to December 2017 were reviewed. Patients fulfilling WHO criteria for probable or confirmed acute dengue fever were included. Patients with definite laboratory evidence of other systemic infections and patients with autoimmune or hematological disease were excluded. Data were obtained for 129 patients and analyzed using IBM-SPSS-21. Frequencies of clinical manifestations and organ involvement were noted. Results: Gastrointestinal manifestations occurred in 89% of patients. Transaminitis, organomegaly, and serositis were common. About 19% had pulmonary involvement, and 9% of patients had neurological features. Renal dysfunction, dyselectrolytemia, ophthalmic, muscular, and lymphoreticular abnormalities were also seen. Conclusion: Systemic involvement in dengue is not uncommon, and organ dysfunction can occur in the absence of severe DHF. Recognition of myriad range of organ involvement is crucial for optimal management.

Comment on "Promoting research for undergraduates of medicine in India: A critical necessity" Premanath Fakirayya Kotur International Journal of Advanced Medical and Health Research 2020 7(2):85-86

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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The Neurologist

Predictors of Good Outcomes in Stroke Thrombolysis Guided by Tissue-Window Background: Recently studies suggested that assessment of tissue-window can effectively guide thrombolysis in acute ischemic stroke patients with unknown time of onset or late presenting. This study aimed to evaluate predictors of good outcomes from thrombolysis in these patients. Methods: Acute ischemic stroke patients received thrombolysis guided by computed tomography perfusion (CTP) from October 2018 to August 2019 were reviewed. Baseline characteristics and outcomes were collected. Good outcomes were defined as modified Rankin scale scores of 0 to 2 at 90 days. Logistic regression analysis was performed and the receiver operating characteristics analysis was used to determine cut-off values for the predictors of outcomes. Results: Sixty-three patients were enrolled. The median age was 64 (interquartile range 57.75 to 72.5) years. The median baseline National Institutes of Health Stroke Scale (NIHSS) score was 8 (interquartile range 3 to 13) and 41 (65.1%) patients had a good outcome at 90 days. Multivariate regression analysis showed smaller perfusion lesion (the sum of ischemic penumbra and infarcted core) (odds ratio: 0.961; 95% confidence interval, 0.931-0.992; P=0.013) and lower baseline NIHSS score (odds ratio: 0.759; 95% confidence interval, 0.644-0.895; P=0.001) were significant predictors for good outcomes. Receiver operating characteristics analysis was utilized to define optimal cut-off values for perfusion lesion [cut-off, 59 mL; area under curve (AUC), 0.761; sensitivity, 0.57; specificity, 0.93; P=0.001], ischemic penumbra (cut-off, 43.5 mL; AUC, 0.761; sensitivity, 0.62; specificity, 0.90; P=0.001), infarcted core (cut-off, 9.5 mL; AUC, 0.665; sensitivity, 0.43; specificity, 0.93; P=0.035), and baseline NIHSS score (cut-off, 8.5; AUC, 0.880; sensitivity, 0.81; specificity, 0.88; P<0.001). Conclusions: This study suggested that smaller perfusion lesion and lower baseline NIHSS score may be helpful to predict favorable prognosis of stroke patients who receive thrombolysis guided by tissue-window.

Effect of Low-Frequency rTMS and Intensive Speech Therapy Treatment on Patients With Nonfluent Aphasia After Stroke Background: To observe the effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on patients with nonfluent aphasia after stroke. Materials and Methods: Thirty patients were divided into control, rTMS, and 2 times a day low-frequency rTMS (2rTMS) groups, and all 3 groups had intensive speech therapy (ST). Patients were assessed by western aphasia battery (WAB) scale. The spontaneous language, listening comprehension, retelling, and naming were scored, respectively. The expression of brain-derived neurotrophic factor (BDNF) in peripheral blood was detected by enzyme-linked immunosorbent assay. Results: There was significant difference in aphasia quotient after treatment in the 3 groups. The values of the 4 dimensions in the WAB score of the rTMS group were higher than those in the control group. The WAB scores in the 2rTMS group were higher than those in the rTMS group. After 2 weeks treatment, the BDNF levels in the rTMS group and the 2rTMS group were significantly higher than those in the control group. Four weeks later, the 2rTMS group was significantly increased compared with the control group and the rTMS group. Conclusions: Low-frequency rTMS combined with conventional ST treatment can effectively improve the language function of patients with nonfluent aphasia after stroke. Two times a day low-frequency rTMS therapy combined with conventional ST treatment can improve the language function of patients with nonfluent aphasia after stroke more effectively and it also promote the expression of BDNF more effectively, thereby improving nerve repair and protecting brain tissue.

Comparative Evaluation of Stroke Awareness of Individuals Whose First-Degree Relatives had a Stroke and that of Individuals Whose First-Degree Relatives Did Not Objective: To assess the stroke awareness levels of individuals whose first-degree relatives had a stroke and to compare the results with those of individuals whose first-degree relatives did not have a stroke. Materials and Methods: This cross-sectional study was conducted between March and May 2019, with first-degree relatives of patients who had a stroke (group 1) and a comparable set of individuals whose first-degree relatives did not have a stroke (group 2). Participants were asked to complete a questionnaire asking about signs and symptoms, risk factors, treatment options, information sources, responses after the development of stroke, and early treatment of stroke. Results: In response to the questions about the signs and symptoms of stroke, group 1 mentioned dizziness and comprehension disorder as a symptom of stroke more frequently than the other group. Stress was the second most frequently mentioned risk factor (by 81% of group 1 and 80.5% in group 2). When the participants were asked about the sources of information about stroke, family circle and friends were the most frequently mentioned sources for both groups. Conclusion: The present study can serve as a guide in planning training to improve stroke awareness in the future, especially by including individuals whose first-degree relatives had a stroke.

Neurological Manifestations of SARS-CoV-2: A Narrative Review Background: Coronavirus disease 2019 (COVID-19) pandemic started as an outbreak in China and soon crossed borders to affect the populations in all countries of the world. During the initial course of the disease, COVID-19 was perceived as a pneumonia-like illness. However, recent findings of COVID-19 patients suggest that the virus has the potential to disseminate to different tissues and organs, and cause significant complications. Summary: Neurological symptoms are of great significance as these usually present in and complicate critical cases. Many case reports and case series have documented the findings of neurological complications in COVID-19 patients. From the existing data, the most frequent symptoms in these patients were broadly classified into the central nervous system (CNS), peripheral nervous system, and skeletal muscular symptoms. CNS symptoms include meningitis, encephalitis, cerebrovascular complications, peripheral nervous system symptoms include anosmia, ageusia, and skeletal muscular symptoms include myalgias. It is postulated that the cause may be direct CNS injury through blood and neuronal pathways or indirectly because of an immune-mediated response, hypoxia caused by decreased oxygen saturation, or by the binding of subacute respiratory syndrome-coronavirus-2 to the host angiotensin-converting enzyme-2 receptors. Striking radiologic findings in COVID-19 patients with neurological symptoms have also emerged. Conclusions: As subacute respiratory syndrome-coronavirus-2 may potentially have lethal implications on the nervous system, it is important that neurologists are better informed about the spectrum of clinical manifestations, radiologic findings, and likely mechanisms of injury. Understanding the symptoms and radiologic imaging allows clinicians to consider brain imaging in any patient with suspected COVID-19 and neurological symptoms.

True Restriction in Diffusion-Weighted Imaging in a Mistreated Patient With Phenylketonuria Introduction: Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism and causes neurological manifestations because of excessive accumulation of phenylalanine (PHE). It can also affect adult patients who discontinue their treatment, even if they had been under adequate metabolic control during childhood. For that reason, it is recommended that PKU treatment should be continued throughout life and target PHE levels for adult patients should range between 120 and 600 μmol/L. Case Report: The authors present an adult patient with PKU who discontinued treatment and developed cognitive dysfunction because of high blood levels of PHE. Brain magnetic resonance imaging (MRI) of the patient was characteristic for PKU, presenting periventricular and callosal white matter hyperintensities in T2 and fluid-attenuated inversion recovery sequences, which were additionally associated with true restriction in diffusion-weighted imaging sequence, a far less recognized PKU neuroimaging feature. Discussion: Cognitive dysfunction and psychiatric disorders can be present in adult patients with PKU who discontinue treatment and have poor PHE metabolic control. The presence of white matter hyperintensities in T2 and fluid-attenuated inversion recovery MRI-sequences is a well-described neuroimaging feature of PKU, but diffusion-weighted imaging sequence may also be reliable in detecting brain lesions in patients with PKU. PKU lesions should be considered in the differential diagnosis of true diffusion restriction in brain MRI of patients with PKU history or those who might have escaped newborn screening diagnosis but present neurocognitive dysfunction. Appropriate treatment for the management of PKU should be initiated for the reversal of the clinical and neuroimaging findings.

Huge Free-Floating Thrombus in the Internal Carotid Artery Under Duplex Ultrasound Surveillance: A Case Report Introduction: Carotid free-floating thrombus (FFT) is an unusual finding in acute ischemic stroke. Atherosclerosis is the most common etiology of FFT formation. Case Report: Here we report a 42-year-old male patient admitted to our department with left temporal and parietal lobe ischemic stroke with normal magnetic resonance angiography. A huge FFT in the left internal carotid artery were found by duplex ultrasound. Acute thrombosis based on atherosclerotic plaque were considered as the reason of this embolization. The thrombus shrunk significantly under anticoagulation and antiplatelet treatment. Conclusions: Evaluation of the intracranial vessel in the emergency is not enough and early carotid duplex ultrasound can help find of the FFT in time, which help to choose the early intervene by neurosurgeon. Early antithrombotic treatment can be a safe treatment option for reducing huge thrombus based on the nature of thrombus formation. Computed tomography angiography and high-resolution magnetic resonance imaging to certify the character of the plaque are recommended for plaque evaluation.

Acute Fluctuant Neurological Symptoms in Stable Chronic Cryptococcus gattii Cryptococcomas: A Novel Disease Complication Background: Cryptococcus, a yeast-like fungus, is the most common cause of fungal meningitis worldwide. The Cryptococcus gattii variety is concentrated in Australia has a greater propensity to infect immunocompetent hosts, cause meningitis and form crytococcomas. This case presents a novel disease complication, that is, acute neurological symptoms without seizures, disease progression or reactivation. Case Presentation: A 58-year-old immunocompetent male was brought to the emergency department with dysarthria and right arm paraesthesias. Computed tomography of the brain brain and magnetic resonance imaging revealed no stroke but found several previously identified crytococcomas that demonstrated no interval change. Blood tests and lumbar puncture found only a low cryptococcal antigen complex titer (CRAG) (1:10) and a negative cell culture. He had remained compliant on his maintenance fluconazole therapy and had no immunocompromise or seizure activity. He was initially treated as a relapse of cryptococcal disease and restarted on induction therapy but after the cell culture returned negative and the symptoms resolved over the following days he was reverted back to maintenance therapy. Discussion and Conclusions: Central nervous system cryptococcomas are difficult to treat, chronic infections, that in our patient had lasted over 10 years despite treatment compliance. A true cryptococcal meningitis relapse is indicated by positive cell cultures in previously sterile fluid but cryptococcoma progression is measured by serial magnetic resonance imaging or computed tomography scans. In the case of progression or relapse induction and consolidation therapy should be restarted. Our patient demonstrated neither relapse nor progression but presented with a novel disease complication of acute fluctuating neurology in chronic stable cryptococcomas.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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Academic Medicine

Editorial Decision Making for Academic Medicine, 2021 No abstract available

Acknowledgment of Academic Medicine Reviewers No abstract available

Trust Is Transparency: Clarify the Clerkship Grading Scale No abstract available

In Reply to Kates No abstract available

Bringing Patient Perspective to the Forefront of High-Value Care No abstract available

In Reply to Daigle and Anand No abstract available

Exposure to Health Care Economics and Policy in Medical School Curricula as an Avenue to Improve Patient Advocacy No abstract available

A Critical Need for Progress in Implementing Education in Health Care Delivery Science No abstract available

Academic Medicine and the Quandary of Term Limits No abstract available

In Reply to Balon No abstract available

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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Therapeutics

Leucine and Sildenafil Combination Therapy Reduces Body Weight and Metformin Enhances the Effect at Low Dose: A Randomized Controlled Trial Background: This study evaluated the potential of activating the fuel-sensing enzymes Adenine monophosphate (AMP)-activated protein kinase and the deacetylase sirtuin1, to promote weight loss. We tested the efficacy of a fixed dose combination of the amino acid leucine and 2 well-characterized agents with established safety profiles to modulate energy metabolism and facilitate weight loss. Study Question: Will a combination of l-leucine with low-dose metformin and sildenafil produce a novel synergistic interaction that reduces body weight? Study Design: We conducted a 24-week randomized controlled trial evaluating the effect on weight loss of leucine 1.1 g and sildenafil 1.0 mg or 4.0 mg, with and without metformin 500 mg (Leu/Sil 1.0, Leu/Sil 4.0, Leu/Met/Sil 1.0, and Leu/Met/Sil 4.0 twice/day). We enrolled 267 participants who were 18–65 years of age without diabetes and with the body mass index (BMI) of 30–45 kg/m2. Measures and Outcomes: The primary endpoint was percentage weight change after 24 weeks. Adverse events were evaluated. The primary analysis was performed using the perprotocol population analysis of covariance estimation. Subgroup analyses of patients residing above certain threshold limits at baseline and in populations at increased risk of obesity were assessed post-hoc as exploratory end points. Results: Placebo-adjusted mean bodyweight reductions in the Leu/Met/Sil 1.0, Leu/Met/Sil 4.0, and Leu/Sil 4.0 groups were −1.99%, −1.69%, and −1.67% (P = 0.015, 0.035, and 0.036, respectively). The most common adverse events were gastrointestinal-related and occurred in the metformin-treated groups consistent with metformin treatment. In African Americans, Leu/Met/Sil 1.0 produced 5.4% mean weight loss. In participants with BMI <40 kg/m2 treated with Leu/Met/Sil 1.0, the weight loss increased to 2.84%, particularly in participants with baseline insulin ≥12mU/L (3.5%). Conclusions: Leu/Met/Sil 1.0 and 4.0 and Leu/Sil 4.0 reduced body weight, but Leu/Met/Sil 1.0 was associated with robust weight loss in African Americans, and individuals with BMI 30–39.9 kg/m2, especially participants with hyperinsulinemia.

Inappropriate Use of Aztreonam Background: Aztreonam is not a preferred empiric antibiotic because of variable susceptibilities compared with alternative agents. In addition, it has no Gram-positive activity, necessitating coadministration with vancomycin when used empirically, and is more costly when compared with other Gram-negative active agents. Aztreonam is often given to patients with a reported penicillin allergy without further investigation into the reaction or other relevant allergy information. Study Question: How frequently is aztreonam being used inappropriately? Study Design: We conducted a retrospective chart review at an academic medical center to assess the appropriateness of our aztreonam use. Measures and Outcomes: Our primary outcome was frequency of appropriate aztreonam use, based on a true IgE-mediated allergy reported for each patient. We evaluated whether the patients had tolerated a beta-lactam in the past, and what the reported allergic reaction was. Results: We included 165 patients and found that 46.7% of our aztreonam use was inappropriate, based on previous use of a beta-lactam, or no documentation of an IgE-mediated response. Of the patients with a documented beta-lactam allergy, 63 (38.2%) patients had no allergy manifestation listed, and 37 (22.4%) patients had a non–IgE-mediated allergy manifestation. Of the total population, 61 (37%) patients had tolerated a beta-lactam in the past. Conclusions: Aztreonam should be avoided, except in the case of a true IgE-mediated allergic reaction. Our goal was to reduce the inappropriate use of aztreonam at our institution by one or more of the following: educating providers, reviewing aztreonam orders, requiring answering of order questions, or requiring an indication for use. Penicillin skin testing and desensitization are options as well.

Prevalence of Colorectal Neoplasms and Mortality in New Users of Low-Dose Aspirin With Lower Gastrointestinal Bleeding Background: Aspirin inhibits platelet function and may therefore accelerate early lower gastrointestinal bleeding (LGIB) from colorectal cancer (CRC) precursor polyps. The bleeding may increase endoscopic polyp detection. Study Question: To estimate the prevalence of polyps and CRC comparing new users of low-dose aspirin with nonusers who all received a diagnosis of LGIB and to investigate the mortality among these patients. Study Design: Using Danish nationwide health registries, we conducted a cohort study (2006–2013) of all new aspirin users who also received a diagnosis of LGIB (n = 40,578). Each new user was matched with 5 nonusers with LGIB by gender and age at the LGIB diagnosis date. Measures and Outcomes: We computed the prevalence and prevalence ratios (PRs) of colorectal polyps and CRCs, and the mortality ratios within 6 months after the LGIB, comparing new users with nonusers. Results: We identified 1038 new aspirin users and 5190 nonusers with LGIB. We observed 220 new users and 950 nonusers recorded with endoscopically detected polyps. New aspirin users had a higher prevalence of conventional {PR = 1.28 [95% confidence interval (CI): 1.06–1.55]} and serrated [PR = 1.31 (95% CI: 0.95–1.80)] polyps. New users and nonusers had a similar prevalence of CRC [PR = 1.04 (95% CI: 0.77–1.39)]. However, after stratifying by location of CRC, the prevalence of proximal tumors was lower [PR = 0.71 (95% CI: 0.35–1.43)] in new users than in nonusers. No difference in mortality was observed. Conclusions: These findings indicate that new use of low-dose aspirin is associated with an increased detection of colorectal polyps compared with nonuse.

Antithrombotic Therapy and Outcomes of Patients With New-Onset Transient Atrial Fibrillation After ST-Segment Elevation Myocardial Infarction Background: Atrial fibrillation (AF) is a common complication of ST-segment elevation myocardial infarction (STEMI), and AF might require anticoagulant treatment in some conditions. Study Question: There are no clear recommendations about vitamin K antagonist (VKA) use in patients with STEMI who complicated with new-onset transient AF. In this study, we examined the association of concomitant use of VKA and dual antiplatelet therapy (DAPT) with clinical outcomes of this patient population. Study Design: A total of 4086 patients with STEMI who underwent primary percutaneous coronary intervention retrospectively investigated. Among these patients, a total of 286 patients who developed new-onset transient AF during hospitalization were enrolled. VKA group consisted of 116 patients treated with warfarin, aspirin, and clopidogrel, and DAPT group consisted of 170 patients treated with aspirin and clopidogrel. Measures and Outcomes: One-year mortality, ischemic stroke, major, and minor bleeding were determined as clinical outcomes. Results: Although VKA group had proportionally lower mortality (17.2% vs. 20.0%) and ischemic stroke (7.8% vs. 11.8%) compared with DAPT group, the differences did not reach to statistical significance, whereas the 1-year major bleeding had higher rates at VKA group and that had 3.5-times higher major bleeding than DAPT group. This relationship was persisted after multivariable analysis (hazard ratio = 3.37, 95% CI, 1.76–10.04, P = 0.012). Conclusions: There is not a widely accepted treatment algorithm in patients with STEMI who complicated with new-onset AF in clinical guidelines. The current study indicated that transient form of new-onset AF might not require long-term VKA. Besides, addition of VKA to DAPT therapy may increase the rates of major and minor bleeding.

Topical Nifedipine for the Treatment of Pressure Ulcer: A Randomized, Placebo-Controlled Clinical Trial Background: Effect of nifedipine on pressure ulcer (PU) healing has not been evaluated in the human subjects yet. Study question: In this study, the effect of topical application of nifedipine 3% ointment on PU healing in critically ill patients was investigated. Study design: This was a randomized, double-blind, placebo-controlled clinical. Measures and outcomes: In this study, 200 patients with stage I or II PU according to 2-digit Stirling Pressure Ulcer Severity Scale were randomized to receive topical nifedipine 3% ointment or placebo twice daily for 14 days. Changes in the size and stage of the ulcers were considered as primary outcome of the study. The stage of the ulcers at baseline and on day 7 and day 14 of study was determined by using 2-digit stirling scale. In addition, the surface area of the wounds was estimated by multiplying width by length. Results: In total, 83 patients in each group completed the study. The groups were matched for the baseline stage and size of PUs. Mean decrease in the stage of PU in the nifedipine group was significantly higher than the placebo group on day 7 (−1.71 vs. −0.16, respectively, P < 0.001) and day 14 (−0.78 vs. −0.09, respectively, P < 0.001). Furthermore, the mean decrease in the surface area of PU was significantly higher in the nifedipine group compared with the placebo group on day 7 (−1.44 vs. −0.32, respectively, P < 0.001) and day 14 (−2.51 vs. −0.24, respectively, P < 0.001) of study. Conclusions: Topical application of nifedipine 3% ointment for 14 days significantly improved the healing process of stage I or II PUs in critically ill patients.

Comparing Nonopioids Versus Opioids for Acute Pain in the Emergency Department: A Literature Review Background: Pain is the most common reason for patient visits in the emergency department (ED). Opioids have been long considered the standard of care for acute pain in the ED. Because of the opioid crisis, investigation and implementation of novel practices to manage pain is needed. The use of various nonopioids has been suggested as a plausible alternative to opioids, with emerging literature to support its use for acute pain in the ED. Study Question: To evaluate the safety, efficacy, opioid-sparing effects of nonopioids in patients who present with acute pain in the ED. Data Sources: We systematically searched PubMed and EMBASE (July 1970 to January 2019). Study Design: Randomized controlled trials that evaluated nonopioids versus opioids in the ED were eligible. The clinical outcomes measured were change in pain scores compared with baseline, the incidence of adverse events, and use of rescue analgesia. Results: Twenty-five randomized controlled trials that evaluated the use of nonopioids in 2323 patients [acetaminophen (APAP) (n = 651), diclofenac (n = 547), ketamine (n = 272), ketorolac (n = 225), lidocaine (n = 219), ibuprofen (n = 162), ibuprofen & APAP (n = 162), hydroxyzine & dihydroergotamine (n = 85)] met inclusion criteria. Four trials found significant greater reductions in pain scores, favoring nonopioids. In all trials, the duration of pain relief provided by nonopioids was not sustained over an extended period. Eighteen trials reported no significant differences in reduction of pain scores. Two trials reported improved pain reduction with opioids and one trial reported noninferiority. Conclusions: Evidence from primary literature suggests that nonopioids could be a feasible alternative to opioids for management of acute pain in the ED as it is effective, safe, and decreases the need for rescue analgesia.

Treatment Failures of Direct Oral Anticoagulants Background: Use of direct oral anticoagulants (DOACs) has increased over the years, because they have become a safe and effective alternative to the Vitamin-K antagonists in various clinical scenarios. With their increased use, reports have emerged describing their failure. Study Question: What are the patient characteristics and clinical settings in which DOAC treatment failure manifests? Data Sources: We searched published reports in Google Scholar, PubMed, MEDLINE, and Embase from the introduction of DOACs in any therapy until March 2019. Study Design: Information on patient characteristics, comorbidities, primary anticoagulation indications, pharmacologic treatment, and outcomes were collected. Primary endpoints were new thrombus formation, failure of resolution of an existing thrombus, or discovery of subtherapeutic drug level. Other endpoints were time to treatment failure, manifestations of treatment failure, and new treatment after DOAC failure. Results: Our search yielded 51 manuscripts, describing 79 patients who exhibited DOAC failure. The most common treatment failures were in patients with antiphospholipid syndrome (44.3%), atrial fibrillation (30.4%), and deep venous thrombosis (6.3%). There was a trend toward higher failure rate for rivaroxaban (65.8%) followed by dabigatran (27.8%), apixaban (7.6%), and then edoxaban (1.3%). Each agent had different median failure times. Most common manifestations of treatment failure were stroke/transient ischemic attack (20.3%), pulmonary embolism (19.0%), and deep venous thrombosis (19.0%). More than half of patients were transitioned to a Vitamin-K antagonist after DOAC failure (55.7%). Conclusions: Our analysis illustrates that DOACs may fail in the setting of Food and Drug Administration and non–Food and Drug Administration- approved indications. In clinical practice, it may be best to choose between available anticoagulant drugs on a case-by-case basis.

Sodium–Glucose Cotransporter-2 Inhibitors and the Risk of Amputation: What Is Currently Known? Background: Diabetes mellitus is a major cause of morbidity and mortality in the United States. Twelve medication classes on the market reduce serum glucose including sodium–glucose cotransporter-2 (SGLT2) inhibitors. Potential benefits of these agents include improved glycemic control, weight loss, reduction in blood pressure, and possible reduction in cardiovascular events in patients with elevated cardiovascular risk. Areas of Uncertainty: Recently, several adverse events have been identified including increased possible risk of amputation associated with SGLT2 inhibitor therapy. Data Source: We conducted a review of published literature and identified 32 trials reviewing incidence of SGLT2 inhibitor-related amputation. Results: The potential increased risk for amputation is mostly of the lower extremities. Of the SGLT2 inhibitors currently available, canagliflozin has the highest association with an increased risk of lower extremity amputation and is the only agent with a Food and drug Administration Black Box Warning. Most canagliflozin amputation occurred in a single study. Risk factors for amputation with SGLT2 inhibitors may include those who have a history of amputations, susceptible to foot ulcers and those with baseline cardiovascular disease. Conclusions: For at-risk patients who desire an agent from this drug class, empagliflozin or dapagliflozin should be considered, as studies have not found a significant increase in amputations when compared with placebo or in retrospective reviews. Despite the increased risk of amputation found with canagliflozin, providers can use SGLT2 inhibitors with frequent monitoring to safely manage diabetes in low-risk patients. Patient education on associated risks is warranted. Diabetes educators can inform patients of risk factors to assist with monitoring.

Drug Repositioning in Oncology Background: The worldwide increase in the occurrence of cancer associated with the limitations of immunotherapy and the emergence of resistance have impaired the prognosis of cancer patients, which leads to the search for alternative treatment methods. Drug repositioning, a well-established process approved by regulatory agencies, is considered an alternative strategy for the fast identification of drugs, because it is relatively less costly and represents lower risks for patients. Areas of Uncertainty: We report the most relevant studies about drug repositioning in oncology, emphasizing that its implementation faces financial and regulatory obstacles, making the creation of incentives necessary to stimulate the involvement of the pharmaceutical industry. Data Sources: We present 63 studies in which 52 non-anticancer drugs with anticancer activity against a number of malignancies are described. Therapeutic Innovations: Some have already been the target of phase III studies, such as the Add-Aspirin trial for nonmetastatic solid tumors, as well as 9 other drugs (aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, and sertraline) in the CUSP9* clinical trial for the treatment of recurrent glioblastoma. Others have already been successful in repositioning such as thalidomide, zoledronic acid, celecoxib, methotrexate, and gemcitabine. Conclusions: Therefore, drug repositioning represents a promising alternative for the treatment of oncological disorders; however, the support from funding agencies and from the government is still needed, the latter regarding regulatory issues.

A New Safety Scoring System for the Use of Psychotropic Drugs During Lactation Background: Psychotropic drugs are frequently used to treat postpartum women with psychiatric diagnoses, especially psychotic disorder, major depression, and bipolar mood episodes. Pharmacotherapy in breastfeeding mothers is a major challenge. Study Question: This article presents a new safety scoring system for the use of psychotropic drugs during lactation. Study Design: The scoring system is based on the following 6 safety parameters: reported total sample, reported maximum relative infant dose, reported sample size for relative infant dose, infant plasma drug levels, prevalence of reported any adverse effect, and reported serious adverse effects. The total score ranges from 0 to 10. Higher scores represent a higher safety profile. Results: According to this scoring system, sertraline and paroxetine, respectively, had the highest scores representing "very good safety profile." Citalopram, olanzapine, and midazolam were assigned to "good safety profile." Among drugs evaluated in this article, trifluoperazine, aripiprazole, amisulpride, clozapine, doxepin, zaleplon, and zolpidem are not recommended owing to safety scores ≤3. Conclusions: Most psychotropic drugs examined in this article have "moderate" or "low" safety profile.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

Telephone consultation 11855 int 1193,

Healthcare Quality (JHQ)

Leadership Lessons From COVID-19 and the Path Forward No abstract available

Processes for Trauma Care at Six Level I Trauma Centers During the COVID-19 Pandemic Introduction: As the COVID-19 pandemic spread, patient care guidelines were published and elective surgeries postponed. However, trauma admissions are not scheduled and cannot be postponed. There is a paucity of information available on continuing trauma care during the pandemic. The study purpose was to describe multicenter trauma care process changes made during the COVID-19 pandemic. Methods: This descriptive survey summarized the response to the COVID-19 pandemic at six Level I trauma centers. The survey was completed in 05/2020. Questions were asked about personal protective equipment, ventilators, intensive care unit (ICU) beds, and negative pressure rooms. Data were summarized as proportions. Results: The survey took an average of 5 days. Sixty-seven percent reused N-95 respirators; 50% sanitized them with 25% using ultraviolet light. One hospital (17%) had regional resources impacted. Thirty-three percent created ventilator allocation protocols. Most hospitals (83%) designated more beds to the ICU; 50% of hospitals designated an ICU for COVID-19 patients. COVID-19 patients were isolated in negative pressure rooms at all hospitals. Conclusions: In response to the COVID-19 pandemic, Level I trauma centers created processes to provide optimal trauma patient care and still protect providers. Other centers can use the processes described to continue care of trauma patients during the COVID-19 pandemic.

Nurse Burnout Predicts Self-Reported Medication Administration Errors in Acute Care Hospitals Background: Every one out of 10 nurses reported suffering from high levels of burnout worldwide. It is unclear if burnout affects job performance, and in turn, impairs patient safety, including medication safety. The purpose of this study is to determine whether nurse burnout predicts self-reported medication administration errors (MAEs). Methods: A cross-sectional study using electronic surveys was conducted from July 2018 through January 2019, using the Copenhagen Burnout Inventory. Staff registered nurses (N = 928) in acute care Alabama hospitals (N = 42) were included in this study. Descriptive statistics, correlational, and multilevel mixed-modeling analyses were examined. Results: All burnout dimensions (Personal, Work-related, and Client-related Burnout) were significantly correlated with age (r = −0.17 to −0.21), years in nursing (r = −0.10 to −0.17), years of hospital work (r = −0.07 to −0.10), and work environment (r = −0.24 to −0.57). The average number of self-reported MAEs in the last 3 months was 2.13. Each burnout dimension was a statistically significant predictor of self-reported MAEs (p < .05). Conclusions: Nurse burnout is a significant factor in predicting MAEs. This study provides important baseline data for actionable interventions to improve nursing care delivery, and ultimately health care, for Alabamians.

The Effect of Numbered Jerseys on Directed Commands, Teamwork, and Clinical Performance During Simulated Emergencies Communication and teamwork are essential during inpatient emergencies such as cardiac arrest and rapid response (RR) codes. We investigated whether wearing numbered jerseys affect directed commands, teamwork, and performance during simulated codes. Eight teams of 6 residents participated in 64 simulations. Four teams were randomized to the experimental group wearing numbered jerseys, and four to the control group wearing work attire. The experimental group used more directed commands (49% vs. 31%, p < .001) and had higher teamwork score (25 vs. 18, p < .001) compared with control group. There was no difference in time to initiation of chest compression, bag-valve-mask ventilation, and correct medications. Time to defibrillation was longer in the experimental group (190 vs. 140 seconds, p = .035). Using numbered jerseys during simulations was associated with increased use of directed commands and better teamwork. Time to performance of clinical actions was similar except for longer time to defibrillation in the jersey group.

Lean in Healthcare: Time for Evolution or Revolution? Lean has gained recognition in healthcare as a quality improvement tool. The purpose of this research was to examine the extent to which quality improvement projects in healthcare adhered to Lean's eight-step process. We analyzed 605 publications identified through a systematic literature review following PRISMA guidelines. Each publication was coded using a structured coding sheet. The most frequent type of publication reported empirical research (48.6%) and most of these (80.3%) shared the results of the Lean projects. Of the 237 publications reporting Lean projects, more than half (71.3%) used an experimental, one-site, pre/postdesign. The impact of the project was most often measured using a single metric (59.1%) that was operational (e.g., waiting time). Although most Lean project publications reported the use of tools to "break down the problem" (84.4%, Step 2) and "see countermeasures through" (70.0%, Step 6), fewer than half described using tools associated with each of the other steps. Projects completed an average of 2.77 steps and none of the projects completed all steps. Although some may perceive low adherence to the tenets of Lean as a deficiency, it may be that Lean approaches are evolving to better meet the needs of healthcare.

Improving Utilization of Vaccine Two-Dimensional (2D) Barcode Scanning Technology Maximizes Accuracy Benefits Background: Recording vaccine data accurately can be problematic in medical documentation, including blank and inaccurate records. Vaccine two-dimensional (2D) barcode scanning has shown promise, yet scanner use to record vaccine data is limited. We sought to identify strategies to improve scanning rates and assess changes in accuracy. Methods: Between January and June 2017, 27 pilot sites within a large health system were assigned to one of four groups to test strategies to maximize scanner use: training only, commitment card, scanning report, or combination. Seventy-two thousand vaccine records were assessed for completeness, accuracy, and scanning. Results: Significant increases in vaccinator scanning rates found with commitment card and scanning report inclusion (alone and paired) compared with the training-only group. Record completeness and accuracy significantly improved with use of scanning. When manually entered, about 1 in 9 records had a missing or inaccurate expiration date; when scanned, this dropped to 1 in 5,000. Conclusions: Pilot findings indicate 2D scanning has the potential to eliminate most omissions and inaccuracies in vaccine records. Such data are critical during a recall or need to trace specific vaccines or patients. Implications: Consistent use and expanded adoption of 2D scanning can meaningfully improve the quality of vaccine records and clinical practices.

Improving Inpatient Tobacco Treatment Measures: Outcomes Through Standardized Treatment, Care Coordination, and Electronic Health Record Optimization Introduction: The Centers for Disease Control and Prevention states that tobacco use is the largest and most preventable cause of disease and mortality in the United States. The Joint Commission implemented inpatient tobacco treatment measures (TTMs) in 2012 to encourage healthcare systems to create processes that help patients quit tobacco use through evidence-based care. Methods: A tobacco cessation care delivery system was implemented at James A. Haley Veterans' Hospital and Clinics, which included: standardized pathways within the Veterans Health Administration (VHA) electronic health record system to improve nicotine replacement therapy ordering; evidence-based tobacco cessation counseling; and improved care coordination for tobacco cessation treatment through the use of technological innovation. Results: Outcomes were obtained from the VHA quality metric reporting system known as Strategic Analytics for Improvement and Learning (SAIL). TOB-2 and TOB-3 (two Joint Commission inpatient TTMs) equivalent to tob20 and tob40 within SAIL improved by greater than 300% after implementation at James A. Haley Veterans' Hospital and Clinics. Conclusion: Implementation of a tobacco cessation care system at James A. Haley Veterans' Hospital and Clinics enhanced interdisciplinary coordination of tobacco cessation care and resulted in improvements of The Joint Commission inpatient TTMs by greater than threefold.

Continuous Cloud-Based Early Warning Score Surveillance to Improve the Safety of Acutely Ill Hospitalized Patients Introduction: This study sought to evaluate the impact of changes made to the process of continually screening hospitalized patients for decompensation. Methods: Patients admitted to hospital wards were screened using a cloud-based early warning score (modified National Early Warning Score [mNEWS]). Patient with mNEWS ≥7 triggered a structured response. Outcomes of this quality improvement study during the intervention period from February through August 2018 (1741 patients) were compared with a control population (1,610 patients) during the same months of 2017. Results: The intervention group improved the time to the first lactate order within 24 hours of mNEWS ≥7 (p < .001), the primary outcome, compared with the control group. There was no significant improvement in time to intensive care unit (ICU) transfer, ICU length of stay (LOS), or hospital mortality. Among patients with a lactate ordered within 24 hours, there was a 47% reduction of in-hospital mortality (odds ratio 0.53, 95% confidence interval 0.3–0.89, p = .02) and a 4.7 day reduction in hospital LOS (p < .001) for intervention versus control cohorts. Conclusions: Cloud-based electronic surveillance can result in earlier detection of clinical decompensation. This intervention resulted in lower hospital LOS and mortality among patients with early detection of and intervention for clinical decompensation.

Assessing the Efficacy of Certificate of Need Laws Through Total Joint Arthroplasty Lawmakers suggest Certificate of Need (CON) laws' main goals are increasing access to healthcare, increasing quality of healthcare, and decreasing healthcare costs. This retrospective database study aims to evaluate the effectiveness of CON through analysis of total knee, hip, and shoulder arthroplasty (TKA, THA, and TSA, respectively). A review was performed using the Humana Insurance PearlDiver national database from 2007 to 2015. Access to care was approximated by the rates of total joint arthroplasty (TJA) in patients diagnosed with arthritis to the corresponding joint. The quality of care was assessed using complication rates after TJA. The total cost of TJA was approximated from average reimbursement to the healthcare facility per procedure. Patients in states without CON programs received TKA, THA, and TSA more frequently (p < .0001, p = .250, p = .019). No significant difference was found in studied complication rates between CON and non-CON states. Similarly, there was no trend found when comparing the cost of each procedure in CON versus non-CON states. These findings are consistent with other recent studies detailing the impact of CON regulation on THA and TKA. The apparent nonsuperiority of CON states in achieving their purported goals may call into question the effectiveness of additional bureaucracy and regulation, suggesting a need for further examination.

Multi-Level Predictors of Discharges Against Medical Advice: Identifying Contributors to Variation Using an All-Payer Database There is increasing evidence of the role of non–patient-level factors on discharge against medical advice (DAMA), but limited quantitative information regarding the extent of their impact. This study quantifies the contribution of discharge-level and hospital-level factors to the variation in DAMA. We grouped variables from the 2014 National Inpatient Sample data and ran incremental mixed-effects logit models with grouping at the level of the discharge, the hospital, and the census region. We obtained the intraclass correlation coefficients (ICCs), and evaluated the incremental change in ICC. The final sample included 2,687,430 discharges. 12.8% of the identified variation in the probability of DAMA was associated with the hospital, and 1.2% of the variation was associated with the census division in which the hospital was located. The final, fully-adjusted model had 7.3% of variation in DAMA associated with the hospital-level, with the greatest percentage reductions because of the addition of patient demographics. Even after adjusting for measured patient-level characteristics, there was a contribution of non–patient-level factors to DAMA outcomes. The findings identify a role for a multi-level approach to addressing DAMA.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

Telephone consultation 11855 int 1193,