Pain

The Prevalence and Potential Role of Pain Beliefs When Managing Later-Life Pain Objectives: In this study of 154 community-dwelling older adults with chronic non-cancer pain, we sought to assess participants' beliefs about pain as well as pain management treatments and determined the influence of those beliefs on participants' willingness to undertake three physician-recommended pain treatments, i.e., a pharmacologic, physical, and psychological therapy. Methods: A 16-item questionnaire was employed to ascertain participants' pain beliefs, divided into four subscales representing (1) negative beliefs about pharmacological treatments, (2) positive beliefs about physical treatment approaches, e.g., exercise; (3) positive beliefs about psychological treatments, and (4) fatalistic beliefs about pain. Participants were asked to rate their willingness to undertake a pharmacologic, physical, or psychological therapy if their physician recommended that they do so. Agreement with each belief was measured, and we examined willingness to undertake each treatment as a function of pain belief subscale scores after controlling for relevant covariates. Results: Positive beliefs about physical treatments (e.g., benefits of exercise) were the most strongly endorsed items on the pain beliefs questionnaire. All three treatment-focused pain beliefs subscales were significantly associated with willingness to undertake that form of treatment (e.g., negative beliefs about pain medication use were associated with decreased willingness to take pain medication). Fatalistic attitudes were significantly associated with a decreased willingness to undertake physical treatments. Discussion: These results support the notion that patients' beliefs about pain and pain treatments can have important effects on treatment engagement and, if assessed, can help guide clinical management of chronic pain in older adults. There are no conflicts of interest. Reprints: M. Carrington Reid, MD, PhD, Division of Geriatrics & Palliative Medicine, Weill Cornell Medical Center, New York, NY 10065, USA (e-mail: mcr2004@med.cornell.edu). Received June 22, 2020 Received in revised form November 22, 2020 Accepted November 25, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Brief Psychological Interventions for Reducing Prescription Opioid Use, Related Harm and Pain Intensity in Patients with Chronic Pain: A Systematic Review and Assessment of Patient Interest Objectives: Brief psychological interventions (BPIs) have demonstrated effectiveness in reducing substance use and related harm. No systematic review has examined their potential to reduce or prevent prescription opioid use or related harm, and/or pain intensity in opioid-using patients with chronic non-cancer pain (CNCP). Recognizing the importance of patient preferences in evidence-based practice, we also sought to assess patient interest in BPIs. Methods: A systematic review of studies published between 1980-2020 was conducted using five databases. Eligible treatment studies included patients ≥18 years old, with CNCP, and who were using prescription opioids. An adjunctive study independent of our review was also undertaken in 188 prescription opioid-using patients (77% female; Mage=49▒y) diagnosed with CNCP. Patients completed pain-related questionnaires online and indicated if they would consider BPI treatment options. Results: The review identified six studies. Given the heterogeneity across studies, a meta-analysis was not conducted. A narrative review found all of the six studies demonstrated some evidence for BPI effectiveness for reducing opioid use or related harms; these were assessed as having mostly low methodological quality. Mixed support for the effect on pain intensity was found in one study. Despite the inconclusive findings and heterogenous studies identified in the review, 92% of patients in our survey reported interest in receiving a BPI. Discussion: In combination, these findings highlight the inconsistency between patient demand and the availability of evidence for BPIs targeting opioid use, related harm and/or pain intensity. Future work should examine the effectiveness of BPIs in higher quality studies. Submission category: Review. Funding sources: No funding sources were provided. Significance: Our findings highlight the inconsistency between patient demand and the availability of evidence for brief psychological interventions (BPIs) in reducing prescription opioid use and related harm, and pain intensity. Based on the success of BPIs in reducing substance-related harm and patient preferences identified in this study, more higher quality research is needed to determine whether BPIs should be a treatment option for improving outcomes for opioid-using patients with chronic non-cancer pain. PROSPERO Pre-registration number: CRD42020149423. Author contributions: RE, JC, MS, and JL were involved in the conceptualization and design of the study. RE, JL, and SSR were involved in the design and execution of the searches with guidance from a librarian. RE and SSR conducted the screening and quality review of studies. All members of the research team were involved in the final selection of included studies. All authors discussed the results and were involved in interpretation. RE drafted the manuscript, and all authors provided critical revisions. All authors approved the final manuscript for submission. Conflict of interest: The authors have no conflicts of interest to declare. Reprints: Rachel Elphinston, PhD, Recover Injury Research Centre, Level 7, 288 Herston Road, Herston, Brisbane, Queensland, Australia 4006 (e-mail: rachelel@uq.edu.au). Received June 17, 2020 Received in revised form November 23, 2020 Accepted November 29, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Pre- versus Postoperative Scalp Block Combined with Incision Line Infiltration for Pain Control after Supratentorial Craniotomy Objective: Postoperative pain after craniotomy is a significant clinical problem which is sometimes underestimated, although moderate or severe pain in early postoperative period complicates up to 60% of cases. The purpose of this prospective randomized multicenter trial is to determine the optimal timing for selective scalp block in patients undergoing general anesthesia for supratentorial craniotomy. Methods: After ethics committee approval and informed consent, 56 adult patients were enrolled, and randomly assigned to receive a selective scalp block combined with incision line infiltration preoperatively or postoperatively. Results: Postoperative pain at 24 hours after the procedure was recorded in all 56 enrolled patients. In patients assigned to receive a scalp block preoperatively, median VAS score at 24 hours after surgery was 0 (0-2), and in patients assigned to receive a scalp block postoperatively it was 0 (0-3) (P>0,05). There was no difference in severity of pain at 24, 12, 6, and 2 hours after surgery between the two study groups, but the amount of fentanyl administered intraoperatively was lower in patients assigned to the preoperative scalp block group (1.6±0.7▒mkg/kg/h vs. 2.4±0.7▒mkg/kg/h (P=0.01)). Discussion: This study confirms and extends available clinical evidence on the safety and efficacy of selective scalp blocks for the prevention of postoperative pain. Recorded data suggest that there is no difference in terms of occurrence and severity of postoperative pain regardless of whether the scalp block is performed preoperatively (after general anesthesia induction) or postoperatively (before extubation). Patients assigned to receive a scalp block combined with incision line infiltration preoperatively needed less intraoperative opioids than those assigned to postoperative scalp block. Financial Disclosures: None Conflicts of interest: None Reprints: Alexander Kulikov, MD, PhD, 125047, 4th Tverskaya-Yamskaya St., 16, Department of Anesthesiology, Burdenko National Medical Research Center of Neurosurgery, Moscow, Russia (e-mail: akulikov@nsi.ru). Received April 25, 2019 Received in revised form August 28, 2020 Accepted November 6, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Video-based Pain Education in Schools: A Study with Adolescents Objective: School-based educational programs have shown positive changes in health-related behaviors among adolescents. The aim of this study was to analyze the changes in pain-related knowledge among adolescents and in the use of positive responses to their peers' pain behaviors after watching a brief educational video. Methods: One hundred and thirty-five adolescents (mean age=13.27; SD=1.17) participated and provided demographic and pain-related information. They also responded to a pain-related knowledge questionnaire before (T1), after (T2) and one month after (T3) watching a brief pain educational video, and to a modified version of the Inventory of Parent/Caregiver Responses to the Children's Pain Experience at T1 and at T3. Results: There was a significant increase in pain knowledge for all participants between T1 and T2 (η2p=0.73) and between T1 and T3 (η2p=0.62). An increase in responses considered to be positive to peers' pain behaviors (i.e., the promotion of well-behaviors and coping responses) one month after watching the educational video was also found. Interestingly, these results were not associated with the chronic pain status of the participant. Discussion: The findings showed that a brief and inexpensive educational video-based intervention in schools helps to increase pain-related knowledge and change responses to students with chronic pain. This has the potential to prevent chronic pain and related disability among students, and decrease bullying-like behaviors towards students with chronic pain. Conflict of interests: The authors declare no conflicts of interest in relation to this study. Reprints: Jordi Miró, PhD, Departament de Psicologia; Universitat Rovira i Virgili; Carretera de Valls, s/n; 43007 Tarragona; Spain (e-mail: jordi.miro@urv.cat). Received July 17, 2020 Received in revised form November 9, 2020 Accepted November 11, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Patients with High Chronic Postoperative Knee Pain 5 years after Total Knee Replacement Demonstrate Low-grad Inflammation, Impairment of Function and High Levels of Pain Catastrophizing Objectives: Total knee replacement (TKR) normally provides improvements of physical function and reduces pain. However, approximately 20% of the patients report chronic postoperative knee pain. The aims of the present study were to assess the pain, physical function, and physiological characteristics 5 years after TKR surgery. Methods: Eighty patients were recruited 5 years after TKR and divided into two groups based on their average 24-hour knee pain intensity assessed on a visual analog scale (VAS 0-10) ("High Pain Group": VAS≥3; "Low Pain Group": VAS<3). The patients completed the painDETECT (PD-Q), Oxford Knee Score (OKS), Pain Catastrophizing Scale (PCS), and Forgotten Joint Score (FJS-12). Furthermore, the patients underwent a clinical examination of the knees and high sensitivity serum C-reactive protein (hs-CRP) was measured as an inflammatory marker. Results: 53% of the patients in the High Pain Group was not satisfied with the outcome, while only 11% of the patients in the Low Pain Group was not satisfied, and the pain intensities in the two groups were 5.1 (4.6-5-6) and 1.1 (0.6-1.5), (P<0.001), respectively. Furthermore, the High Pain Group demonstrates worse scores in: FJS-12 (P=0.001), OKS function (P<0.001), OKS pain (P<0.001), and PCS (P<0.001). The High Pain Group demonstrated increased level of hs-CRP (4.3▒mg/L (3.2-5.5) vs. 1.7▒mg/L (1.2-2.2), P<0.001), and decreased range of motion in the knee (110-degrees ROM vs. 119-degrees ROM, P=0.013). Discussion: Patients with high chronic postoperative knee pain 5 years after TKR demonstrate decreased physical function, higher levels of catastrophizing thoughts, and increased levels of inflammation. Original paper for: Clinical Journal of Pain Article Type: Original Research Conflicts of Interest and Source of Funding: The authors declare no conflict of interest. Reprints: Peter Skrejborg, MSc, PhD-fellow, SMI, Department of Health Science and Technology, School of Medicine, Aalborg University, Fredrik Bajers Vej 7 D3, DK-9220 Aalborg, Denmark (e-mail: peter@skrejborg.dk). Received May 18, 2020 Received in revised form November 19, 2020 Accepted November 23, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Physical Activity as a Predictor of Chronic Pain Following Pediatric Spinal Surgery Objectives: (1) Characterize objective physical activity patterns via actigraphy over 4 months post-spinal fusion surgery, and (2) examine associations between activity patterns at 2-weeks and chronic post-surgical pain (CPSP) status at 4-months. Methods: Data from 109 youth (10-18▒y) who underwent spinal fusion surgery at a children's hospital in the northwestern United States were analyzed. Youth completed questionnaires and actigraphic assessment of physical activity pre-surgery, and 2-weeks and 4-months post-surgery. Results: 18% of youth developed CPSP at 4-months. Pre-surgery physical activity was similar for youth with and without CPSP. At 2-weeks post-surgery, daily activity levels were lower for youth who developed CPSP as compared to those who did not, including lower mean activity (168 vs. 212 counts/minute, P=0.01), fewer activity bouts (n=1.7 vs. 2.6, P=0.02), and shorter bout duration (27 vs. 40▒min, P=0.02). Differences in activity were maintained at 4-months such that youth with CPSP had lower mean activity (284 vs. 334 counts/min, P=0.03), as well as greater proportion time spent sedentary and lower proportion time in light activity than youth without CPSP. In adjusted models examining 2-week actigraphy as a predictor of 4-month pain status, mean activity (OR=0.99, P=0.04) and number of activity bouts (OR=0.79, P=0.02) were associated with subsequent CPSP status. Discussion: Lower activity engagement during the initial weeks following spinal fusion surgery was associated with development of CPSP, suggesting early physical activity limitations as a risk factor for CPSP in youth. Understanding recovery patterns is critical for identifying those at risk for chronic pain and implementing early interventions. https://www.seattlechildrens.org/rabbitts-lab/ Funding Source: This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, at the National Institutes of Health under Grant No. K23HD078239 (P.I.: J.A. Rabbitts). Abbreviations: CPSP, chronic postsurgical pain; MVPA, Moderate to vigorous activity; NRS, Numeric Rating Scale; REDCap, Research Electronic Data Capture System. Conflict of Interest: The authors have no conflicts of interest to disclose. Reprints: Jennifer A. Rabbitts, MB, ChB, Seattle Children's Hospital, 4800 Sand Point Way NE MB.11.500.3, Seattle WA 98105 (e-mail: jennifer.rabbitts@seattlechildrens.org). Received April 9, 2020 Received in revised form October 9, 2020 Accepted November 11, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

The Impact of Parental Pain- and Non-pain-attending Responses upon Child Pain Behavior in the Context of Cancer-related Painful Procedures: The Moderating Role of Parental Self-oriented Distress Objectives: Literature has demonstrated inconsistent findings regarding the impact of parental responses upon child pain-related outcomes. Yet, research into factors that may underlie inconsistent findings regarding the variable impact of parental responses is lacking. The current study investigated the moderating role of parental distress in understanding the impact of parental pain-attending (e.g., reassuring the child) and non-pain-attending (e.g., distracting the child with humor) responses upon child pain behavior (e.g., crying). Methods: Children (≤18▒y) suffering from leukemia, undergoing a lumbar puncture (LP) and/or bone marrow aspiration (BMA) procedure, and one of their parents, were recruited from the Pediatric Ghent University Hospital. Parent-child interactions were videotaped after the procedure allowing coding of parental responses and child pain behavior. Parents self-reported on experienced personal distress. Results: Participants consisted of 42 children (24 boys, 18 girls) with leukemia and one of their parents. Children were 0.6-15 (7.08±4.39) years old. Findings indicated a positive association between parental pain-attending and child pain behavior, but only when parents reported high levels of distress (β=0.56, P=0.001). No association was observed for parents reporting low levels of distress (β=-0.09, ns). Parental non-pain-attending responses contributed to lower child pain behavior (β=-0.24, P=0.045), independently from parental distress (β=-0.07, ns). Discussion: The current findings point to the moderating role of parental distress in understanding the impact of parental responses upon child pain behavior and highlight the importance of interventions targeting parental emotion regulation to promote more optimal child pain outcomes. Disclosures: Grant support for Emma Rheel was provided by a Chair funded by the Berekuyl Academy / European College for Decongestive Lymphatic Therapy, the Netherlands and awarded to the Vrije Universiteit Brussel, Belgium. Kelly Ickmans is a postdoctoral research fellow, partly funded by the Research Foundation – Flanders (FWO). Line Caes was funded by the Research Foundation – Flanders (FWO). None of these sponsors played a role in the (1) study design, (2) collection, analysis and interpretation of data, (3) writing of the report, (4) decision to submit the paper for publication. The authors report no conflicts of interest. Reprints: Emma Rheel, MSc, Address of correspondence and reprints requests to Emma Rheel, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium (e-mail: emma.rheel@vub.be). Received June 5, 2020 Received in revised form November 4, 2020 Accepted November 11, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

What Mediates Treatment Effects in a Pre-surgery Physiotherapy Treatment in Surgical Candidates with Degenerative Lumbar Spine Disorders? A Mediation and Conditional Process Analysis of the PREPARE Randomized Controlled Trial Objectives: Treatment guidelines recommend targeting both physical and psychological factors in interventions for degenerative lumbar spine disorders. Studying treatment mechanisms gives information on key factors explaining outcome improvement which can refine treatments for future research. This study explores treatment mediators in a physiotherapy treatment on disability, pain intensity and health related quality of life (HRQoL) in surgical candidates with degenerative lumbar spine disorders compared to waiting-list controls. An additional aim was to evaluate patients´ expectation as a moderator of treatment outcome. Methods: Data collected from 197 patients in a single blinded randomized controlled trial comparing 9 weeks of multifaceted physiotherapy to waiting-list were used in this conditional process analysis. Analysis was carried out on group differences for change in Oswestry Disability Index (ODI), Pain Visual Analog Scale (VAS) back pain, EuroQol-5D (EQ-5D) and EQ-VAS. The putative moderation role of expectations and mediation role of change in physical variables and psychosocial variables were tested. Results: Change in self-efficacy mediated improvement in all outcomes. Improvement in ODI was also mediated by change in depression, VAS was mediated by change in fear avoidance beliefs and EQ-VAS was mediated by change in activity level and fear avoidance beliefs. Improvements were moderated by patients´ treatment expectations. Discussion: Self-efficacy, fear avoidance beliefs, physical activity level and patients´ treatment expectations were found to be important factors explaining treatment effects. Self-efficacy was the consistent mediator for effects of the pre-surgical physiotherapy on disability, back pain intensity and HRQoL. Sources of grant support: Research Council in Southeast Sweden (grant number: FORSS*660371), the Swedish Research Council (grant number:2017*01444) and Region Östergötland (LIO-921021). Approved by the Regional Ethics Committee in Linköping (dnr 2012/167-31). Trial registration: NCT02454400. Trail registration date: August 31st, 2015, retrospectively registered. The authors declare no conflict of interest. Reprints: Maria Fors, RPT, MSc, Linkopings universitet Medicinska Fakulteten Linköping, SWEDEN (e-mail: maria.fors@liu.se). Received March 31, 2020 Received in revised form October 28, 2020 Accepted November 3, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Deep Cervical Plexus Block for Neck and Shoulder Pain Due to Myofascial Pain: A Randomized Clinical Trial Objectives: Myofascial pain is one of the most common causes of regional pain yet with no definitive treatment modality. This randomized clinical trial was conducted to assess the efficacy of deep cervical plexus block versus placebo injection (sham block) for the treatment of myofascial neck and shoulder pain in terms of analgesic consumption and pain during a follow up period of two weeks after performing the block. Methods: Patients were randomly divided into two groups. Group I (Block) received deep cervical plexus block and group II (Placebo) received normal saline. A total of 66 patients were included in the study, 34 patients in the block group and 32 patients in the placebo group. Results: Two weeks after the intervention, average pain duration was significantly lower in the block group (1.38±1.39 vs. 5.25±1.72) for the block and placebo groups respectively (P-value<0.0001). Pain intensity was significantly less in the block group such that 2.9% of patients in the block group had severe pain compared to 53.1% of patients in the placebo group (P-value<0.0001). Two weeks after receiving the block, the mean opioid consumption calculated as tramadol equivalent was 21.1±44.2▒mg compared to 166.1±118.8▒mg for the block and placebo groups respectively. Multivariate analysis revealed that patients with a longer history of pain had a higher pain score after two weeks. The possibility of recovery is affected by pain duration since patients with chronic history of pain were least affected by the block. Discussion: This technique could be an alternative to pharmacological and non-pharmacological treatments for myofascial pain. Disclosures: Funding: none Conflict of interest: none declared Reprints: Zoher Naja, MD, PhD, Anesthesia and Pain Management Department - Makassed General Hospital, P.O. Box: 11-6301 Riad EI-Solh 11072210, Beirut – Lebanon (e-mail: zouhnaja@yahoo.com). Received September 18, 2019 Received in revised form November 10, 2020 Accepted November 17, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

The Effect of Perioperative Lidocaine Infusion on Postoperative Pain and Postsurgical Recovery Parameters in Gynecological Cancer Surgery Objectives: The primary objective of this prospective non-blinded randomized study was to investigate the effect of perioperative systemic lidocaine infusion on pain control after major gynecologic oncology surgery. Patient-reported outcomes, postoperative recovery parameters, and complications were secondary endpoints of the study. Methods: Seventy-five patients with ASA I-III was divided into three groups based on perioperative analgesia methods: The opioid group: patient-controlled analgesia (PCA) with morphine, The lidocaine group: perioperative intravenous lidocaine infusion, plus PCA with morphine, and the epidural group: PCA with bupivacaine. The Visual Analog Scale (VAS) was recorded postoperatively. In addition, nausea-vomiting, time to first oral intake, time to first ambulation, time to first flatus, and length of hospital stay were recorded. Results: VAS scores (rest) at 24 hours at rest and VAS scores (cough) at 12 and 24 hours were significantly lower in the epidural group than in the opioid group (P<0.05). VAS scores were found to be similar between the lidocaine and epidural group. The nausea-vomiting incidence was lower in the lidocaine group than in the opioid group(P<0.05). Compared to the other two groups, first flatus time was shorter in the lidocaine group (P<0.05). Discussion: Perioperative lidocaine infusion is effective as epidural analgesia, which is often advocated as the gold-standard analgesic technique for abdominal surgery and is superior to the others in terms of time to first flatus, and the incidence of nausea-vomiting. Conflicts of Interest: The authors declare that they have no conflicts of interest. Reprints: Menşure Kaya, MD, Associate Professor, Department of Anesthesiology and Reanimation, University of Health Sciences Dr. AY Oncology Training and Research Hospital, Demetevler 13. Cad. 06180, Ankara, Turkey (e-mail: mensurekaya@yahoo.com). Received April 3, 2020 Received in revised form October 28, 2020 Accepted November 3, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Critical Care Medicine

Changes in the Plethysmographic Perfusion Index During an End-Expiratory Occlusion Detect a Positive Passive Leg Raising Test Objectives: The end-expiratory occlusion test for assessing preload responsiveness consists in interrupting mechanical ventilation for 15 seconds at end-expiration and measuring the cardiac index changes. The perfusion index is the ratio between the pulsatile and the nonpulsatile portions of the plethysmography signal and is, in part, determined by stroke volume. We tested whether the end-expiratory occlusion-induced changes in perfusion index could detect a positive passive leg raising test, suggesting preload responsiveness. Design: Observational study. Setting: Medical ICU. Patients: Thirty-one ventilated patients without atrial fibrillation. Interventions: We measured perfusion index (Radical-7 device; Masimo Corp., Irvine, CA) and cardiac index (PiCCO2; Pulsion Medical Systems, Feldkirchen, Germany) before and during a passive leg raising test and a 15-second end-expiratory occlusion. Measurements and Main Results: In 19 patients with a positive passive leg raising test (increase in cardiac index ≥ 10%), compared to the baseline value and expressed as a relative change, passive leg raising increased cardiac index and perfusion index by 17% ± 7% and 49% ± 23%, respectively, In these patients, end-expiratory occlusion increased cardiac index and perfusion index by 6% ± 2% and 11% ± 8%, respectively. In the 12 patients with a negative passive leg raising test, perfusion index did not significantly change during passive leg raising and end-expiratory occlusion. Relative changes in perfusion index and cardiac index observed during all interventions were significantly correlated (r = 0.83). An end-expiratory occlusion-induced relative increase in perfusion index greater than or equal to 2.5% ([perfusion index during end-expiratory occlusion–perfusion index at baseline]/perfusion index at baseline × 100) detected a positive passive leg raising test with an area under the receiver operating characteristic curve of 0.95 ± 0.03. This threshold is larger than the least significant change observed for perfusion index (1.62% ± 0.80%). Conclusions: Perfusion index could be used as a reliable surrogate of cardiac index for performing the end-expiratory occlusion test. Confirming previous results, the relative changes in perfusion index also reliably detected a positive passive leg raising test. 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 (http://journals.lww.com/ccmjournal). Dr. Beurton collected the data, performed data analysis, drafted the article, and approved its final version. Dr. Teboul conceived the study, participated in analyzing the data and to writing the article, and approved its final version. Drs. Gavelli and De Vita contributed to data recording and approved the final version of the article. Dr. Monnet conceived the study, supervised data analysis, drafted the article, and approved its final version. All authors read and approved the final article. Dr. Teboul received funding from Getinge/Pulsion. Dr. Monnet received funding from Pulsion Medical Systems, and he received support for article research from Assistance publique-Hôpitaux de Paris. Drs. Teboul and Monnet are members of the Medical Advisory Board of Pulsion Medical Systems and have given lectures for Masimo Corp. The remaining authors have disclosed that they do not have any potential conflicts of interest. Information and consent obtained for each patient. Name of the ethics committee that approved the study and the committee's reference number: Comité pour la Protection des Personnes, Ile-de-France VII. Trial registration ID RCB: 2016-A00959-42. Registered June 27, 2016. The patients were included prospectively. Information and consent obtained for each patient. For information regarding this article, E-mail: alexandra.beurton@aphp.fr Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

CNS Complications in Adult Patients Treated With Extracorporeal Membrane Oxygenation Objectives: To describe the incidence and outcomes of radiologically confirmed acute CNS complications in extracorporeal membrane oxygenation patients at an Australian extracorporeal membrane oxygenation referral center and identify associated patient characteristics. Design: Retrospective cohort study. Setting: Single-center tertiary institution. Patients: Four-hundred twelve consecutive adult patients supported with extracorporeal membrane oxygenation from 2009 to 2017. Results: Fifty-five patients (13.3%) had a CNS complication confirmed by CT or MRI, including ischemic stroke (7.0%), intracerebral hemorrhage (3.4%), hypoxic ischemic encephalopathy (3.6%), and spinal cord injury (1.2%). CNS complication rates in the venoarterial, venovenous, and veno-pulmonary artery extracorporeal membrane oxygenation subgroups were 18.0%, 4.6%, and 13.6%, respectively. Neurologic complications were independently associated with the use of venoarterial extracorporeal membrane oxygenation (p = 0.002) and renal replacement therapy (p = 0.04). Sixty-five percent of patients with a neurologic complication died during their hospital admission compared with 32% of patients without this complication (p < 0.001). Venoarterial extracorporeal membrane oxygenation, renal replacement therapy, and days of extracorporeal membrane oxygenation support were also associated with hospital mortality and remained so after adjustment in a multivariable regression model (p = 0.01, p < 0.001, and p = 0.003, respectively). Conclusions: CNS complications appear to occur more frequently in patients requiring circulatory as opposed to respiratory support on extracorporeal membrane oxygenation and are independently associated with mortality. It remains unclear if these complications are causative of a poor outcome or a marker of severity of the underlying condition. Further research is required to better elucidate modifiable or preventable aspects through better patient selection and change in ongoing care. 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 (http://journals.lww.com/ccmjournal). Dr. Kerr disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed at Department of Intensive Care Medicine, St Vincent's Hospital, Darlinghurst, NSW, Australia. For information regarding this article, E-mail: Hergen.Buscher@svha.org.au Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Mortality of Older Patients Admitted to an ICU: A Systematic Review Objectives: To conduct a systematic review of mortality and factors independently associated with mortality in older patients admitted to ICU. Data Sources: MEDLINE via PubMed, EMBASE, the Cochrane Library, and references of included studies. Study Selection: Two reviewers independently selected studies conducted after 2000 evaluating mortality of older patients (≥ 75 yr old) admitted to ICU. Data Extraction: General characteristics, mortality rate, and factors independently associated with mortality were extracted independently by two reviewers. Disagreements were solved by discussion within the study team. Data Synthesis: Because of expected heterogeneity, no meta-analysis was performed. We selected 129 studies (median year of publication, 2015; interquartile range, 2012–2017) including 17 based on a national registry. Most were conducted in Europe and North America. The median number of included patients was 278 (interquartile range, 124–1,068). ICU and in-hospital mortality were most frequently reported with considerable heterogeneity observed across studies that was not explained by study design or location. ICU mortality ranged from 1% to 51%, in-hospital mortality from 10% to 76%, 6-month mortality from 21% to 58%, and 1-year mortality from 33% to 72%. Factors addressed in multivariate analyses were also heterogeneous across studies. Severity score, diagnosis at admission, and use of mechanical ventilation were the independent factors most frequently associated with ICU mortality, whereas age, comorbidities, functional status, and severity score at admission were the independent factors most frequently associated with 3– 6 and 12 months mortality. Conclusions: In this systematic review of older patients admitted to intensive care, we have documented substantial variation in short- and long-term mortality as well as in prognostic factors evaluated. To better understand this variation, we need consistent, high-quality data on pre-ICU conditions, ICU physiology and treatments, structure and system factors, and post-ICU trajectories. These data could inform geriatric care bundles as well as a core data set of prognostic factors to inform patient-centered decision-making. 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 (http://journals.lww.com/ccmjournal). Supported, in part, by institutional sources. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: helene.vallet@aphp.fr Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Surrogate Humane Endpoints in Small Animal Models of Acute Lung Injury: A Modified Delphi Consensus Study of Researchers and Laboratory Animal Veterinarians Objectives: In many jurisdictions, ethical concerns require surrogate humane endpoints to replace death in small animal models of acute lung injury. Heterogenous selection and reporting of surrogate endpoints render interpretation and generalizability of findings between studies difficult. We aimed to establish expert-guided consensus among preclinical scientists and laboratory animal veterinarians on selection and reporting of surrogate endpoints, monitoring of these models, and the use of analgesia. Design: A three-round consensus process, using modified Delphi methodology, with researchers who use small animal models of acute lung injury and laboratory animal veterinarians who provide care for these animals. Statements on the selection and reporting of surrogate endpoints, monitoring, and analgesia were generated through a systematic search of MEDLINE and Embase. Participants were asked to suggest any additional potential statements for evaluation. Setting: A web-based survey of participants representing the two stakeholder groups (researchers, laboratory animal veterinarians). Statements were rated on level of evidence and strength of support by participants. A final face-to-face meeting was then held to discuss results. Subjects: None. Interventions: None. Measurements and Main Results: Forty-two statements were evaluated, and 29 were rated as important, with varying strength of evidence. The majority of evidence was based on rodent models of acute lung injury. Endpoints with strong support and evidence included temperature changes and body weight loss. Behavioral signs and respiratory distress also received support but were associated with lower levels of evidence. Participants strongly agreed that analgesia affects outcomes in these models and that none may be necessary following nonsurgical induction of acute lung injury. Finally, participants strongly supported transparent reporting of surrogate endpoints. A prototype composite score was also developed based on participant feedback. Conclusions: We provide a preliminary framework that researchers and animal welfare committees may adapt for their needs. We have identified knowledge gaps that future research should address. 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 (http://journals.lww.com/ccmjournal). Drs. Fergusson, Stewart, McIntyre, and Lalu contributed to conceptualization. Drs. Fergusson, Stewart, McIntyre, Stacey, and Lalu contributed to methodology. Drs. McGinn, MacNeil, and Lalu contributed to formal analysis. Drs. McGinn, Fergusson, Stewart, MacNeil, and Lalu contributed to investigation. Drs. McGinn and Lalu contributed to data curation. Drs. McGinn, Barron, and Lalu contributed to writing—original draft. Drs. McGinn, MacNeil, and Lalu contributed to visualization. Drs. Fergusson, Stewart, and Lalu contributed to supervision. Drs. McGinn, Barron, MacNeil, and Lalu contributed to project administration. Drs. Fergusson, Stewart, McIntyre, and Lalu contributed to funding acquisition. All coauthors contributed to writing, review, and editing. Supported, in part, by a planning and dissemination grant from the Canadian Institutes for Health Research (no 345325), a New Ideas Grant from the Ontario Institutes for Regenerative Medicine, and a Grant-in-Aid from the Ontario Lung Association (Drs. Stewart, McIntyre, and Lalu). Drs. McGinn, Fergusson, Barron, Liu, and Lalu institutions received funding from Canadian Institutes of Health Research (CIHR). Dr. Kristof received funding from Ottawa Hospital Research Institute (travel costs). Dr. Downey received support for article research from the National Institutes of Health. Dr. Brown received support for article research from CIHR. Dr. dos Santos disclosed that she is funded by CIHR. Dr. Lalu is supported by The Ottawa Hospital Anesthesia Alternate Funds Association and the University of Ottawa Junior Research Chair in Innovative Translational Research. All of work was completed at the Ottawa Hospital Research Institute in Ottawa, ON, Canada. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mlalu@toh.ca or manojlalu@gmail.com Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Effectiveness of Bundle Interventions on ICU Delirium: A Meta-Analysis Objective: To evaluate the impact of bundle interventions on ICU delirium prevalence, duration, and other patients' adverse outcomes. Data Sources: The Cochrane Library, PubMed, CINAHL, EMBASE, PsychINFO, and MEDLINE from January 2000 to July 2020. The protocol of the study was registered in International prospective register of systematic reviews (CRD42020163147). Study Selection: Randomized clinical trials or cohort studies that examined the following outcomes were included in the current study: ICU delirium prevalence and duration, proportion of patient-days with coma, ventilator-free days, mechanical ventilation days, ICU or hospital length of stay, and ICU or inhospital or 28-day mortality. Data Extraction: Using a standardized data-collection form, two authors screened the studies and extracted the data independently, and assessed the studies' quality using the Modified Jadad Score Scale for randomized clinical trials and the Newcastle-Ottawa Scale for cohort studies. Data Synthesis: Eleven studies with a total of 26,384 adult participants were included in the meta-analysis. Five studies (three randomized clinical trials and two cohort studies) involving 18,638 patients demonstrated that ICU delirium prevalence was not reduced (risk ratio = 0.92; 95% CI, 0.68–1.24). Meta-analysis showed that the use of bundle interventions was not associated with shortening the duration of ICU delirium (mean difference = –1.42 d; 95% CI, –3.06 to 0.22; two randomized clinical trials and one cohort study), increasing ventilator-free days (mean difference = 1.56 d; 95% CI, –1.56 to 4.68; three randomized clinical trials), decreasing mechanical ventilation days (mean difference = –0.83 d; 95% CI, –1.80 to 0.14; four randomized clinical trials and two cohort studies), ICU length of stay (mean difference = –1.08 d; 95% CI, –2.16 to 0.00; seven randomized clinical trials and two cohort studies), and inhospital mortality (risk ratio = 0.86; 95% CI, 0.70–1.06; five randomized clinical trials and four cohort studies). However, bundle interventions are effective in reducing the proportion of patient-days experiencing coma (risk ratio = 0.47; 95% CI, 0.39–0.57; two cohort studies), hospital length of stay (mean difference = –1.47 d; 95% CI, –2.80 to –0.15; four randomized clinical trials and one cohort study), and 28-day mortality by 18% (risk ratio = 0.82; 95% CI, 0.69–0.99; three randomized clinical trials). Conclusions: This meta-analysis fails to support that bundle interventions are effective in reducing ICU delirium prevalence and duration, but supports that bundle interventions are effective in reducing the proportion of patient-days with coma, hospital length of stay, and 28-day mortality. Larger randomized clinical trials are needed to evaluate the impact of bundle interventions on ICU delirium and other clinical outcomes. 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 (http://journals.lww.com/ccmjournal). The funding source had no role in the study design, data collection, data analysis, data explanation, or article writing. Dr. Wu is receiving a grant (#71661167008) from "the National Natural Science Foundation of China." The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: helenywu@vip.163.com 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. Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Inspiratory Muscle Training With an Electronic Resistive Loading Device Improves Prolonged Weaning Outcomes in a Randomized Controlled Trial Objectives: To test if the use of an inspiratory muscle training program with an electronic resistive loading device is associated with benefits as to muscle strength, weaning, and survival in the ICU. Design: Prospective randomized controlled trial. Settings: Study conducted at the ICU of a Navy's hospital, Rio de Janeiro, Brazil, from January 2016 to September 2018. Patients: Tracheostomized patients (18–86 yr) on prolonged weaning. Interventions: Participants were assigned to inspiratory muscle training (intervention group) or a traditional T-piece protocol (control group). In the inspiratory muscle training group, participants underwent training with an electronic inspiratory training device (POWERbreathe K-5; Technologies Ltd, Birmingham, United Kingdom). MEASUREMENTS AND MAIN RESULTS: Changes in respiratory muscle strength and rates of ICU survival and weaning success were compared between groups. Forty-eight participants in the inspiratory muscle training group and 53 ones in the control group were included in the final analysis. The inspiratory muscle training was associated with a substantially higher gain on muscle strength as assessed by the maximal inspiratory pressure (70.5 [51.0–82.5] vs –48.0 cm H2O [36.0–72.0 cm H2O]; p = 0.003) and the timed inspiratory effort index (1.56 [1.25–2.08] vs 0.99 cm H2O/s [0.65–1.71 cm H2O/s]; p = 0.001). Outcomes at the 60th day of ICU were significantly better in the intervention group regarding both survival (71.1% vs 48.9%; p = 0.030) and weaning success (74.8% vs 44.5%; p = 0.001). Conclusions: The use of an inspiratory muscle training program with an electronic resistive loading device was associated with substantial muscle strength gain and positive impacts in two very relevant clinical outcomes: the rates of ICU survival and successful weaning. This work was performed at Hospital Naval Marcilio Dias, Rio de Janiero, Brazil (Brazil's Navy). This study was approved by the local Research Ethics Committee and was registered in a publicly accessible clinical trial database (ClinicalTrials.gov ID: NCT02932189). Approved by the institution's ethics committee under the number 45060215.3.0000.0065. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. All authors contributed substantially to the study design, data analysis and interpretation, and the writing of the article. All authors read and approved the final article. 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 (http://journals.lww.com/ccmjournal). Dr. de Souza disclosed that this study was partially supported by Universidade Estácio de Sá by a research productivity program and disclosed off-label product use of the digital vacuometer MVD 300 (Globalmed, Porto Alegre, Brazil) and the device POWERbreathe K-5 and the software (BreatheLink; Power Breathe International, Warwickshire, United Kingdom). Dr. Alvim disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: brunoguimaraespneumo@yahoo.com.br Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Timing, Outcome, and Risk Factors of Intracranial Hemorrhage in Acute Respiratory Distress Syndrome Patients During Venovenous Extracorporeal Membrane Oxygenation Objectives: Intracranial hemorrhage is a serious complication in patients receiving venovenous extracorporeal membrane oxygenation during treatment of the acute respiratory distress syndrome. We analyzed timing, outcome, and risk factors of intracranial hemorrhage in patients on venovenous extracorporeal membrane oxygenation. Design: Retrospective cohort study. Setting: Single acute respiratory distress syndrome referral center. Patients: Patients receiving venovenous extracorporeal membrane oxygenation were identified from a cohort of 1,044 patients with acute respiratory distress syndrome. Patients developing an intracranial hemorrhage during venovenous extracorporeal membrane oxygenation therapy were compared with patients without evidence for intracranial hemorrhage. The primary objective was to assess the association of intracranial hemorrhage with 60-day mortality. Further objectives included the identification of risk factors for intracranial hemorrhage and the evaluation of clinical cutoff values. Interventions: None. Measurements and Main Results: Among 444 patients treated with venovenous extracorporeal membrane oxygenation, 49 patients (11.0% [95% CI, 8.3–14.4%]) developed an intracranial hemorrhage. The median time to intracranial hemorrhage occurrence was 4 days (95% CI, 2–7 d). Patients who developed an intracranial hemorrhage had a higher 60-day mortality compared with patients without intracranial hemorrhage (69.4% [54.4–81.3%] vs 44.6% [39.6–49.6%]; odds ratio 3.05 [95% CI, 1.54–6.32%]; p = 0.001). A low platelet count, a high positive end expiratory pressure, and a major initial decrease of PaCO2 were identified as independent risk factors for the occurrence of intracranial hemorrhage. A platelet count greater than 100/nL and a positive end expiratory pressure less than or equal to 14 cm H2O during the first 7 days of venovenous extracorporeal membrane oxygenation therapy as well as a decrease of PaCO2 less than 24 mm Hg during venovenous extracorporeal membrane oxygenation initiation were identified as clinical cutoff values to prevent intracranial hemorrhage (sensitivity 91% [95% CI, 82–99%], 94% [85–99%], and 67% [48–81%], respectively). Conclusions: Intracranial hemorrhage occurs early during venovenous extracorporeal membrane oxygenation and is a determinant for 60-day mortality. Appropriate adjustment of identified modifiable risk factors might lower the prevalence of intracranial hemorrhage during venovenous extracorporeal membrane oxygenation therapy. The study was approved by the Medical Ethics Committee of Charité-Universitätsmedizin Berlin (No. EA1/007/19). Data are available from the corresponding author. Drs. Graw and Menk are co-senior authors. Dr. Menk contributed to conception and design and study supervision. Drs. Hunsicker, Beck, Graw, and Menk contributed to acquisition of data. Drs. Hunsicker, Beck, Weber-Carstens, Graw, and Menk contributed to interpretation of data. Drs. Hunsicker, Krannich, and Menk contributed to statistical analysis. Drs. Hunsicker, Graw, and Menk contributed to drafting of the article. All authors contributed to critical revision of the article for important intellectual content. Drs. Hunsicker, Weber-Carstens, Spies, Graw, and Menk contributed to final revision of article. 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 (http://journals.lww.com/ccmjournal). Supported, in part, by institutional sources only. Dr. Graw received funding from CSL Behring, and he is a participant in the BIH-Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Mario Menk, MD, PhD, Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: mario.menk@charite.de Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Procalcitonin Is Useful for Antibiotic Deescalation in Sepsis No abstract available

Determining Thresholds for Three Indices of Autoregulation to Identify the Lower Limit of Autoregulation During Cardiac Surgery Objectives: Monitoring cerebral autoregulation may help identify the lower limit of autoregulation in individual patients. Mean arterial blood pressure below lower limit of autoregulation appears to be a risk factor for postoperative acute kidney injury. Cerebral autoregulation can be monitored in real time using correlation approaches. However, the precise thresholds for different cerebral autoregulation indexes that identify the lower limit of autoregulation are unknown. We identified thresholds for intact autoregulation in patients during cardiopulmonary bypass surgery and examined the relevance of these thresholds to postoperative acute kidney injury. Design: A single-center retrospective analysis. Setting: Tertiary academic medical center. Patients: Data from 59 patients was used to determine precise cerebral autoregulation thresholds for identification of the lower limit of autoregulation. These thresholds were validated in a larger cohort of 226 patients. Methods and Main Results: Invasive mean arterial blood pressure, cerebral blood flow velocities, regional cortical oxygen saturation, and total hemoglobin were recorded simultaneously. Three cerebral autoregulation indices were calculated, including mean flow index, cerebral oximetry index, and hemoglobin volume index. Cerebral autoregulation curves for the three indices were plotted, and thresholds for each index were used to generate threshold- and index-specific lower limit of autoregulations. A reference lower limit of autoregulation could be identified in 59 patients by plotting cerebral blood flow velocity against mean arterial blood pressure to generate gold-standard Lassen curves. The lower limit of autoregulations defined at each threshold were compared with the gold-standard lower limit of autoregulation determined from Lassen curves. The results identified the following thresholds: mean flow index (0.45), cerebral oximetry index (0.35), and hemoglobin volume index (0.3). We then calculated the product of magnitude and duration of mean arterial blood pressure less than lower limit of autoregulation in a larger cohort of 226 patients. When using the lower limit of autoregulations identified by the optimal thresholds above, mean arterial blood pressure less than lower limit of autoregulation was greater in patients with acute kidney injury than in those without acute kidney injury. Conclusions: This study identified thresholds of intact and impaired cerebral autoregulation for three indices and showed that mean arterial blood pressure below lower limit of autoregulation is a risk factor for acute kidney injury after cardiac surgery. 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 (http://journals.lww.com/ccmjournal). Supported, in part, by the National Institutes of Health (NIH) K76 AG057020 (to Dr. Brown) and by NIH R01 NS107417 and the American Heart Association Transformational Project Award (cofunded by the Lawrence J. and Florence A. DeGeorge Charitable Trust) (to Dr. Lee). Drs. Lee, Hogue, and Brown received support for article research from the National Institutes of Health (NIH). Dr. Lee has received support from and been a paid consultant for Medtronic, and she received research support from Edwards Life Sciences. Dr. Lee's arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Some methods used to measure and monitor autoregulation as described in this article were patented by The Johns Hopkins University, listing Dr. Brady as a coinventor. These patents are exclusively licensed to Medtronic. Dr. Brown reported receiving grants from the NIH during the conduct of the study, and consulting for and participating in a data share with Medtronic. Dr. Brady is listed as inventor on patents awarded and assigned to the Johns Hopkins University. These patents are related to the monitoring technology described in this article and are exclusively licensed to Medtronic, and Dr. Brady received a portion of the licensing fee. Dr. Venkataraman received funding from Vixiar Medical (consulting) and from universities for speaker honorariums, and she was supported by the National Science Foundation CAREER award 1845430. Dr. Hogue reported receiving grants and personal fees for being a consultant and providing lectures for Medtronic/Covidien, being a consultant to Merck, and receiving grants from the NIH outside of the submitted work, and he disclosed off-label product use of autoregulation monitoring is investigational. Drs. Czosnyka and Smielewski received funding from licensing ICM+ through Cambridge Enterprise Ltd, United Kingdom. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: liuxiuyun1@gmail.com Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Stability of Do-Not-Resuscitate Orders in Hospitalized Adults: A Population-Based Cohort Study Objectives: Prior work has shown substantial between-hospital variation in do-not-resuscitate orders, but stability of do-not-resuscitate preferences between hospitalizations and the institutional influence on do-not-resuscitate reversals are unclear. We determined the extent of do-not-resuscitate reversals between hospitalizations and the association of the readmission hospital with do-not-resuscitate reversal. Design: Retrospective cohort study. Setting: California Patient Discharge Database, 2016–2018. Patients: Nonsurgical patients admitted to an acute care hospital with an early do-not-resuscitate order (within 24 hr of admission). Interventions: None. Measurements and Main Results: We identified nonsurgical adult patients who survived an initial hospitalization with an early-do-not-resuscitate order and were readmitted within 30 days. The primary outcome was the association of do-not-resuscitate reversal with readmission to the same or different hospital from the initial hospital. Secondary outcomes included association of readmission to a low versus high do-not-resuscitate-rate hospital with do-not-resuscitate reversal. Among 49,336 patients readmitted within 30 days following a first do-not-resuscitate hospitalization, 22,251 (45.1%) experienced do-not-resuscitate reversal upon readmission. Patients readmitted to a different hospital versus the same hospital were at higher risk of do-not-resuscitate reversal (59.5% vs 38.5%; p < 0.001; adjusted odds ratio = 2.4; 95% CI, 2.3–2.5). Patients readmitted to low versus high do-not-resuscitate-rate hospitals were more likely to have do-not-resuscitate reversals (do-not-resuscitate-rate quartile 1 77.0% vs quartile 4 27.2%; p < 0.001; adjusted odds ratio = 11.9; 95% CI, 10.7–13.2). When readmitted to a different versus the same hospital, patients with do-not-resuscitate reversal had higher rates of mechanical ventilation (adjusted odds ratio = 1.9; 95% CI, 1.6–2.1) and hospital death (adjusted odds ratio = 1.2; 95% CI, 1.1–1.3). Conclusions: Do-not-resuscitate reversals at the time of readmission are more common than previously reported. Although changes in patient preferences may partially explain between-hospital differences, we observed a strong hospital effect contributing to high do-not-resuscitate-reversal rates with significant implications for patient outcomes and resource. Drs. Mehta, Walkey, and Douglas conceived the study. Dr. Mehta was responsible for data collection. Drs. Mehta, Walkey, Curran-Everett, and Douglas were responsible for data analysis and interpretation. Drs. Mehta drafted the article. All the authors were responsible for critical revisions of article and provided final approval for the manuscript. Dr. Mehta had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Mehta conducted all aspects of data analysis. 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 (http://journals.lww.com/ccmjournal). Supported, in part, by the National Institutes of Health (NIH) K23HL141704 (to Dr. Mehta; primary funding source), NIH R01HL136660 and R01HL139751 (to Dr. Walkey), NIH R01HL136403 (to Dr. Matlock), and NIH R01NR016459 (to Dr. Douglas). Drs. Mehta and Walkey's institutions received funding from the National Institutes of Health (NIH). Drs. Mehta and Matlock received support for article research from the NIH. Dr. Walkey received funding from UptoDate. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Anuj B. Mehta, MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, 1400 Jackson Street J209, Denver, CO. E-mail: mehtaa@njhealth.org Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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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,

Public Health Dentistry

President's Message K Pushpanjali Journal of Indian Association of Public Health Dentistry 2020 18(4):273-274

Honorary Secretary's Message Vamsi Krishna Reddy Journal of Indian Association of Public Health Dentistry 2020 18(4):275-275

From the Editor's Desk KR Sowmya Journal of Indian Association of Public Health Dentistry 2020 18(4):276-276

Dental public health: Fallout of the COVID-19 pandemic Venkitachalam Ramanarayanan, Vineetha Karuveettil, Chandrashekar Janakiram Journal of Indian Association of Public Health Dentistry 2020 18(4):277-278

Herbal irrigants in primary teeth: A step toward green dentistry based on the wisdom of past Archna Agnihotri, Rosy Arora, Urvashi Sharma, Poonam Sood Journal of Indian Association of Public Health Dentistry 2020 18(4):279-284 A wide plethora of chemical endodontic irrigants are used to achieve the desired results in terms of disinfection and removal of debris besides mechanical means. However, their detrimental properties such as allergic potential, cytotoxicity, antimicrobial resistance, and safety concerns have intrigued researchers over the years to look for safer options. During the past decade, the number of studies has increased utilizing herbs as irrigating solutions. This literature review was conducted to summarize the existing knowledge and provide a comprehensive review of clinical trials on herbal irrigating solutions in pediatric dental patients. An exhaustive literature search was performed in the indexed databases electronically for publications in peer reviewed scientific journals to find the relevant clinical studies evaluating efficacy of herbal root canal irrigants employed in primary teeth.

Awareness of night brushing and its importance in oral health in parents and among their children P Akhil, Jyothsna V Setty, Ila Srinivasan, Clarissa Suting, Swathi Kakathkar, KM Nayana Journal of Indian Association of Public Health Dentistry 2020 18(4):285-289 Background: One of the goals of a pediatric dentist is providing awareness among children and their parents about oral hygiene and health. Night brushing is an important step in the prevention of plaque accumulation and caries and is inevitable in maintaining good oral health. Aim: The aim of the study was to assess the awareness of importance of night brushing and its significance on oral health among parents and their children aged 3–13 years in East Bangalore, Karnataka. Materials and Methods: Sample of 300 children was divided into three age range groups, and each group was subdivided into five socioeconomic strata (SES). Separate questionnaires, which were validated by pediatric dentists, were used to record data from the child and the parent. Descriptive analysis of all the explanatory and outcome parameters was done using mean and standard deviation for quantitative variables, frequency, and proportions for categorical variables. SPSS for Windows version 22.0 was used to perform statistical analyses, and the value of P < 0.05 was considered statistically significant. Results: There is an increase in awareness about night brushing in all SES due to increased educational standards and influences of social media and advertisements, but the frequency of practicing the same is questionable. The total child awareness scores in Class I SES demonstrated that 3–6-year age group showed a significant difference as compared with 7–10-year age group (P < 0.001) and 11–13-year age group (P = 0.003). In Class II, 3–6-year age group showed a greater awareness as compared to 7–10-year age group (P = 0.02) and total parent awareness scores in Class III and Class V demonstrated that 3–6-year age group showed significant differences with 7–10-year age group and 11–13-year age group. Conclusion: The awareness of the importance of night brushing is an essential factor affecting oral health. The extent of awareness varies in different SES among the various age groups of children and their parents.

Association of oral health status and oral health-related quality of life among adult patients with type 2 diabetes mellitus: A cross-sectional study Nagashree Savanur Ravindranath, Rekha Raju Journal of Indian Association of Public Health Dentistry 2020 18(4):290-295 Background: The growing burden of noncommunicable diseases like type II diabetes mellitus is a challenge worldwide. Type II diabetes mellitus has a number complications which includes oral conditions like periodontitis, tooth loss, dry mouth, and taste alterations. However, it is unclear if these oral conditions affect the oral health-related quality of life (OHRQoL) in diabetic patients. Aim: The aim of this study was to explore the association between oral health status and OHRQoL in adult type II diabetes patients. Materials and Methods: A cross-sectional study was done in a teaching dental hospital setting on a convenient sample of 350 participants. The WHO Oral Health Survey Proforma 2013 was used to assess oral health status, and Oral Health Impact Profile-20 (OHIP-20) questionnaire was used to collect information on OHRQoL. The mean OHIP score of the participants was compared between the different categories of the oral health status variables using independent t-test and Chi-square test. P < 0.05 was considered statistically significant. The Statistical Package for the Social Sciences version 19 was used for analysis. Results: Decayed, Missing, and Filled Teeth score, bleeding on probing, loss of attachment, and presence of denture were significantly associated with high OHIP scores as compared to the absence of these conditions (P < 0.001). The presence of oral mucosal lesions was not associated with OHIP scores (P = 0.099). Conclusion: The present study found an association between oral health status and OHRQoL in type II diabetes mellitus patients.

Knowledge, perceptions and practices about tooth brush sterilization among dental students and faculty in Andhra pradesh, South India – A Cross sectional study Kuna Vandana, S Harikrishnam Raju, D Rajesh Kumar, J Narendra Babu Journal of Indian Association of Public Health Dentistry 2020 18(4):296-301 Background: Toothbrush is habitually used as an oral hygiene aid to maintain good oral health. The contamination of toothbrushes leads to oral and systemic diseases. Awareness on toothbrush disinfection is essential for oral health-care professionals in order to educate people. Aim: The aim was to assess the knowledge, perceptions, and practices about toothbrush storage, contamination, and disinfection among dental professionals in Andhra Pradesh, South India. Materials and Methods: A cross-sectional study was conducted using a self-administered questionnaire among 450 oral health professionals categorized into three groups (faculty, postgraduates, and interns) in Andhra Pradesh. The statistics were computed with the Statistical Package of Social Sciences version 22. Chi-square test and analysis of variance were used for statistical analyses. P < 0.05 is considered statistically significant. Results: There was a statistically significant difference between the three groups regarding the P value denoted by (*) is considered as statistically significant, frequency of brushing, change of toothbrush, storage of toothbrush and knowledge on toothbrush disinfection (P value is 0.01), whereas knowledge on toothbrush contamination (P value is 0.04). P value denoted by (**) is considered as statistically highly significant. A highly statistical significance was noticed pertaining to the factors on type of toothpaste,reason behind change of toothbrush,contact between toothbrushes during storage and sharing of toothpaste with family members ( P value is <0.001). Conclusion: The study conclude that there were varied opinions regarding the toothbrush contamination and disinfection among faculty, postgraduates, and interns which might be attributed to the difference in academic knowledge, exposure to a wide range of information, and clinical experience over the years between the groups.

Access and dental health service utilization by children of government schools in Bangalore, India: A parent perspective Vinod Kumar A, Romshi Raina, Ranjini Narayanaswamy, Varsha K Pavithran Journal of Indian Association of Public Health Dentistry 2020 18(4):302-307 Background: Access to oral health care refers to patient's ability to utilize oral health care. The availability of oral health services is very scarce in rural India; therefore, the unmet treatment needs of rural population are very high. Aim: We aimed to determine the dental service utilization and factors affecting the same among the 6–12-year-old government schoolchildren in Bangalore South-1, Karnataka, India. Methodology: In-depth interviews regarding access, utilization of dental services, and factors affecting them were conducted with 1080 parents/guardians of 6–12-year-old government schoolchildren from Bangalore South-1 in this cross-sectional analytical study. Chi-square test and multiple logistic regression analysis were used for data analysis using SPSS version 20.0 (IBM Corp. Ltd.). Statistical significance was set at P < 0.05. Results: The most common ailment reported by parents was gum problem (17.5%). Only 7.80% of the parents visited dental facility in the past 12 months. Majority of the parents (62.1%) had access to private dental health services. The barriers to utilization of dental services majorly included financial constraints (45.19%) and parent's unawareness of the oral health-care facilities nearby (21.84%). Multiple regression analyses showed that the head of the household with middle school education and high school education (odds ratio = 1.55; 1.74) had a higher probability of having visited a dentist in the past 1 year. Conclusion: Dental service utilization rate was very low in the past 12 months. Relief from pain was the sole reason for visiting a dentist. Oral health-promoting programs and provision of government hospitals are required for increased utilization of dental services so as to improve the dental attitude, accessibility, and affordability and overcome the barriers among the parents.

Perception toward low-cost generic medicines and their usage among dental patients visiting community outreach programs in the peripheral areas of Bangalore South: An exploratory cross-sectional survey Nigy Johnson, Y Shweta Somasundara, Padma K Bhat, Santhosh Kumar, M Nayana Journal of Indian Association of Public Health Dentistry 2020 18(4):308-312 Background: The burden and prevalence of oral diseases are higher in developing countries, especially among the poor and disadvantaged populations. These people may suffer from various dental and systemic illnesses. Hence, provision of reducing the out-of-pocket money by purchasing generic drugs might enable better oral and general health-care-seeking behavior. Objectives: The objective was to assess the perception toward low-cost generic medicines available through the Pradhana Manthri Bhartiya Janaushadhi Pariyojana and their usage among dental patients visiting community dental outreach programs conducted in the villages near a tertiary care dental teaching hospital, Bangalore South. Materials and Methods: An exploratory descriptive cross-sectional survey was carried out over a period of 3 months among 200 residents participating in the dental outreach programs in 15 villages of Bangalore South. Data were collected using a prevalidated closed-ended interviewer-administered questionnaire. Results: Most respondents (82.5%) were not aware of Prime Minister Jan Aushadhi Kendra (PMJAK) and only 17.5% knew about the nearest PMJAK. The majority (96.5%) were not aware of the availability of dental-related medicines in PMJAK and (95.5%) preferred to buy Jan Aushadhi drugs over branded medicine if the quality of generic and branded medicine is the same. Most respondents (98%) liked to have more awareness through mass media about PMJAKs/medicines. Conclusion: The results indicate that more awareness must be created, and strict laws implemented about the Jan Aushadhi scheme to save health cost expenditure; if the quality of generic and branded medicine is the same, most people are willing to use the medicines sold at PMJA Kendras.

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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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Cardiovascular Pharmacology

Arrhythmia mechanisms in human induced pluripotent stem cell-derived cardiomyocytes Despite major efforts by clinicians and researchers, cardiac arrhythmia remains a leading cause of morbidity and mortality in the world. Experimental work has relied on combining high-throughput strategies with standard molecular and electrophysiological studies, which are, to a great extent, based on the use of animal models. As this poses major challenges for translation, the progress in the development of novel antiarrhythmic agents and clinical care has been mostly disappointing. Recently, the advent of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has opened new avenues for both basic cardiac research and drug discovery: now there is an unlimited source of CMs of human origin, both from healthy individuals and patients with cardiac diseases. Understanding arrhythmic mechanisms is one the main use-cases of hiPSC-CMs, in addition to pharmacological cardiotoxicity and efficacy testing, in vitro disease modeling, developing patient-specific models and personalized drugs, and regenerative medicine. Here, we review the advances that the hiPSC-based modeling systems have brought so far regarding the understanding of both arrhythmogenic triggers and substrates, while also briefly speculating about the possibilities in the future. Corresponding author: Jussi T. Koivumäki, Arvo Ylpön katu 34, FI-33520 Tampere, Finland, +358 40 5813 290, jussi.koivumaki@iki.fi This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

A Perspective on Personalized Therapies in Hypertrophic Cardiomyopathy A dominant mechanism of sudden cardiac death in the young is the progression of maladaptive responses to genes encoding proteins linked to hypertrophic cardiomyopathy (HCM). Most are mutant sarcomere proteins that trigger the progression by imposing a biophysical defect on the dynamics and levels of myofilament tension generation. We discuss approaches for personalized treatments that are indicated by recent advanced understanding of the progression Corresponding Author: R. John Solaro, PhD, Department of Physiology and Biophysics (M/C 901), University of Illinois at Chicago, College of Medicine, 835 South Wolcott Avenue, Chicago, IL 60612, eMail: solarorj@uic.edu Online date: 00 00, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Heat shock protein 70 is associated with cardioversion outcome and recurrence of symptomatic recent onset atrial fibrillation in hypertensive patients Accumulating evidence indicates that heat shock proteins (HSPs) may represent a suitable biomarker to predict atrial fibrillation (AF). We investigated the relation of circulating heat shock protein 70 (sHSP70) with inflammatory cytokines and recurrence of symptomatic recent onset AF (ROAF). We enrolled 90 patients with ROAF (duration from onset of symptoms ≤24 hours) and 30 controls. Patients received amiodarone for cardioversion and rhythm control. The association of serum HSP70, interleukin-2 (sIL-2) and interleukin-4 (sIL-4) with the presence, cardioversion and AF recurrence within a year was investigated. TLR4 signaling dependence for IL-2 and IL-4 induction in response to stimulation with HSP70 was tested in rat aortic vascular smooth muscle cell (SMC) cultures. Patients had higher sHSP70 and sIL-2 and lower sIL-4 compared to controls. sHSP70 was independently associated with ROAF (P=0.005) and correlated with sIL-2 (r =0.494, P<0.001) and sIL-4 (r=-0.550, P<0.001). By 48 hours 71/90 patients were cardioverted, with non-cardioverted patients having higher sHSP70 and sIL-2 and lower sIL-4, which were the only independent factors associated with cardioversion. AF recurred in 38/71 cardioverted patients in one year. A cut-off value of sHSP70 ≥0.65 ng/ml and sIL-2 ≥0.21 pg/ml were the only independent factors associated with AF recurrence (HR: 3.311, 95% CI: 1.503-7.293, P=0.003 and HR: 3.144, 95% CI: 1.341-7.374, P=0.008, respectively). Exposure of SMC to HSP70 in vitro increased the expression of IL-2 (5x) and IL-4 (1.5x) through TLR4-dependent and receptor-independent mechanisms. In conclusion, sHSP70 and sIL-2 might constitute a prognostic tool for determining the cardioversion and recurrence likelihood in ROAF. Corresponding author: Dr. Angelos G. Rigopoulos, MD, FESC, Mid-German Heart Center, Department of Internal Medicine III, Division of Cardiology, Angiology and Intensive Medical Care, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, D-06120 Halle (Saale), Germany, Tel.: +49 176 79844001, Fax: +49 345 5572072 E-Mail: angelos.rigopoulos@gmail.com Online date: 00 00, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Circular RNA circ-BANP regulates ox-LDL-induced endothelial cell injury through targeting the miR-370/TXNIP axis Dysfunction of endothelial cells is now recognized as an important contributor to the pathogenesis of atherosclerosis (AS). Circular RNAs (circRNAs) have been demonstrated to be involved in AS pathogenesis. The purpose of this study was to explore the biological action of circRNA BTG3 associated nuclear protein (circ-BANP, hsa_circ_0040824) on the dysfunction of human umbilical vein endothelial cells (HUVECs) induced by oxidized low-density lipoprotein (ox-LDL). The levels of circ-BANP, miR-370 and thioredoxin-interacting protein (TXNIP) were gauged by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Subcellular fractionation assay was used to determine the localization of circ-BANP, and ribonuclease R (RNase R) assay was performed to evaluate the stability of circ-BANP. Cell viability, apoptosis, migration, invasion and tube formation abilities were assessed by the Cell Counting Kit-8 (CCK-8), flow cytometry, transwell, and tube formation assays. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and IL-1β were detected by enzyme-linked immunosorbent assay (ELISA). Targeted relationships among circ-BANP, miR-370 and TXNIP were confirmed by a dual-luciferase reporter assay. Our data showed that circ-BANP expression was up-regulated in AS blood and ox-LDL-induced HUVECs. The inhibition of circ-BANP promoted cell viability, migration, invasion, tube formation, and repressed cell inflammation and apoptosis in ox-LDL-induced HUVECs, demonstrating that circ-BANP silencing alleviated ox-LDL-induced HUVEC injury. Mechanistically, circ-BANP directly targeted miR-370. Moreover, miR-370 mediated the regulation of circ-BANP in ox-LDL-induced cell injury in HUVECs. TXNIP was a target of miR-370, and miR-370 overexpression relieved ox-LDL-induced HUVEC injury by down-regulating TXNIP. Furthermore, circ-BANP modulated TXNIP expression by targeting miR-370. Our findings demonstrated that circ-BANP regulated ox-LDL-induced cell injury in HUVECs at least in part through targeting the miR-370/TXNIP axis, illuminating circ-BANP as a potential target for AS detection and treatment. Corresponding author: Lijun Gao, Department of General Internal Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Zhongjing Building, No. 16369, Jingshi Road, Lixia District, Jinan, Shandong, 250014, China, Tel: +86-0531-68617110; E-mail: gljsdzhyy0812@163.com Online date: 00 00, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Evaluation of sacubitril/valsartan initiation in outpatient heart failure patients Despite sacubitril/valsartan being on the market since 2015, clinicians are still determining the best way to initiate therapy in order to optimize outcomes and minimize potential for side effects. The purpose of this study is to investigate real-world outpatient experience of prescribing sacubitril/valsartan therapy based on appropriate patient selection, dosing conversion, and tolerability. This retrospective cohort study evaluated patients prescribed sacubitril/valsartan therapy in cardiology clinics associated with an academic institution between February 1, 2016 and August 30, 2018. Patients were excluded if they were less than 18 years of age, enrolled in a clinical trial involving sacubitril/valsartan, or had insufficient data. The primary outcome was to determine how many heart failure patients initiated on sacubitril/valsartan were done so appropriately based on guideline and package insert recommendations. Select secondary outcomes included rates of adverse events and need for adjustment of concomitant heart failure medications. A total of 250 patients were included in this study. For the primary outcome, 125 patients (50%) were appropriately initiated on sacubitril/valsartan. Those who were inappropriately initiated on the medication experienced more symptoms of hypotension (16% in appropriate start group vs. 28% in inappropriate start group; p=0.022) and required more dose decreases of sacubitril/valsartan (6% in appropriate start group vs. 13% in inappropriate start group; p=0.049). In outpatient clinical practice, almost half of patients initiated on sacubitril/valsartan were done so outside of guideline recommendations, which was associated with an increased risk of hypotension and dose reductions. Corresponding Author: Lindsey Rerick, PharmD, Allegheny Health Network, West Mifflin, PA UNITED STATES Online date: 00 00, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Lipoprotein(a) reduction with proprotein convertase subtilisin/kexin type 9 inhibitors: a systematic review and meta-analysis. Lipoprotein(a) (Lp(a)) is a cardiovascular factor, for which there is no approved specific lowering treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to have lowering effects on Lp(a). Aim of this systematic review is to synthesize the current literature and quantify the effects of PCSK9 inhibitors on the serum Lp(a) levels in human subjects. Double-blind, phase 2 or 3, randomized controlled trials comparing PCSK9 inhibitors (alirocumab or evolocumab) to placebo and/or ezetimibe and/or other lipid lowering therapy were deemed eligible for inclusion. We searched MEDLINE (via PubMed), CENTRAL, Scopus and Web of Science as of 17 June 2020. Quality assessment was performed using the Revised Cochrane risk-of-bias tool for randomized trials (RoB2). Forty-three studies were identified (64107 patients randomized) and 41 studies were included in the quantitative analysis. PCSK9 inhibitors reduced Lp(a) levels by -26.7% (95% CI -29.5% to -23.9%) with a significant heterogeneity within studies. There was significant difference in Lp(a) change from baseline according to comparator (placebo: mean -27.9%, 95% CI -31.1% to -24.6% vs. ezetimibe: mean -22.2%, 95% CI -27.2% to -17.2%, p=0.04) and duration of treatment (≤12 weeks: mean -30.9%, 95% CI -34.7% to -27.1% vs. >12 weeks: mean -21.9%, 95% CI -25.2% to -18.6%, p<0.01). Meta-regression analysis showed that only the mean percentage change from baseline LDL-C due to the intervention is significantly associated with the effect size difference (p<0.0001). PCSK9 inhibitors reduced LDL-C by -54% (95% CI -57.6% to -50.6%). There is substantial efficacy of the currently approved PCSK9 inhibitors in the lowering of Lp(a) levels. Dedicated RCTs are needed to establish the benefit of this intervention. Corresponding author: George Giannakoulas, MD, PhD, Associate Professor of Cardiology, Aristotle University of Thessaloniki, AHEPA Hospital, Cardiology Department, Stilp. Kiriakidi 1, 54637, Thessaloniki, Greece, Tel: +302313303589, Email: ggiannakoulas@auth.gr Online date: 00 00, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Is spironolactone the preferred renin-angiotensin-aldosterone inhibitor for protection against COVID-19? The high mortality of specific groups from COVID-19 highlights the importance of host-viral interactions and the potential benefits from enhancing host defenses. SARS-CoV-2 requires angiotensin converting enzyme (ACE)2 as a receptor for cell entry and infection. While both ACE inhibitors and spironolactone can upregulate tissue ACE2, there are important points of discrimination between these approaches. The virus requires proteolytic processing of its spike protein by transmembrane protease receptor serine type 2 (TMPRSS2) to enable binding to cellular ACE2. Since TMPRSS2 contains an androgen promoter, it may be downregulated by the antiandrogenic actions of spironolactone. Furin and plasmin also process the spike protein. They are inhibited by protease nexin 1 or serine E2 (PN1) that is upregulated by angiotensin II but downregulated by aldosterone. Therefore, spironolactone should selectively downregulate furin and plasmin. Furin also promotes pulmonary edema while plasmin promotes hemovascular dysfunction. Thus, a downregulation of furin and plasmin by PN1 could be a further benefit of MRAs beyond their well established organ protection. We review the evidence that spironolactone may be the preferred RASSi to increase PN1 and decrease TMPRSS2, furin and plasmin activities and thereby to reduce viral cell binding, entry, infectivity and bad outcomes. This hypothesis requires direct investigation. Address for correspondence: Christopher Wilcox, MD, PhD, 3800 Reservoir Road, NW, PHC F6003, Washington, DC 20007, Fax: 877-625-1483, Email: wilcoxch@georgetown.edu Sources of Funding: Work in CSW's laboratory is supported by the Smith-Kogod Family Trust, the Gildenhorn-Speisman Family Trust, the Georgetown University Hypertension Research Center and the Walters Family Chair of Cardiovascular Research, all located in Washington DC. Disclosures: CSW, none. BP, none. 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. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Intermittent optogenetic tachypacing of atrial engineered heart tissue induces only limited electrical remodelling Atrial tachypacing is an accepted model for atrial fibrillation (AF) in large animals and in cellular models. Human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CM) provide a novel, human source to model cardiovascular diseases. Here we investigated whether optogenetic tachypacing of atrial-like hiPSC-CMs grown into engineered heart tissue (aEHT) can induce AF-remodeling. After differentiation of atrial-like cardiomyocytes from hiPSCs using retinoic acid, aEHTs were generated from ∼1 million atrial-like hiPSC-CMs per aEHT. AEHTs were transduced with lentivirus expressing channelrhodopsin-2 to enable optogenetic stimulation by blue light pulses. AEHTs underwent optical tachypacing at 5 Hz for 15 s twice a minute over three weeks and compared to transduced spontaneously beating isogenic aEHTs (1.95±0.07 Hz). Force and action potential duration did not differ between spontaneously beating and tachypaced aEHTs. Action potentials in tachypaced aEHTs showed higher upstroke velocity (138±15 V/s vs. 87±11 V/s, n=15-13/3; p=0.018), possibly corresponding to a tendency for more negative diastolic potentials (73.0±1.8 mV vs. 68.0±1.9 mV; p=0.07). Tachypaced aEHTs exhibited a more irregular spontaneous beating pattern (beat-to-beat scatter: 0.07±0.01 vs. 0.03±0.004 s, n=15-13/3; p=0.008). Targeted expression analysis showed higher RNA levels of KCNJ12 (Kir2.2, inward rectifier (IK1); 69±7 vs. 44±4, p=0.014) and NPPB (NT-proBNP; 39690±4834 vs. 23671±3691; p=0.024). Intermittent tachypacing in aEHTs induces some electrical alterations found in AF and induces an arrhythmic spontaneous beating pattern, but does not affect resting force. Further studies using longer, continuous, or more aggressive stimulation might clarify the contribution of different rate patterns on the changes in aEHT mimicking the remodeling process from paroxysmal to persistent atrial fibrillation. Address for Correspondence: PD. Dr. med. Torsten Christ, Institut für Experimentelle Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany, Tel +49 40 7410 52180, Fax+49 40 7410 54876, E-mail address: t.christ@uke.de * These authors contributed equally # Current Address: Nanion Technologies GmbH, Ganghoferstraße 70a, 80339 München, Germany. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC) , where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Knockdown of long non-coding RNA SNHG14 protects H9c2 cells against hypoxia-induced injury by modulating miR-25-3p/KLF4 axis in vitro Cyanotic congenital heart disease (CCHD) is the main cause of death in infants worldwide. Long non-coding RNAs (lncRNAs) have been pointed to exert crucial roles in development of CHD. The current research is designed to illuminate the impact and potential mechanism of lncRNA SNHG14 in CCHD in vitro. The embryonic rat ventricular myocardial cells (H9c2 cells) were exposed to hypoxia to establish the model of CCHD in vitro. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to examine relative expressions of SNHG14, miR-25-3p and KLF4. Cell viability was determined by MTT assay. Lactate dehydrogenase (LDH) was measured by an LDH assay kit. Apoptosis-related proteins (Bax and Bcl-2) and KLF4 were detected by Western Blot. The targets of SNHG14 and miR-25-3p were verified by dual-luciferase reporter (DLR) assay. SNHG14 and KLF4 were up-regulated, while miR-25-3p was down-regulated in hypoxia-induced H9c2 cells and cardiac tissues of patients with CCHD compared with their controls. Knockdown of SNHG14 or overexpression of miR-25-3p facilitated cell viability, while depressing cell apoptosis and release of LDH in hypoxia-induced H9c2 cells. MiR-25-3p was a target of SNHG14 and inversely modulated by SNHG14. MiR-25-3p could directly target KLF4 and negatively regulate expression of KLF4. Repression of miR-25-3p or overexpression of KLF4 reversed the suppression impacts of sh-SNHG14 on cell apoptosis and release of LDH as well as the promotion impact of sh-SNHG14 on cell viability in hypoxia-induced H9c2 cells. Sh-SNHG14 protected H9c2 cells against hypoxia-induced injury by modulating miR-25-3p/KLF4 axis in vitro. Corresponding author: Zhaoyun Cheng, Address: Department of Cardiovascular Surgery, Fuwai Central China Cardiovascular Hospital, Heart Center of Henan Provincial People's Hospital, No.1, Fuwai Road, Zhengdong New District, Zhengzhou City, Henan Province, 451464, China. Phone number: 86-13903712068, Email: chengzhaoyun287@163.com Conflict of Interest: The authors have no conflict of interest to disclose. Received July 20, 2020 Accepted November 05, 2020 Online date: 00 00, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Leonurine Attenuates Myocardial Fibrosis through Upregulation of miR-29a-3p in Mice Post-myocardial Infarction Abstract: Myocardial fibrosis (MF) is a pathological process that accelerates cardiac remodeling in myocardial infarction (MI), and miR-29 has become one of the foci of research into MF. As an alkaloid extracted from Herba leonuri, leonurine (LE) has been found to be an effective natural active ingredient for inhibiting fibrosis in many preclinical experiments. However, whether LE protects against MF after MI through modifying miR-29 remains unclear. The present study aimed to investigate the therapeutic effects of LE on MF, and to elucidate the underlying mechanisms involved. A mouse model of MI was established, followed by administration of LE for 4 weeks. We found that LE effectively improved cardiac function, and attenuated fibrosis and cardiac remodeling in mice post-MI. In vitro, LE simultaneously inhibited proliferation and migration of neonatal mouse cardiac fibroblasts (CFs) exposed to angiotensin II (Ang II), and the activation of collagen synthesis and myofibroblast generation was markedly suppressed by LE. Notably, we found that all mature miR-29 family members were downregulated in the myocardial tissues of mice post-MI, while, LE significantly upregulated miR-29a-3p expression, and such upregulation was also detected in LE-treated CFs under Ang II stimulation. Knockdown of miR-29a-3p by a specific miRNA inhibitor upregulated the protein levels of TGF-β, Collagen III, and Collagen I in CFs, and completely reversed the antifibrotic effects of LE on CFs. Our study suggests that LE exerts cardioprotective effects against MF, possibly through the upregulation of miR-29a-3p. Corresponding author: Dr. Jiadan Yang. Department of Pharmacy, the First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing 400016, P.R. China. E-mail address: yangjiadan11@126.com The authors report no conflicts of interest. † These two authors contributed equally to this work. Online date: 00 00, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

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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,