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,

Medical Sciences

The Journey of MAMCJMS - Looking back with satisfaction! Pawanindra Lal MAMC Journal of Medical Sciences 2020 6(3):149-150

Responding to the COVID-19 Pandemic: the Experience and the Road Ahead for the Largest Medical College in India's Capital City Nandini Sharma MAMC Journal of Medical Sciences 2020 6(3):151-152

COVID 19 Pandemic: Managing One: Preventing Another Mohit D Gupta MAMC Journal of Medical Sciences 2020 6(3):153-155

Response to COVID-19: Best Practices From the Department of Community Medicine of a Medical College in Delhi Nandini Sharma, Bratati Banerjee, Shivani Rao, Amod Laxmikant Borle, Nidhi Bhatnagar, Pragya Sharma, Rajesh Kumar, Mongjam Meghachandra Singh, Panna Lal, Gajendra Singh Meena, Suneela Garg MAMC Journal of Medical Sciences 2020 6(3):156-162 Public health response and measures are vital to contain an infectious disease outbreak/epidemic. The discipline of Community Medicine, which provides comprehensive primary health care to the entire population at all times, plays a crucial role in times of disease outbreak/epidemic also, being equipped with skills in providing managerial, clinical, and community care, through policy making, surveillance activities, preventive strategies, primary care, capacity building, and awareness generation in addition to generation of evidence-based strategies. The Departments of Community Medicine in Medical Colleges can play a crucial role in this direction and should be involved to share the expertise as well as the best practices adopted, which will go a long way in containing an epidemic at the earliest. The Department of Community Medicine of a leading Medical College in Delhi, along with the clinical departments, is playing a stellar role in response to the pandemic of Corona Virus Disease of 2019 (COVID-19). This article highlights the response to the situation, the challenges faced, and the success stories. Activities have been categorized as Fair, Good, and Best. Activities that are routinely performed are taken to be “Fair” and activities that are beyond routine activities have been labelled “Good”. “Best” practices have been identified to be those that involve representation at the national/State/District level, activities for capacity building, contribution toward evidence generation, and work with risk of exposure. The best practices adopted by the Department of Community Medicine of this institution can be collated for future use in teaching hospitals where Community Medicine departments are equipped with manpower skilled to face such a challenge. It will serve as a blueprint for action, if the need be, for handling similar situations in the future.

Surgery in Covid 19 Times: A Comprehensive Review Lovenish Bains, Anurag Mishra, Lalit Gupta, Rajdeep Singh, Pawanindra Lal MAMC Journal of Medical Sciences 2020 6(3):163-175 The problems faced by surgeons are unique during the Covid pandemic. In the absence of concrete information, we have to resort to extreme degrees of precautions during surgery. Precautions have to start from the point patient enters the hospital, to the point he is discharged. Changes in the patient flow and having sanitization protocols can help in this regard. Since the epidemiology of SARS-Cov 2 is still evolving, the consent process has to necessarily include the risks involved. Preoperative testing is not full proof and the increased risk for the COVID positive patient undergoing surgery has to be communicated. The operating room has to be modified with regard to the number of air changes, an aspect which the surgeons were unaware of prior to this pandemic. Changes in the follow-up protocol, such as use of telemedicine, will help minimize patient contact.

Imaging Appearances of Pediatric Hepatic Masses − A Review Shruti Mittal, Sapna Singh, Radhika Batra MAMC Journal of Medical Sciences 2020 6(3):176-185 In the pediatric population, a wide spectrum of focal liver lesions is seen, which can be categorised into congenital, inflammatory or neoplastic origin. Majority of the patients with focal liver masses present with abdominal pain, abdominal distention or palpable abdominal lump. However, some lesions can be detected incidentally. After physical examination and clinical history, imaging plays a vital role in evaluating pediatric patients with suspected focal liver lesions. Abdominal radiography may provide some imaging findings suggesting the presence of focal hepatic mass such as hepatomegaly, presence of calcification and displacement of bowel loops. Ultrasound is the first line imaging modality as it does not involve ionising radiation. It can detect, characterise and provide the extent of lesion. However, computerised tomography and magnetic resonance imaging are performed subsequently for further characterisation of liver lesions on the basis of morphology, vascularity, enhancement pattern and for detection of associated metastases in malignant neoplasms. In this review article, we aim to describe the imaging appearances of various benign and malignant hepatic mass lesions in the paediatric age group and to provide differential diagnosis for liver lesions in a child on the basis of available imaging and clinical data. Imaging is therefore essential for making prompt and accurate diagnosis which further helps in appropriate treatment and optimal patient management.

Acute Hepatitis B or Chronic Hepatitis B with Acute Exacerbation: Differentiating Clinical, Biochemical, Immunonological, and Virological Parameters Ravi Kant Thakur, Sunit Kumar Shukla, Vinod Kumar Dixit, Dawesh Yadav, Piyush Thakur, Tuhin Mitra MAMC Journal of Medical Sciences 2020 6(3):186-193 Background and Aims: Acute hepatitis B virus (HBV) infection and chronic HBV infection presenting as acute illness have differing prognosis. Differentiation between acute viral hepatitis B (AVH-B) and chronic hepatitis B with an acute exacerbation (CHB-AE) is difficult if prior hepatitis B surface antigen (HBsAg) status is unknown. This prospective study was undertaken to screen various factors that could help with this differentiation. Methods: All consecutive patients presenting with AVH-B like illness were enrolled in this study and were evaluated as per predefined study protocol. Patients were divided into AVH-B and CHB-AE groups based on HBsAg status at the end of 6 months. Results: Significant differences in clinical and laboratory parameters were found between AVH-B and CHB-AE. No statistically significant difference in prodromal symptoms and jaundice was seen. Ascites (40%) and hepatic encephalopathy (10%) were seen only in patients with CHB-AE (P = 0.002 and 0.244, respectively). Anti-hepatitis B virus core antigen immunoglobulin M (IgM anti-HBc) levels ≥10.15 signal-cutoff-ratio (S/CO) had positive predictive value (PPV) and negative predictive value (NPV) of 90% for diagnosis of AVH-B. Hepatitis B virus deoxyriboNucleic acid (HBV DNA) levels ≥25032 IU/mLhas 62.5% PPV and 69% NPV for diagnosis of CHB-AE. Alpha-feto protein (AFP) at >22.5 ng/mLmL for diagnosing CHB-AE has PPV and NPV of 83% and 62%, respectively. All six mortalities were seen in CHB-AE group with median survival of 2 months. Conclusions: Differentiation of AVH-B and CHB-AE is important as management and prognosis differ. Low IgM anti-HBc levels (<10.15 S/CO), high HBV DNA levels (≥25032 IU/mLmL), and high AFP (>22.5 ng/mL) favor CHB-AE over AVH-B.

Methods to Handle Incomplete Data Vinny Johny, Mariamma Philip, Swathi Augustine MAMC Journal of Medical Sciences 2020 6(3):194-198 Context: The major question for data analysis is determining the appropriate analytic approach in the presence of incomplete observations. The most common solution to handle missing data in a data set is imputation, where missing values are estimated and filled in. An important problem of imputation is to maintain the statistical significance of the data set. Aim: To compare different imputation techniques − complete case analysis, last observation carried forward (LOCF), mean imputation, hot deck Imputation, regression imputation, and multiple imputation (MI). Settings and Design: The data for the study were collected from a prospective study to find out the predictors of early response to treatment in drug naïve schizophrenia patients from a tertiary care centre, India. Methods and Material: The present study tries to compare four imputation methods: complete case analysis, LOCF, mean imputation, hot deck Imputation, regression imputation and MI, in filling up the missing values of the outcome variable. Statistical analysis used: Paired t test was used to compare the imputation methods. Results: At the fourth week, the positive and negative syndrome scale scores were missing for about a minority of the subjects (41%). Mean imputation differed significantly from LOCF (P = 0.001), regression imputation (P = 0.010) and MI (P = 0.002). LOCF differed significantly from all these methods − regression imputation (P = 0.001), hot deck imputation (P = 0.011) and MI (P = 0.001). Conclusions: LOCF and mean imputation methods are different from other imputation methods, and there is no difference between hot deck imputation, MI, and regression imputation.

Evaluation of Safety and Efficacy of Postpartum Intrauterine Contraceptive Devices (PPIUCD) in Vaginal and Caesarean Section Deliveries: A Hospital Based Study Radha Agarwal, Shubhra Singh MAMC Journal of Medical Sciences 2020 6(3):199-203 Background: Immediate postpartum intrauterine contraceptive device (PPIUCD) is a lucrative postpartum family planning method which provide an effective reversible contraception for women in delivery settings. PPIUCD can be inserted post-placental, intra-caesarean and within 48 hours postpartum. We conducted this study to determine the outcome, satisfaction rate and continuation rate of PPIUCD. Materials and Method: This was a prospective observational study conducted in a tertiary care teaching institute. CuT 380A was inserted within 10 minutes of placental delivery in accepters who fulfilled the Medical Eligibility Criteria and had no contraindications for PPIUCD. They were then followed up for 3 months. A Cohort of 260 vaginal and caesarean deliveries with PPIUCD in situ were studied over seven months period and follow-up results were compared between Vaginal and Caesarean groups. Result: Overall expulsion rate was 8.47%, removal rate was 14.83% and continuation rate was 76.7%. There was no significant difference in removal rate of two groups. Spontaneous expulsion occurred in 8.47% cases and were significantly higher in vaginal insertion group (p value 0.0017). Overall complication rate was low. No case of perforation or accidental pregnancy was reported. Conclusion: PPIUCD is a safe, highly effective, long acting, cost effective method of postpartum contraception, which can be used during institutional delivery visit and eliminates the need for a return visit to start contraception. PPIUCD is a strong weapon in the family planning armory and should be encouraged in both vaginal and caesarean deliveries.

Patients Knowledge of Prescribed Medications and Factors Affecting it in a Tertiary Care, Public, Teaching Hospital in New Delhi, India Vandana Roy, Vandana Tayal, Anirudh Kansal MAMC Journal of Medical Sciences 2020 6(3):204-210 Objectives: To study patients’ knowledge about their prescribed medication and factors affecting it. Patients and Methods: An observational, cross-sectional study was conducted in 500 outpatients in the Medicine department of a tertiary care teaching hospital. The patients were interviewed about prescribed medicines using a structured questionnaire. The average consultation time and average dispensing time was also recorded for 100 interactions each. Results: Among 500 patients interviewed, 55% were females. Hindi was the primary language in 99.6% of the patients and majority of the patients 75.2% could not read English. The mean total score for patients’ medication knowledge was 38.87 ± 10.42 (maximum 60). 95% of participants had ‘Adequate to Good Knowledge’, and 5% had ‘Poor Knowledge’. Only 1.8% of the patients surveyed had complete knowledge of their prescribed medications. Various factors like age > 60 years, female gender, illiteracy, inability to read English, the doctor informing the patient only in writing and the pharmacist not explaining the medication information were associated with lower scores. The average consultation time was 284.6 ± 172.87 seconds and the average dispensing time was 60.45 ± 22.3 seconds. Conclusion: Overall the patients appear to have an adequate basic knowledge of their prescribed medications despite inability to understand the language and less time given for doctor patient pharmacist interaction. Interventions are required to improve health care providers understanding of what is required to educate the patients about the same. This is especially so for patients with risk factors contributing to their low knowledge about prescribed treatment.

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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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Blood Pressure Monitoring

Validation of the single-cuff oscillometric blood pressure monitor InBody BPBIO750 for public spaces according to the Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization Universal Standard Objective The aim of this study was to evaluate the accuracy of the single upper-arm cuff oscillometric blood pressure (BP) monitor InBody BPBIO750 developed for self-measurement by adults in public spaces (kiosk) according to the Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Universal Standard (ISO 81060-2:2018). Methods Subjects were recruited to fulfil the age, gender, BP and cuff distribution criteria of the AAMI/ESH/ISO Universal Standard in general population using the same arm sequential BP measurement method. Results A total of 102 subjects were recruited and 85 were analyzed [mean age 56.7 ± 15.4 (SD) years, 40 men, arm circumference 32.3 ± 5.3 cm, range 22–42 cm]. For validation criterion 1, the mean ± SD of the differences between the test device and reference BP readings was 2.2 ± 6.1/−2.2 ± 5.2 mmHg (systolic/diastolic). For criterion 2, the SD of the averaged BP differences between the test device and reference BP per subject was 5.00/4.63 mmHg (systolic/diastolic). Conclusion The InBody BPBIO750 device fulfilled all the requirements of the AAMI/ESH/ISO Universal Standard (ISO 81060-2:2018) in general population and can be recommended for clinical use in adults. Received 14 September 2020 Accepted 16 November 2020 Correspondence to George S. Stergiou, MD, FRCP, Hypertension Center STRIDE-7, National and Kapodistrian University of Athens, School of Medicine, Third Department of Medicine, Sotiria Hospital, 152 Mesogion Avenue, Athens 11527, Greece, Tel: +30 2107763117; fax: +30 2107719981; e-mail: gstergi@med.uoa.gr Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Association between inter-arm difference in SBP and central blood pressure in a Beijing community cohort Objective The inter-arm SBP difference (IASBPD) can serve as a predictor of cardiovascular disease (CVD). In this study, we aimed to determine the relationship between IASBPD and central blood pressure (CBP). Methods The study cohort comprised of 7842 eligible individuals. Their BPs were assessed simultaneously in both arms using an Omron BP-203RPEIII vascular profiler, and the IASBPD was measured as the absolute difference in these values (absolute value of left minus right). The CBP was noninvasively measured using an Omron HEM-9000AI device. Multivariate regression analysis was used to assess the association between the central SBP (cSBP) and the IASBPD. Results An IASBPD of ≥10 mmHg was positively associated with the cSBP (β = 2.26; 95% confidence interval, 1.04–3.48; P < 0.001). The interaction test showed no significant interactions between the IASBPD and any of the assessed covariates (age group; sex; BMI; smoking status; heart rate group; the presence of hypertension, diabetes, or CVD; and antihypertensive drug use) when the cSBP was used as the outcome in the subgroup analysis. Conclusion The mechanism underlying the ability of the IASBPD to predict CVD may partly involve an increase in the CBP. Received 8 February 2020 Accepted 9 November 2020 Correspondence to Yan Zhang, Division of Cardiology, Peking University First Hospital Dahongluochang Street, Xicheng District, Beijing, 100034, China, Tel: +86 136 2106 2738; fax: +86 10 6613 7748; e-mail: drzhy1108@163.com Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Relation between nocturnal decline in blood pressure and choroidal thickness: a comparative analysis in dipper vs. non-dipper hypertensive patients Purpose To compare choroidal thickness (ChT) and echocardiographical changes in patients with dipper and non-dipper systemic arterial hypertension (HT). Methods Patients with HT were evaluated in two groups according to the 24-hour ambulatory BP monitoring. Compared to day-time values, those whose night-time SBP decreased ≥10% were defined as dippers, and those whose SBP decreased <10% were defined as non-dippers. Transthoracic echocardiography was conducted in all patients. ChT and central macular thickness were measured with spectral-domain optical coherence tomography. ChT was obtained at the subfoveal, 1500 µm nasal and temporal to the fovea. Results Thirty non-dipper (18 females and 12 males) and 23 dipper (16 females and seven males) hypertensive patients were recruited. Sex distribution and the mean age were similar between the groups (P = 0.472; P = 0.12). Disease duration was longer in the non-dipper group (8 ± 3.39 vs. 4.96 ± 1.19 years, P = 0.001). The non-dipper group had lower ChT in subfoveal and temporal locations (P = 0.02 and 0.03, respectively) and higher left atrial volume index (LAVI) and pulmonary valve maximum flow (PV-max; P < 0.001). The night-time SBP was negatively correlated with ChT (P = 0.048) and positive correlated with LAVI and PV-max (P < 0.05). However those correlations were not significant when were controlled by the possible confounding factors as disease duration, age and gender. Conclusion Non-dipper HT patients may have thinner choroid than dippers due to longer duration of HT and higher ambulatory BP levels. Received 27 May 2020 Accepted 28 October 2020 Correspondence to Sedat Tas, MD, Department of Cardiology Manisa City Hospital, 45040 Manisa, Turkey, Tel: +905052919458; e-mail: sedattas2000@yahoo.com Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Could aortic arch calcification help in detection of hypertensive retinopathy? Objective Hypertension-induced end-organ damage is one of the important determinants of morbidity and mortality in patients with hypertension. All types of hypertension-induced end-organ damages start with vascular damage. Vascular calcification is a marker of vascular damage and aortic arch calcification (AAC) is one of the easily identifiable types of vascular calcification. We hypothesized that AAC predicts retinopathy in hypertensive patients. Methods Consecutive hypertensive patients without diabetes mellitus were included. Chest radiography in the posterior-anterior was used to assess the presence of AAC. All patients underwent ophthalmologic examination for retinopathy. Results We included 495 hypertensive patients in this study. Of these, 306 (62%) had hypertensive retinopathy. Patients with hypertensive retinopathy had significantly higher prevalence of AAC as compared to the patients without hypertensive retinopathy (88% vs. 22%, P < 0.001). We found a strong and positive correlation between hypertensive retinopathy and AAC grades (r = 639, P < 0.001). Receiver operator characteristics curve analysis yielded a strong predictive ability of AAC for the presence of hypertensive retinopathy [area under curve = 0.814, 95% confidence interval (CI): 0.775–0.853, P < 0.0001]. In multivariate logistic regression analysis, presence of AAC [odds ratio (OR) 13.128; CI: 7.894–21.832] and serum glucose levels (OR 1.020; CI: 1.003–1.037) were strongly and independently associated with hypertensive retinopathy. Conclusion Presence of AAC on chest radiograph is strongly and independently associated with retinopathy in nondiabetic hypertensive patients. This simple, inexpensive and widely available tool may help in early detection of retinopathy in patients with hypertension. Received 22 October 2019 Accepted 8 October 2020 Correspondence to Adem Adar, MD, Department of Cardiology, Karabuk University Faculty of Medicine, Karabuk, Turkey, Tel: +90 507 231 68 78; e-mail: aadar@karabuk.edu.tr Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Abnormal diurnal blood pressure profile and hypertension-mediated organ damage in nondiabetic chronic kidney disease G1-G3b patients Objective Chronic kidney disease (CKD) is associated with high cardiovascular risk. Prevalence of hypertension and hypertension-mediated organ damage (HMOD) increases with CKD progression. Nocturnal blood pressure (BP) is a strong predictor of cardiovascular complications. This cross-sectional study investigated the link between the diurnal BP profile and HMOD in nondiabetic CKD G1-G3b patients. Methods We investigated 109 CKD patients and 41 apparently healthy persons as controls. All subjects underwent 24-ambulatory blood pressure monitoring (ABPM), echocardiography with left ventricular mass index (LVMI) calculation and pulse wave velocity (PWV) measurement. Results Hypertension was present in 84% of CKD patients. SBP-24 and DBP-24, SBP-day and DBP-day did not differ between CKD and controls. Significant differences were found in SBP-night and DBP-night. The nondipping BP profile (SBP-night/SBP-day ratio ≥0.9) was found in 62% of CKD patients and 32% of controls (P < 0.005). Nocturnal hypertension was found in 56% of CKD patients. LVMI was higher in CKD compared to controls, higher in nondipping than dipping CKD patients, and higher in patients with nocturnal hypertension than without nocturnal hypertension. Abnormal left ventricular geometry was found in 72% nondipping and 43% dipping CKD patients. PWV was higher in CKD than in controls, in patients with nocturnal hypertension than without nocturnal hypertension but did not differ between CKD nondippers and dippers. Conclusion The nondipping BP profile and nocturnal hypertension are associated with HMOD in G1-G3b CKD patients. Hence, there is a need for more extensive use of ABPM for individual risk assessment and personalization of antihypertensive treatment in CKD patients. Received 5 May 2020 Accepted 22 September 2020 Correspondence to Paweł Stróżecki, MD, PhD, Department of Transplantology and Surgery, University Hospital No 1, Skłodowskiej-Curie 9, 85-094 Bydgoszcz, Poland, Tel: +48 525854386; fax: +48 525854450; e-mail: st_pawel@cm.umk.pl Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Association of vitamin D deficiency with arterial stiffness in newly diagnosed hypertension Objective Vitamin D has beneficial effects on vascular endothelial function, blood pressure (BP) and arterial stiffness. Arterial stiffness increases in early-stage hypertensive patients and it is a strong predictor of cardiovascular morbidity and mortality. The purpose of this study was to assess the association between serum 25-hydroxyvitamin D (25-OH D) levels and arterial stiffness in patients with newly diagnosed hypertension. Method Our study included 100 newly diagnosed hypertensive patients (63 male, 37 female and mean age: 51.7 ± 10.3 years) without cardiovascular disease, malignancy, chronic kidney disease and diabetes mellitus. Patients were divided into two groups: vitamin D deficiency group (<20 ng/ml) and normal vitamin D group (≥20 ng/ml). Twenty-four-hour, daytime and nighttime ambulatory BP readings were recorded. Mobil-O-Graph ARC solver algorithm was used to evaluate arterial stiffness parameters of pulse wave velocity (PWV) (m/s), augmentation index normalized with 75/min heart rate (Alx@75). Results Patients with vitamin D deficency had higher values of Alx@75 and PWV values (20.9 ± 9 vs. 16.8 ± 6.9, P = 0.018 and 8.37 ± 1.16 vs. 6.9 ± 0.9, P = 0.001, respectively) despite similar 24-hour ambulatory BP monitoring in both groups. Level of serum calcium was significantly higher in vitamin D deficiency group (9.5 ± 0.23 vs. 9.3 ± 0.12, P = 0.007). Nighttime SBP was higher in vitamin D deficiency group (133.2 ± 14.3 mmHg vs. 126.3 ± 17.2 mmHg; P = 0.03) and also, vitamin D deficiency group had non-dipping SBP pattern compared to normal Vitamin D group (P = 0.013). Conclusion Vitamin D deficiency is associated with increased arterial stiffness in newly diagnosed hypertensive patients in terms of increased PWV and Alx@75 values. Received 20 May 2020 Accepted 28 September 2020 Correspondence to Sinem Cakal, MD, Department of Cardiology, Haseki Training and Research Hospital, Uğur Mumcu, Belediye Sokak No:7, 34265 Sultangazi/İstanbul, Turkey, Tel: +(90) 505 755 17 70; fax: +(90) 212 453 20 00; e-mail: sinemdnz@gmail.com Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Evaluation of cuff deflation and inflation rates on a deep learning-based automatic blood pressure measurement method: a pilot evaluation study Objective The aim of this study was to evaluate the performance of using a deep learning-based method for measuring SBPs and DBPs and the effects of cuff inflation and deflation rates on the deep learning-based blood pressure (BP) measurement (in comparison with the manual auscultatory method). Methods Forty healthy subjects were recruited. SBP and DBP were measured under four conditions (i.e. standard deflation, fast deflation, slow inflation and fast inflation) using both our newly developed deep learning-based method and the reference manual auscultatory method. The BPs measured under each condition were compared between the two methods. The performance of using the deep learning-based method to measure BP changes was also evaluated. Results There were no significant BP differences between the two methods (P > 0.05), except for the DBPs measured during the slow and fast inflation conditions. By applying the deep learning-based method, SBPs measured from fast deflation, slow inflation and fast inflation decreased significantly by 3.0, 3.5 and 4.7 mmHg (all P < 0.05), respectively, in comparison with the standard deflation condition. Whereas, corresponding DBPs measured from the slow and fast inflation conditions increased significantly by 5.0 and 6.8 mmHg, respectively (both P < 0.05). There were no significant differences in BP changes measured by the two methods in most cases (all P > 0.05, except for DBP change in the slow and fast inflation conditions). Conclusion This study demonstrated that the deep learning-based method can achieve accurate BP measurement under the deflation and inflation conditions with different rates. Received 18 June 2020 Accepted 28 October 2020 Correspondence to Peiyu He, PhD, College of Electronics and Information Engineering, Sichuan University, Chengdu 610064, China, Tel: +8602885463873; e-mail: hpysbsy@163.com Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Hemodynamic response to heated water immersion in older individuals with hypertension The aim of this study was to evaluate blood pressure (BP), heart rate, arterial stiffness and endothelial reactivity responses to heated water immersion in older individuals with hypertension. Thirty-five sedentary individuals (67 ± 5 years) under treatment for hypertension were randomly assigned to water-based [n = 20; 30 min of seated resting in a heated swimming pool (30–32 ºC)] or land-based group [n = 15; 30 min of seated resting in a quiet room with controlled temperature (21–23 ºC)]. BP, heart rate, arterial stiffness and endothelial reactivity were measured before, immediately after (post) and 45 min after (recovery) each session. Heart rate reduced (P < 0.05) during the land-based session, and the reduction was maintained at post (~7 bpm) and recovery (~9 bpm), but no heart rate changes occurred during and after the water-based session. Systolic/diastolic BP increased (P = <0.001) at post (~29/10 mmHg) and recovery (~10/7 mmHg) in the water-based group, but not in the land-based group. No significant changes in pulse wave velocity and endothelial reactivity occurred in both groups. These results suggest that the hemodynamic response to heated water immersion should be taken into account when assessing the effect of heated water-based exercise on postexercise hypotension in older individuals with hypertension. Received 24 June 2020 Accepted 13 October 2020 Correspondence to Emmanuel Gomes Ciolac, PhD, Faculdade de Ciências, Departamento de Educação Física, Laboratório de Pesquisas em Exercício Físico e Doenças Crônicas, Universidade Estadual Paulista – UNESP, Avenue Engenheiro Luiz Edmundo Carrijo Coube 14-06, Bauru, Brazil,17033-360, Tel: +55 14 3103 9437; fax: +55 14 3103 6082; e-mail: emmanuel.ciolac@unesp.br/Twitter: @ProfessorCiolac Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Validation of the blood pressure measurement technology used in the Novacor Diasys 3 (DIS-0001-00) upper arm device for ambulatory blood pressure measurement, according to the requirements of the AAMI/ANSI/ISO 81060-2: 2013 standard (for both a general study and a cardiac-stress study in adults) and of the European Society of Hypertension International Protocol revision 2010 Objective The objective of this study was to determine the accuracy of the oscillometric blood pressure measurement technology of the Novacor Diasys 3 (model number DIS-0001-00) blood pressure monitor, intended for ambulatory blood pressure measurement, when used with the recommended Standard (ACC-0213-00), Large (ACC-0214-00) and Paediatric (ACC-0215-00) cuffs. Methods The Novacor Diasys 3 (model number DIS-0001-00) was evaluated according to the requirements of the AAMI/ANSI/ISO 81060-2:2013 standard, including an additional cardiac-stress study, a requirement for ambulatory blood pressure measurement devices. It was also validated according to the requirements of the European Society of Hypertension International Protocol revision 2010. The protocol requirements for all thee studies were followed precisely. Results The Novacor Diasys 3 (model number DIS-0001-00) fulfilled all of the requirements for a pass in each of the three studies. In the primary AAMI/ANSI/ISO 81060-2:2013 study, the Criterion 1 errors were +3.9 mmHg ± 2.9 mmHg for SBP and +3.4 ± 2.5 mmHg for DBP. Conclusion The Novacor Diasys 3 (model number DIS-0001-00), when used with the recommended cuffs, can be recommended for ambulatory blood pressure measurement in the adult population. Received 22 June 20209September2020 Accepted 17 September 2020 Correspondence to Neil Atkins, Medaval Ltd., Unit 107, SBC, Serpentine Ave., Ballsbridge, Dublin D04 H522, Ireland, Tel: +353 1 664 3768; e-mail: neil.atkins@medaval.ie Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Prevalence of aberrant blood pressure readings across two automated intraoperative blood pressure monitoring systems among patients undergoing caesarean delivery Objectives Aberrant automated blood pressure (BP) readings during caesarean delivery may lead to disruptions in monitoring. The present study compared the frequency of aberrant BP readings across two types of commercially available BP monitoring systems in use during caesarean delivery. Methods This was a retrospective observational study using two comparable patient cohorts that resulted from simultaneous introduction of two types of monitors into a single obstetric surgical center in which similar patients were treated for the same surgical procedure by the same set of clinicians during the same year. Our primary hypothesis was that aberrant readings were significantly associated with the type of monitor being used for BP measurement, controlling for a variety of relevant covariates as specified in the analytic plan Results A total of 1418 cesarean delivery patients met inclusion criteria. Gaps of at least 6 min in machine-captured BP readings occurred in 159 (21.1%) of cases done in the operating room using a Datex-Ohmeda monitor vs. 183 (27.5%) of cases in the operating rooms using Phillips monitors (P = 0.005). In multivariable logistic regression analysis, the relative odds of the occurrence of monitoring gaps was 35% higher in rooms with the Phillips BP monitors as compared to the Datex-Ohmeda monitor while controlling for pre-specified covariates (odds ratio = 1.35, 95% confidence interval = 1.04–1.74, P = 0.02). Conclusion The present analysis suggests that aberrant BP readings for parturients undergoing caesarean delivery are significantly different between the two types of automated BP monitoring systems used in the operating rooms at our institution. Received 15 July 2020 Accepted 22 September 2020 Correspondence to Robert B. Schonberger, MD MHS, Department of Anesthesiology, Yale School of Medicine, TMP-3, 333 Cedar Street, P.O. Box 208051, New Haven, CT 06520-8051, USA, Tel: +203 785 2802; fax: +203 785 6664; e-mail: robert.schonberger@yale.edu 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,