Perspectives in Clinical Research

New clinical trial rules: Academic trials and tribulations Arun Bhatt Perspectives in Clinical Research 2019 10(3):103-105

Does India need more medical scientists? Suhasini Sharma Perspectives in Clinical Research 2019 10(3):106-107

Indian Council of Medical Research's National Ethical Guidelines for biomedical and health research involving human participants: The way forward from 2006 to 2017 Sapan Kumar Behera, Saibal Das, Alphienes Stanley Xavier, Sandhiya Selvarajan, Nishanthi Anandabaskar Perspectives in Clinical Research 2019 10(3):108-114 The Indian Council of Medical Research (ICMR) recently published the third revised guidelines “National Ethical Guidelines for Biomedical and Health-Related Research Involving Human Participants” in 2017. The changes to the guidelines were needed to acculturate the rapid advances in the research environment and advances in science and technology. The revised guidelines propose substantial changes/ modifications compared to the previous version. These include the introduction of broad consent, ethical issues related to deception, review of multi-centric research by a single ethics committee and ethical issues involved in implementation research and other issues related to public health research. The revised guidelines also incorporate modifications and minor changes to the previous version. Although most of the changes in the revised guidelines are in parallel to most of the international guidelines, we have also highlighted the minor differences compared to other international guidelines.

Assessing knowledge, attitude, and practices of health-care providers toward pharmacovigilance and adverse drug reaction reporting at a comprehensive cancer center in Jordan Abeer Ahmad Al Rabayah, Esra'a Mahmoud Hanoun, Ruba Hab Al Rumman Perspectives in Clinical Research 2019 10(3):115-120 Background and Objective: Cancer patients are more likely to experience adverse drug reactions (ADRs) than other patients, because of both the complexity of the treatment regimens and the severity of disease. The objectives of this study were to determine the knowledge, attitude, and practice of health-care providers toward pharmacovigilance and ADR reporting, barriers to ADR reporting, and the association between the demographics of health-care providers and their knowledge and attitude toward reporting. Materials and Methods: A cross-sectional survey was conducted at the King Hussein Cancer Center. A self-administered questionnaire was distributed to dispensary pharmacists, clinical pharmacists, physicians, and nurses. Descriptive analysis was used, with testing for associations between variables. Results: Of the 373 questionnaires, 306 were returned (response rate, 82%). Pharmacists and nurses were more knowledgeable than physicians; however, all participants had a highly positive attitude toward pharmacovigilance and ADR reporting, with a mean score of 3.87 out of 5. The main knowledge gaps were filling in an ADR reporting form, assessing the severity of ADRs, and differentiating between ADRs and adverse events. The main barriers to ADR reporting (37.5% of responses) were considered to be lack of training and of understanding reporting rules. No associations were found with age, gender, years of experience, attitude, or knowledge. Conclusion and Recommendations: Understanding of pharmacovigilance and ADR reporting could further be improved among health-care providers at our center.

Clinical trials in Asia: A World Health Organization database study Sheraz Ali, Oluwaseun Egunsola, Zaheer Ud Din Babar, Syed Shahzad Hasan Perspectives in Clinical Research 2019 10(3):121-124 Background and Objective: The Asian continent appears to be a growing destination for conducting cost-effective clinical trials, utilizing the available pool of treatment naïve subjects. This study aims to determine the growth rate of clinical trials in Asia. Methods: A database review was conducted. Registered clinical trials conducted in selected countries in Asia, Europe, Australia, and North America between 2008 and 2017 were searched from the International Clinical Trial Registry Platform. Compound Annual Growth Rate was determined for registered clinical trials. Results: During the 10-year period, a total of 125,918 registered clinical trials were conducted in Asia. There was a 7-fold increase in the number of registered clinical trials in Asia. More trials were registered in Japan than any other Asian country (30.8%). The average annual increase in the number of registered trials was generally higher in Asia than the United States of America, Canada, EU countries, or Australia. Iran recorded the highest average annual increase in the number of all clinical trials in Asia (41.9%). The number of pediatric clinical trials in Iran also increased annually by an average of 30.4%, more than any other country included in this study. Conclusions: Clinical trials recruitment in Asia is increasing faster than Europe, North America, and Australia. Lower trial cost and large patient pool may be contributory to this increase.

Quality of life among HIV-tuberculosis co-infected patients Dharmendra Kumar Jha, Jyotsna Jha, Anshu Kumar Jha, Basavaprabhu Achappa, Ramesh Holla Perspectives in Clinical Research 2019 10(3):125-129 Background: India is the world's third leading country in terms of people living with human deficiency virus (HIV) (2.1 million) with 0.4 million deaths due to HIV-associated tuberculosis (TB). Physical and mental stress degrades the quality of life (QOL) in these patients. Studies have been done in HIV patients but very few on HIV-TB co-infected patients. Our study aims at assessing and comparing the QOL in HIV patients with and without TB. Materials and Methods: It was a cross-sectional study done at Antiretroviral Treatment Center of KMC, Mangalore and District Wenlock Hospital, Mangalore, over 6 months. A sample size was 104. Semi-structured questionnaire to collect clinico-demographic data, World Health Organization QOL (WHOQOL)-HIV BREF to assess the QoL, and Beck's Depression Inventory Scale (Physical health, psychological well-being, social relationship, environmental health, level of independence, and spiritual health) to identify depression were used. The Cronbach's alpha was used to measure the internal consistency for each domain of the WHOQOL-HIV instrument. Results: HIV-TB co-infected patients had a lower mean score in all domains as compare to only HIV patients, suggesting that HIV-TB co-infected patients had a poor QOL (P < 0.05). Internal consistency of each domain was good (α >0.7). Conclusion: To improve the QOL in HIV patients, it is important to identify the determinants of QOL and work toward its improvement.

Utilization of antimicrobial agents in patients on ventilator in medical Intensive Care Unit at a tertiary care teaching hospital: A prospective study Raj Khirasaria, Neeta Kanani, Angelika Batta Perspectives in Clinical Research 2019 10(3):130-136 Background: The burden of bacterial infections is huge and grossly underrepresented in the current health-care system. Inappropriate use of antimicrobial agents (AMAs) poses a potential hazard to patients by causing antibiotic resistance. In addition, the field of antimicrobials is witnessing constant development and introduction of new drugs for which holistic utilization, effectiveness, and side-effects studies are the need of the hour. The current study aims at studying the prescription pattern of AMAs in patients on ventilator and focuses on their prescribing trends. Methodology: A prospective, observational study was conducted in Medical Intensive Care Unit (ICU) of a tertiary care hospital of Western India for 6 months. Prescription pattern of AMAs was analyzed using predesigned format. Statistical Analysis: Descriptive statistics was used being an observational study Results: Five-hundred and twenty patients who were on ventilator and were prescribed one or more AMAs were enrolled in the study with a mean patient age of 40.7 years. The intended purpose of the use of AMAs was prophylactic in 59% of patients. Empirical therapy was given in 92% of patients. β-lactams group of AMAs along with metronidazole were most frequently used. 73% required concurrent use of two or more AMAs. 9% of the patients required addition or substitution of one or more other AMAs on the basis of culture and sensitivity report or inadequate clinical response and expert opinion. The outcome of therapy with AMAs showed infection was effectively prevented in 34% of the patients. Conclusion: This study provides a baseline data for improving the utilization of AMAs in ICU settings by rationalizing their use and also carrying out further studies on prescribing pattern of AMAs in a tertiary care unit.

Study designs: Part 4 – Interventional studies Rakesh Aggarwal, Priya Ranganathan Perspectives in Clinical Research 2019 10(3):137-139 In the fourth piece of this series on research study designs, we look at interventional studies (clinical trials). These studies differ from observational studies in that the investigator decides whether or not a participant will receive the exposure (or intervention). In this article, we describe the key features and types of interventional studies.

Pivotal role of Pharmacovigilance Programme of India in containment of antimicrobial resistance in India Vijit Agrawal, Tarani Prakash Shrivastava, Pramod Kumar Adusumilli, Kalaiselvan Vivekanandan, Prasad Thota, Shashi Bhushan Perspectives in Clinical Research 2019 10(3):140-144 Misuse of antimicrobials has become one of the grave concerns of public health. In last two decades, this has been largely contributing in the emergence of antimicrobial resistance (AMR) among all the pathogens. A 2013 report of Centres for Disease Control and Prevention, USA figured that at least 2 million people get an antibiotic-resistant infection every year and as many as 23,000 people lost their life. A multi-country survey in Southeast Asia region conducted by World Health Organization (WHO) in 2015, identified several gaps in knowledge and awareness about the optimal use of antimicrobials and AMR. Following this, the Ministry of Health and Family Welfare (MoHFW), Government of India, developed National Action Plan in the year 2017 to combat AMR. Pharmacovigilance Programme of India (PvPI) being a flagship programme of MoHFW holds the responsibility of ensuring safety of medicines used by India population and has recently identified AMR as one of the strategic priorities. This article intends to provide insights of the recent attempts and deliberate efforts made by PvPI in the containment of AMR in India and it also intends to sensitize healthcare fraternity on restricting AMR in public interest.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Academic Medicine

What Makes the "Perfect" Inpatient Consultation? A Qualitative Analysis of Resident and Fellow Perspectives Purpose: To characterize the methods of inpatient consult communication, given new communication modalities; to explore residents' and fellows' perspectives on the ideal consult and how this affects their teaching, learning, and patient safety; and to identify barriers to and strategies for optimizing consultations. Method: Using qualitative grounded theory, the authors conducted semistructured focus groups with pediatric residents and fellows at Lucile Packard Children's Hospital at Stanford University from October 2016 to September 2017, using questions developed by expert consensus to address study objectives. Sessions were audio recorded and transcribed verbatim. Two authors independently coded the transcripts and reconciled codes to develop categories and themes using constant comparison. The third author validated the codes, categories, and themes. To ensure trustworthiness, participants edited the themes for accuracy. Results: Twenty-seven residents and 16 fellows participated in seven focus groups (three with residents, four with fellows). Four themes emerged: (1) many forms of communication are successfully used for initial inpatient consult recommendations (in person, phone, text messages, notes in electronic medical records); (2) residents and fellows prefer in-person communication for consults, believing it leads to improved teaching, learning, and patient safety; (3) multiple strategies can optimize consults regardless of communication modality; (4) how residents request the initial consult affects the interaction and can increase fellow engagement, which leads to more fellow teaching, resident's improved understanding, and better patient care. Conclusions: Residents and fellows believe that structured initial consults conducted in person improve teaching, learning, and patient care. Several strategies exist to optimize this process. Supplemental digital content for this article is available at http://links.lww.com/ACADMED/A708. Acknowledgments: This work could not have been completed without the help of the Stanford Medicine Pediatric Medical Education Scholarly Concentration group. Funding/Support: None reported. Other disclosures: None reported. Ethical approval: The project received IRB approval through the Stanford University review committee. Previous presentations: The abstract was presented at the Pediatric Academic Societies 2018 meeting and the Association of Pediatric Program Directors 2018 spring meeting. Correspondence should be addressed to Sara Pavitt, Department of Pediatrics, Stanford School of Medicine, 725 Welch Road, MC 5906, Palo Alto, CA 94304; telephone: (650) 497-8979; email: Scady@stanford.edu. © 2019 by the Association of American Medical Colleges

Fostering Meaning in Residency to Curb the Epidemic of Resident Burnout: Recommendations From Four Chief Medical Residents Burnout has become commonplace in residency training, affecting more than half of residents and having negative implications for both their well-being and their ability to care for patients. During the authors' year as chief medical residents at Brigham and Women's Hospital in 2017-2018, they became intimately familiar with the burnout epidemic in residency training. The authors argue that addressing resident burnout requires residency programs and teaching hospitals to focus not on the individual contributors to burnout, but instead on fostering meaning within residency to help residents find purpose and professional satisfaction in their work. In this Perspective, they highlight four important elements of residency that provide meaning: patient care, intellectual engagement, respect, and community. Patient care, intellectual engagement, and community provide residents with a focus that is larger than themselves, while respect is necessary for a resident's sense of belonging. The authors provide examples from their own experiences and from the literature to suggest ways in which residency programs and teaching hospitals can strengthen each of these elements within residency and curb the epidemic of burnout. The authors have informed the journal that they agree that David D. Berg, Sanjay Divakaran, Robert M. Stern, and Lindsay N. Warner all completed the intellectual and other work typical of the first author. Acknowledgments: The authors would like to thank Dr. Joel T. Katz and Dr. Joseph Loscalzo for their mentorship and review of the manuscript. Funding/Support: D.D. Berg is supported by a T32 postdoctoral training grant from the National Heart, Lung, and Blood Institute (T32 HL007604). S. Divakaran is supported by a T32 postdoctoral training grant from the National Heart, Lung, and Blood Institute (T32 HL094301). Other disclosures: None reported. Ethical approval: Reported as not applicable. Previous presentations: Brigham and Women's Hospital Medical Grand Rounds; June 1, 2018; Boston, Massachusetts. Correspondence should be addressed to Robert M. Stern, Dana Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02115; telephone: 617-732-3779; email: Robert_Stern@dfci.harvard.edu. 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. © 2019 by the Association of American Medical Colleges

Learners as Leaders: A Global Groundswell of Students Leading Choosing Wisely Initiatives in Medical Education Resource stewardship and reducing low-value care have emerged as urgent priorities for health care delivery systems worldwide. However, few medical school curricula include adequate content to allow learners to master the knowledge, skills, and attitudes needed to contribute to this transformation toward value-based health care. This article describes a program to launch student-led curriculum enhancement initiatives in 7 countries. The program, called STARS (Students and Trainees Advocating for Resource Stewardship), was inspired by Choosing Wisely, a campaign by the American Board of Internal Medicine Foundation that seeks to promote conversations on avoiding unnecessary medical tests, treatments, and procedures. The initial STARS model, which originated in Canada in 2015, included a leadership summit, where students from multiple medical schools learned about Choosing Wisely principles, leadership, and advocacy. These students then led grassroots efforts at their local medical schools with faculty and other students to raise awareness and advocate for changes related to resource stewardship. Student-led efforts resulted in the integration of Choosing Wisely principles into case-based learning, the creation of student interest groups and electives, the launch of social media campaigns, and the organization of special presentations by local experts. The rapid spread of similar programs in 6 other countries (Italy, Japan, the Netherlands, New Zealand, Norway, and the United States) by 2018 suggests that STARS resonates across multiple settings and signals the potential for such a model to advance other important areas in medical education. This article documents results and lessons learned from the first 4 years of the program. The authors have informed the journal that they agree that both Karen B. Born and Christopher Moriates completed the intellectual and other work typical of the first author. Acknowledgments: The authors thank the students and faculty across the world engaged in Choosing Wisely STARS programs for their contributions to the STARS model. Funding/Support: Choosing Wisely Canada STARS was funded by an ABIM Foundation education grant. The U.S. Choosing Wisely STARS program was funded by grants from the ABIM Foundation and the Josiah Macy Jr. Foundation. Other disclosures: None reported. Ethical approval: Choosing Wisely STARS was approved by the University of Texas Institutional Review Board in 2017. The University of Toronto Research Ethics Board approved of this study in June 2018. Previous presentations: Choosing Wisely STARS U.S. was presented during poster presentations at the 2018 High Value Practice Academic Alliance national meeting, September 2018, Baltimore, MD, and Learn Serve Lead 2018: The AAMC Annual Meeting, November 2018, Austin, Texas. Correspondence should be addressed to Brian M. Wong, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Room H466, Toronto, ON M4N 3M5, Canada; telephone: (416)480-6100, ext. 83709; email: BrianM.Wong@sunnybrook.ca; Twitter: @Brian_M_Wong. © 2019 by the Association of American Medical Colleges

Supporting New Physicians and New Parents: A Call to Create A Standard Parental Leave Policy for Residents Parents taking leave after the birth of a child is associated with significant benefits for infants, mothers, and fathers. Although nearly 40% of residents have or plan to have children during residency, there is no standard parental leave policy for these trainees. In this Perspective, the authors discuss the benefits of parental leave, synthesize findings about maternity bias and other negative effects of the current variable approaches to parental leave during residency, and explore underlying causes of the lack of a standard parental leave policy for residents. They also call on the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties to work together to address this issue, recommending a standard parental leave policy that ensures a minimum of eight weeks of paid leave for all residents without requiring them to extend training or becoming ineligible to sit for board certification exams. Creating evidence-based and family-friendly guidelines for parental leave is important to the progress of academic medicine in the modern era, as it supports parental and child health, promotes resident wellness, and reduces gender disparities in medicine to the benefit of all. Acknowledgements: The authors wish to thank Julie Oyler, MD, Lisa Willett, MD, and Angela Castellanos, MD, for their critical review of this article. Funding/Support: None reported. Other disclosures: None reported. Ethical approval: Reported as not applicable. Correspondence should be addressed to Anna Volerman, University of Chicago Medicine, 5841 South Maryland Ave, MC 2007, Chicago, IL 60637; telephone: (773) 702-6840; email: avolerman@uchicago.edu; Twitter: @annavolerman. © 2019 by the Association of American Medical Colleges

The Empirical Challenge of 21st Century Medical Education Medical education is at a crossroads. Facing challenges wrought by science and technology as well as societal change, the curriculum is increasingly out of synch with new needs in teaching content and medical practice. The path to significant curricular reform is difficult due to a variety of factors, including deeply entrenched values, the natural resistance to change, and the accreditation process. Indeed, even the very definition of what it means to be a professional is changing with profound implications for the future role of the physician and the sacrosanct doctor-patient relationship. In this Invited Commentary, the author enumerates challenges facing medical education in the current era. To address these challenges, the author recommends specific curricular emphases for 21st century medical education: knowledge capture and curation; collaboration with and management of artificial intelligence applications; a deep understanding of probabilistic reasoning; and the cultivation of empathy and compassion in accordance with ethical standards. Given these needs, it is imperative that schools act today to undertake significant curricular reform, and, in so doing, strive to make the hard changes necessary to produce optimal practitioners in a rapidly transforming 21st century. The author provides first steps an institution can take to begin to address these challenges. Funding/Support: None reported. Other disclosures: None reported. Ethical approval: Reported as not applicable. Disclaimer: This Invited Commentary represents solely the views of the author. Previous presentations: This Invited Commentary is based on the 2019 Brodie Medical Education Award Lecture given by S.A. Wartman at the University of Virginia Medical School, Charlottesville, VA, February 27, 2019. Correspondence should be addressed to Steven A. Wartman, email: swartman@aahcdc.org. © 2019 by the Association of American Medical Colleges

Silent Night [Excerpt] Commentary on an Excerpt From Silent Night No abstract available

Invoking the Medical Humanities to Develop a #MedicineWeCanTrust Trust is a complex phenomenon that resists easy definition, but it is easily recognizable, or rather its absence is impossible to miss. The author draws inspiration from the #MedsWeCanTrust movement to advocate for #MedicineWeCanTrust. Trust can be seen as a "soft," "tender minded," optimistic condition fighting for survival in a "hard," "tough minded," jaundiced medicine. Modern medicine is traditionally patriarchal, individualistic, and resistant to encouraging democratic, collaborative habits as it socializes its young into hierarchical structures, or eats them whole. Yet trust is a health intervention and essential for the innovative expansion of medical culture as it encourages authentic democracy, interprofessional clinical teamwork, and patient-centeredness. Increases in trust lead to greater tolerance of uncertainty, one of the primary goals of medical education. Recent curriculum development work has shown that the medical humanities offer a superb delivery mechanism for ensuring democratic habits in medicine that align with social justice agendas, key to addressing links between social inequalities and compromised physical and mental health. Where lack of trust is associated with cynicism in doctors, increasing trust loosens dependence upon suffocating control mechanisms. This allows medicine to take on the moral concerns and uncertainties of an adulthood that also promises emotional warmth, guidance, support, and improved communication between colleagues and with patients. Medicine must embrace trust as the matrix of health care, and the medical humanities can educate for values such as tolerance of uncertainty and ambiguity as a basis to engendering trust. To read other New Conversations pieces and to contribute, browse the New Conversations collection on the journal's web site (https://journals.lww.com/academicmedicine/pages/collectiondetails.aspx?TopicalCollectionId=65) follow the discussion on AM Rounds (academicmedicineblog.org) and Twitter (@AcadMedJournal using #AcMedConversations), and submit manuscripts using the article type "New Conversations" (see Dr. Sklar's announcement of the current topic in the December 2018 issue for submission instructions and for more information about this feature). Editor's Note: This New Conversations contribution is part of the journal's ongoing conversation on trust in health care and health professions education. Acknowledgments: The author is grateful to Dr. Arno Kumagai for stimulating conversations on medical humanities and social justice issues. Funding/Support: None reported. Other disclosures: None reported. Ethical approval: Not applicable reported. Correspondence should be addressed to Alan Bleakley, Poldown Cottage, Escalls Cliff, Sennen, Penzance, Cornwall TR19 7BB United Kingdom; telephone: (+44) 1736-871797; e-mail: alan.bleakley@plymouth.ac.uk. © 2019 by the Association of American Medical Colleges

Collaborative Solutions to Antibiotic Stewardship in Small Community and Critical Access Hospitals The overuse and misuse of antibiotics affects patients in many ways, including by driving antibiotic resistance, a serious public health threat in the United States and around the world. To improve patient safety and address rising rates of resistance, an increasing number of health care facilities have created antibiotic stewardship programs (ASPs). ASPs have been successful in slowing the emergence of resistance and improving patient outcomes. However, there are serious geographic and resource barriers to ASP adoption in small community hospitals and critical access hospitals. Fortunately, many barriers can be overcome by using collaborative models to bring together key stakeholders, including large hospitals and health systems and academic medical centers; hospital associations; federal, state, and local public health organizations; and federal and state offices of rural health. These stakeholders are ideally positioned to assist with stewardship efforts in small community and critical access hospitals and, in doing so, can improve patient safety while stemming the spread of resistant bacteria. Acknowledgments: The authors acknowledge Elisa Arespacochaga for her support of the initiative. Funding/Support: None reported. Other disclosures: None reported. Ethical approval: Reported as not applicable. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the American Hospital Association, University of Illinois College of Law, the Centers for Disease Control and Prevention, the Federal Office of Rural Health Policy, or The Pew Charitable Trusts. Correspondence should be addressed to Jay Bhatt, 155 North Wacker Drive, Suite 400 Chicago, IL 60606; @bhangrajay: email: jbhatt@aha.org. Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a "work of the United States Government" for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government. © 2019 by the Association of American Medical Colleges

Professionalism as the Bedrock of High-Value Care "High-value care" has become a popular mantra and a call to action among health system leaders, policy makers, and educators who are advocating widespread practice changes to reduce costs, minimize overuse, and optimize outcomes in the United States. Regrettably, current research does not demonstrate significant progress in improving high-value care. Many investigators have looked to payment models, benefit design, and policy changes as the main levers to reduce low-value care delivery; thus, the prevailing approach to ensuring high-value care has been to identify and limit low-value services. This approach has a clear limitation: the number of identified low-value services has become too numerous for individual physicians to track. Using professionalism as a key driver of practice change presents an important opportunity to shift from a deficit-based reactive model to one that is proactive and uses the concepts of intrinsic motivation and medical stewardship to effect high-value care. Transforming aspirational values such as professionalism into actions that engage all physician stakeholders regardless of their position or influence, and regardless of system agility or payment structure, has the potential for bringing about real change. These concepts can be integrated into medical education, introduced early in training, and modeled by educators to drive long-term sustainable change. Physicians can, and should, embrace professionalism as the motivation for redesigning care. Payment reform incentives that align with their professional values should follow and encourage these efforts; that is, payment reform should not be the impetus for redesigning care. Funding/Support: None reported. Other disclosures: Christopher Moriates reports receiving royalties from McGraw-Hill for the textbook Understanding Value-Based Healthcare. Ethical approval: Reported as not applicable. Correspondence should be addressed to Leah M. Marcotte, Department of Medicine, University of Washington, 1107 NE 45th Street, Suite 355, Seattle, WA 98105; telephone: (206) 543-3163; email: leahmar@uw.edu; Twitter: @marcottl. © 2019 by the Association of American Medical Colleges

A Comparison of Costs: How California Teaching Hospitals Achieved Slower Growth Than Nonteaching Hospitals in Operating Room Costs From 2005 to 2014 Purpose: Historically, teaching hospitals have had higher costs than their nonteaching counterparts, introducing potential financial risk in value-based payment models. This study compared risk-adjusted operating room (OR) costs between teaching and nonteaching hospitals in California. Method: Using 2,992 financial statements from fiscal years (FYs) 2005–2014, the authors extracted data for OR total costs, components of direct costs, and indirect costs. Cross-sectional and longitudinal models estimated OR costs per minute of surgery by teaching status, ownership, case mix index, and geographic area. Results: The risk-adjusted cost was $9.44 per minute less in teaching than nonteaching hospitals in FY2014 (95% CI 3.03, 15.85, P = .004). Between FY2005 and FY2014, OR costs grew more slowly at teaching hospitals due to slower wage growth and indirect costs per minute (respectively, -$0.13 and -$0.77 per minute per year, P = .005 and P < .001). Hourly pay rose more at teaching hospitals ($0.26 per hour per year, P = .008), but was more than offset by slower full-time equivalents growth (-0.002 per 10,000 OR minutes per year, P = .001). Between FY2005 and FY2014, operative volume increased at teaching hospitals and decreased at nonteaching hospitals. Conclusions: By 2014, California teaching hospitals had lower OR costs per minute than nonteaching hospitals due to relative labor productivity gains and slower indirect cost growth. The latter likely resulted from a shift of volume from nonteaching to teaching facilities. These trends will help teaching hospitals compete under value-based models. Implications for patients and nonteaching hospitals warrant evaluation. Supplemental digital content for this article is available at http://links.lww.com/ACADMED/A702. Funding/Support: Christopher Childers is funded by AHRQ#F32HS025079. AHRQ had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, approval of the manuscript; or decision to submit for publication. Other disclosures: None reported. Ethical approval: The UCLA Institutional Review Board determined that the study was not human subjects research. Previous presentations: This work was presented at the American College of Surgeons 104th Annual Clinical Congress, Scientific Forum, Boston, MA, October 22, 2018. Correspondence should be addressed to Christopher P. Childers, Department of Surgery, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., CHS 72-247, Los Angeles, CA 90095; email: cchilders@mednet.ucla.edu; Twitter: @cchildersmd. © 2019 by the Association of American Medical Colleges

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Neonatal Care

Role of the Neonatal Nurse Practitioner in the Community Hospital Background: The role of the neonatal nurse practitioner (NNP) is well established in the neonatal intensive care unit. The level IV NNP is traditionally supported by large multidisciplinary teams while the level I to III NNP may be the sole in-house provider with limited resources. Purpose: The purpose of this research project is to identify the NNP role, responsibilities, and barriers to practice in the level I, II, and III newborn care settings. Methods: This study used a descriptive, exploratory design to examine NNP roles and responsibilities in level I, II, and III care centers via an online survey. Results: Of the respondents (171), the majority (71.3%) work 24-hour shifts, 51.5% being the single NNP during the day with 67.8% being alone at night. Nearly 27% have limited or are without ancillary support while 29.8% cannot meet some standards of care due to inadequate resources. Almost 22% lack written protocols and procedural opportunities are limited or a concern for 15.8% of the NNPs. Implications for Practice: A better understanding of the responsibilities of the level I to III NNP will assist with developing staffing guidelines, influence practice models, and guide recruitment and retention of the NNP. Implications for Research: A systematic literature review yielded articles on the value of nurse practitioners and their ability to deliver safe, effective and cost-conscience care but not on what the role entails on a daily basis. Further studies are needed to specifically compare the role of the level IV NNP to the level I, II, and III NNP to further delineate NNP functionality according to level of care. Correspondence: Barbara Snapp, DNP, NNP-BC, Mary Washington Hospital, Neonatal Intensive Care, 3rd Floor, 1001 Sam Perry Blvd, Fredericksburg, VA 22401 (bsnapp@childrensnational.org). The authors declare no conflicts of interest. © 2019 by The National Association of Neonatal Nurses

Maternal Distress in the Neonatal Intensive Care Unit: A Concept Analysis Background: The neonatal intensive care unit (NICU) can cause significant psychological distress in a mother. There is no common definition of maternal distress in the NICU currently in use. Purpose: To develop a clear conceptual understanding of maternal distress in the NICU using conceptual definitions and empirical findings. Methods/Search Strategy: A literature search was conducted using EBSCOhost, MEDLINE, CINAHL, PsychINFO, and Google Scholar. The concept analysis was guided by Walker and Avant's (2011) guide. Findings/Results: Maternal distress in the NICU consists of a combination of depressive, anxiety, trauma, and posttraumatic stress symptoms. The symptoms occur together on a spectrum and present differently in each mother. The antecedents to maternal distress are a NICU hospitalization and a perceived interruption to the transition to motherhood. Consequences of maternal distress in the NICU are issues with developing a healthy maternal–infant bond, adverse infant development, and decreased maternal quality of life. Implications for Practice: A complete understanding of maternal distress in the NICU will lead to increased awareness of adverse mental health states in this population. Implications for Research: Identification of mothers at risk for maternal distress in the NICU, as well as the identification of antecedents and consequences related to the mother and the infant from maternal distress in the NICU. Using a single, clear definition of maternal distress in the NICU population will lead to a more cohesive body of literature. Correspondence: Morgan A. Staver, BSN, RN, College of Nursing, University of Nebraska Medical Center, 4101 Dewey Ave, Omaha, NE 68131 (morgan.staver@unmc.edu). The authors declare no conflicts of interest. © 2019 by The National Association of Neonatal Nurses

Malassezia furfur Emergence and Candidemia Trends in a Neonatal Intensive Care Unit During 10 Years: The Experience of Fluconazole Prophylaxis in a Single Hospital Background: Because Candida spp is a major cause of mortality and morbidity in preterm infants, fluconazole prophylaxis has been suggested by some experts and hospital policy. In our hospital, fluconazole prophylaxis was used in eligible preterm infants and set as the neonatal intensive care unit (NICU) practice in 2014. Purpose: This study focused on fungal bloodstream infections and aimed to evaluate the benefit and harm of fluconazole prophylaxis. Methods/Search Strategy: This retrospective, descriptive study involved medical record reviews in our hospital from April 2005 to October 2016. NICU patients were included if Candida species, yeast-like organisms, or Malassezia species were cultured from their venous catheter tips or blood cultures. Findings/Results: After fluconazole prophylaxis, cases of Candida spp decreased and those of Malassezia furfur emerged. We reviewed 19 cases of catheter-related M furfur colonization and 1 case of M furfur fungemia. The gestational age was 27.3 ± 2.0 weeks and birth weight was 959.2 ± 229.8 g. Hyperalimentation with lipid infusion was used in all cases. All of the neonates survived with antifungal agent use. Implications for Practice: This study highlights that prophylactic fluconazole may be an associated factor of Malassezia colonization; M furfur remains a potential concern for fungemia in the care of premature infants and thus requires our attention. Implications for Research: Future studies should further investigate the incidence and impact of noncandidal fungal infections with fluconazole prophylaxis use in premature infants. Correspondence: Kuang-Che Kuo, MD, Division of Infectious Disease, Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Dapi Rd, Niaosong District, Kaohsiung City 833, Taiwan, ROC (light@cgmh.org.tw). The authors declare no conflicts of interest. 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. © 2019 by The National Association of Neonatal Nurses

Improving Staff Knowledge and Attitudes Toward Providing Psychosocial Support to NICU Parents Through an Online Education Course Background: Provider–parent communication is a critical determinant of how neonatal intensive care unit (NICU) parents cope, yet staff feel inadequately trained in communication techniques; many parents are not satisfied with the support they receive from hospital providers. Purpose: This study evaluated whether NICU staff would demonstrate improved knowledge and attitudes about providing psychosocial support to parents after taking an online course. Methods: After providing demographic information, staff at 2 NICUs took a 33-item survey both before and after taking a 7-module online course "Caring for Babies and Their Families," and again at 6-month follow-up. Scores (means ± standard deviation) from all time periods were compared and effect sizes calculated for each of the course modules. Results: NICU staff participants (n = 114) included nurses (88%), social workers (7%), physicians (4%), and occupational therapists (1%). NICU staff showed significant improvement in both knowledge and attitudes in all modules after taking the course, and improvements in all module subscores remained significant at the 6-month follow-up mark. Night staff and staff with less experience had lower pretest scores on several items, which improved on posttest. Implications for Practice: This course, developed by an interprofessional group that included graduate NICU parents, was highly effective in improving staff knowledge and attitudes regarding the provision of psychosocial support to NICU parents, and in eliminating differences related to shift worked and duration of work experience in the NICU. Implications for Research: Future research should evaluate course efficacy across NICU disciplines beyond nursing, impact on staff performance, and whether parent satisfaction with care is improved. Correspondence: Sue L. Hall, MD, 145 N. Crimea Street, Ventura, CA 93001 (suehallmd@gmail.com). This work was supported in part by unrestricted support from Medela, The Wellness Network, and Prolacta Bioscience. Dr. Hall is a consultant for The Wellness Network. The authors declare no conflicts of interest. 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 Web site (www.advancesinneonatalcare.org). 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. © 2019 by The National Association of Neonatal Nurses

Pharmacologic Management of Neonatal Abstinence Syndrome Using a Protocol Background: The opioid epidemic in the United States has reached unprecedented proportions with far-reaching impacts on the most vulnerable population. The number of neonates born addicted to opioids has grown exponentially over the last several decades, leading to increased neonatal intensive care unit admissions and rising healthcare costs. Recent studies have yielded mixed results regarding which medication is most effective at relieving the symptoms of opioid withdrawal and reducing the weaning timeframe for babies with neonatal abstinence syndrome (NAS). Purpose: To explore and compare the effectiveness of morphine versus methadone in the treatment for NAS using a standardized protocol. Method: A literature search of PubMed and CINAHL was performed. The search yielded 10 quantitative studies that were analyzed for potential practice changes. Conclusion: Based on current literature, following a standardized, stringent weaning protocol is more beneficial than the pharmacologic agent used. Studies reveal shorter weaning times and hospital stays in almost every group that followed rigid guidelines. Implication for Research: Although current studies are promising for the desired outcome, more research is needed to develop appropriate protocol-based weaning regimens for management of NAS. Implication for Practice: As the occurrence of NAS continues to rise, its management must vigorously meet the challenges of the diagnosis. Institutions should reevaluate their current protocols based on reassuring data showing that stringent guidelines using morphine or methadone can improve clinical outcomes, reduce hospital length, and lower healthcare costs. Correspondence: Lieutenant Brandi L. Gibson, MSN, RN, RNC-NIC, Nurse Corps, US Navy, Duke University School of Nursing, Box 3322, Durham, NC 27710 (Brandi.gibson@duke.edu). All the authors have read and approved this article for publication and have all contributed equal substance to this work. This manuscript has not been submitted for consideration by another journal. The views expressed in this article are those of the author(s) and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government. LT Gibson is a military service member. This work was prepared as part of her official duties Title 17, USC, §105 provides that "Copyright protection under this title is not available for any work of the U.S. Government." Title 17, USC, §101 defines a "U.S. Government work as a work prepared by a military service member or employees of the U.S. Government as part of that person's official duties." Written work prepared by employees of the Federal Government as part of their official duties is, under the US Copyright Act, a "work of the United States Government" for which copyright is not available. As such, copyright does not extend to the contributions of employees of the Federal Government. The authors declare no conflicts of interest. © 2019 by The National Association of Neonatal Nurses

Outcomes of Neonates With Complex Medical Needs Background: Children with complex medical needs (CMN) are high healthcare resource utilizers, have varying underlying diagnoses, and experience repeated hospitalizations. Outcomes on neonatal intensive care (NICU) patients with CMN are unknown. Purpose: The primary aim is to describe the clinical profile, resource use, prevalence, and both in-hospital and postdischarge outcomes of neonates with CMN. The secondary aim is to assess the feasibility of sustaining the use of the neonatal complex care team (NCCT). Methods: A retrospective cohort study was conducted after implementing a new model of care for neonates with CMN in the NICU. All neonates born between January 2013 and December 2016 and who met the criteria for CMN and were cared for by the NCCT were included. Results: One hundred forty-seven neonates with a mean (standard deviation) gestational age of 34 (5) weeks were included. The major underlying diagnoses were genetic/chromosomal abnormalities (48%), extreme prematurity (26%), neurological abnormality (12%), and congenital anomalies (11%). Interventions received included mechanical ventilation (69%), parenteral nutrition (68%), and technology dependency at discharge (91%). Mortality was 3% before discharge and 17% after discharge. Postdischarge hospital attendances included emergency department visits (44%) and inpatient admissions (58%), which involved pediatric intensive care unit admissions (26%). Implications for Practice: Neonates with CMN have multiple comorbidities, high resource needs, significant postdischarge mortality, and rehospitalization rates. These cohorts of NICU patients can be identified early during their NICU course and serve as targets for implementing innovative care models to meet their unique needs. Implications for Research: Future studies should explore the feasibility of implementing innovative care models and their potential impact on patient outcomes and cost-effectiveness. Correspondence: Sandesh Shivananda, MD, MSc, FRCPC, Division of Neonatology, BC Women's Hospital and Health Centre, 4500 Oak St, Room No. 1R-19, Vancouver, BC V6H 3V4, Canada (sandesh.shivananda@cw.bc.ca). The authors thank Marissa Gibbard for review of the manuscript. The authors thank all past and present members of neonatal complex care teams for their commitment, dedication, and untiring efforts to improve the care of neonates with complex medical needs. The authors thank all BCWH NICU neonatologists, house staff, allied staff, and point-of-care providers, senior executives as well as BC Children's Hospital subspecialists for encouragement and support while implementing the complex care team model. All authors have no conflicts of interest to disclose. 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 Web site (www.advancesinneonatalcare.org). © 2019 by The National Association of Neonatal Nurses

Use of Potassium Hydroxide (KOH) Test Reduces Antifungal Medication Prescription for Suspected Monilial Diaper Dermatitis in the Neonatal Intensive Care Unit: A Quality Improvement Project Background: Despite availability of rapid fungal potassium hydroxide (KOH) tests, many care providers rely on visual assessment to determine the diagnosis of monilial diaper dermatitis (MDD). Purpose: To determine whether a KOH test, when MDD is suspected, would result in more accurate diagnoses, with decreased antifungal medication prescription and exposure. Methods: Quality improvement project from 2016 through 2017 with protocol implemented in 2017 for treatment of MDD after positive KOH testing. If monilial rash suspected, after 2 negative KOH tests, then antifungal ordered (considered false negative). χ2 testing and cost determination were performed. Sample: Neonates in 2 level III neonatal intensive care units. Outcome Variables: KOH test results, use of antifungal medication, and cost. Results: The patient census included 1051 and 1015 patients in the year before and after the protocol initiation. The medical orders for antifungal medication decreased from 143 to 36 (P < .001; 95% odds ratio confidence interval, 2.24-4.38). There was a 75% reduction in both use and cost, as charged, of antifungal agents. Overall charges, including KOH test costs, decreased by 12%. Three infants received multiple negative KOH tests, then a positive one. These met the definition of false-negative tests, per protocol. There were no cases of fungal sepsis. Implications for Practice: Use of a quality improvement protocol, in which the use of KOH testing is required, before antifungal agents are prescribed, results in decreased exposure and costs. Implications for Research: To test the feasibility of bedside "point-of-care" KOH testing, and whether KOH testing and reduced antifungal medication use affects antimicrobial resistance or invasive fungal sepsis. Correspondence: Elena Bosque, PhD, ARNP, NNP-BC, Department of Neonatology, Seattle Children's Hospital, PO Box 5371/M1-12, Seattle, WA 98145 (elena.bosque@seattlechildrens.org). The authors declare no conflicts of interest. © 2019 by The National Association of Neonatal Nurses

ZAP-VAP: A Quality Improvement Initiative to Decrease Ventilator-Associated Pneumonia in the Neonatal Intensive Care Unit, 2012-2016 Background: Ventilator-associated pneumonia (VAP) is the second most frequent hospital-acquired infection in neonatal intensive care units (NICUs) and significantly affects neonatal morbidity and mortality. The population most at risk for VAP are extremely preterm infants. Purpose: The objectives of this quality improvement project were to create and evaluate the effectiveness of a VAP prevention bundle ("ZAP-VAP") in reducing VAP. Methods: The development of the ZAP-VAP bundle and creation of audit tools were documented. A targeted gestational age less than 29 weeks was selected for this study. Electronic medical record review was used to determine the preintervention baseline for patient outcomes. Patient medical record data were analyzed retrospectively to measure patient outcomes preimplementation. VAP rates (number of VAP cases per 1000 ventilator days) were calculated pre- and postintervention. After implementation, data were analyzed prospectively to measure patient outcomes between neonates who developed VAP and those who did not. Results: The VAP rate significantly decreased from 8.5 (2010-2011) to 2.5 (P = .0004) postintervention (2016). Median mechanical ventilation days decreased among VAP cases (47 vs 33 days) and slightly increased among non-VAP cases (19 vs 24 days) during the intervention period. Median length of stay decreased for VAP cases (136 vs 100 days) but remained unchanged for non-VAP cases (85 vs 84 days). Implications for Practice: The intervention was implemented from 2012 to 2016. The protocol was readily accepted by our neonatal intensive care unit (NICU) team through education and practice changes. ZAP-VAP is an effective and straightforward protocol that improved VAP outcomes in our level IIIB NICU. An interdisciplinary team successfully implemented this intervention for mechanically ventilated infants of all gestational ages in our unit and has been a model for these practice changes in other units and other hospitals. Implications for Research: Future studies should focus on how to create sustainable interventions to decrease VAP in NICUs and to expand the approaches to other units in our hospital and other hospitals in our city among patients at risk for VAP. Correspondence: Breanna Jacobs Pepin, APRN, CNNP, Neonatal Intensive Care Unit, Children's Minnesota, 345 North Smith Ave, St Paul, MN 55102 (Breanna.Pepin@childrensmn.org). The authors report no conflicts of interest for this project. 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 Web site (www.advancesinneonatalcare.org). © 2019 by The National Association of Neonatal Nurses

Improving the Efficiency and Effectiveness of Parent Education in the Neonatal Intensive Care Unit Background: March of Dimes partners with hospitals across the country to implement NICU Family Support (NFS) Core Curriculum, a program providing education to parents in neonatal intensive care units (NICUs) across the country. Purpose: This NFS project's goal was to increase the efficiency and effectiveness of NICU parent education by establishing consistency, improving quality, and identifying best practices. Methods/Search Strategy: A 5 topic curriculum was developed and implemented across NFS program sites. The project studied 4 main outcomes of interest related to efficiency and effectiveness: increase in parenting confidence, parent learning, knowledge change, and satisfaction. Data were collected from speakers and attendees immediately following educational sessions. Analytical approaches included descriptive statistics such as frequency, percentage, and response rate, and inferential approaches such as t test, χ2, and analysis of variance. Findings/Results: Findings suggest that the NFS Core Curriculum improved both program efficiency and effectiveness. Sessions fully implemented according to recommended strategies had better outcomes than sessions not fully implemented according to recommended strategies (P < .0001). Across the 3648 attendees at 41 sites, 77% of parents reported learning "a lot" at the session they attended and 85% of attendees reported increased confidence. Attendees also reported positive knowledge change and high satisfaction. Implications for Practice: Parent education best practices identified through this initiative can be utilized for future NFS Core Curriculum topics and potentially generalized to all NICU parent education and family education in other hospital intensive care units. Implications for Research: Content and best practices identified through this project will require regular review to ensure medical accuracy and appropriateness of best practices as the physical design of NICUs evolves. Correspondence: Lori G. Gunther, MS, March of Dimes, 1550 Crystal Dr, Ste 1300, Arlington, VA 22202 (loriggunther@gmail.com). The authors declare no conflicts of interest. © 2019 by The National Association of Neonatal Nurses

Noteworthy Professional News No abstract available

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Cardiovascular Pharmacology

Direct Oral Anticoagulants in octogenarians with atrial fibrillation: it's never too late. Abstract: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, and age is one of the strongest predictors/risk factors for ischaemic stroke in patients with AF. Elderly patients, in particular patients ≥ 80 years old, are at higher risk of both ischemic and bleeding events compared to younger patients. Vitamin K antagonists reduce the risk of ischemic stroke, especially in the elderly, but increases the bleeding risk. In addition, frequent international normalized ratio monitoring is needed, to ensure the optimal level of anticoagulation. Furthermore, vitamin K antagonists have multiple drug and food interactions. Direct oral anticoagulants have recently emerged as alternatives to Vitamin K Antagonists and are gradually increasing their popularity mainly because of their fewer drug and food interactions and ease of use. Their effectiveness and safety have been well-established in the general population but the benefit in the very elderly (≥80 years old) is still unclear. Data about the safety and the effectiveness of DOACs in patients >75 years old are available in literature, but the evidences of the use of DOACs in ≥80 years old are lacking. This review aims to give light to the differences, in terms of benefits and safety, of the DOACs in this subset of patients. Corresponding author: Dr Vincenzo Russo, Chair of Cardiology, University of Campania "Luigi Vanvitelli", Monaldi Hospital, AORN dei Colli, via Leonardo Bianchi 1, 80131 Napoli, e-mail: v.p.russo@libero.it Conflict of interests: none. Author contributions: Russo V and Carbone A designed the research, performed research and wrote the paper; Rago A, Golino P and Nigro G reviewed the paper. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Cyclodextrin ameliorates the progression of atherosclerosis via increasing HDL-C plasma levels and anti-inflammatory effects in rabbits Abstract: To investigate the therapeutic effects of cyclodextrin on the development of atherosclerosis in rabbits, we evaluated the effects of (2-hydroxypropyl)-β-cyclodextrin(HPβCD)therapy on the organ coefficient, lipid profiles, inflammatory cytokines and atherosclerotic plaques in rabbits fed a high-fat diet. Our results demonstrated that HPβCD therapy reduced plasma triglyceride levels and inflammatory cytokine levels but increased plasma high-density lipoprotein cholesterol (HDL-C) levels. HPβCD therapy produced a significant decrease in the atherosclerotic lesion area and reduced macrophage and collagen content in the lesions. The expression levels of inflammatory genes in aortic plaques were significantly reduced by HPβCD treatment, but the expression of ATP-binding cassette (ABC) transporters A1 (ABCA1) and G1 (ABCG1) in aortic plaques and livers increased significantly. HPβCD therapy may produce additional anti-atherosclerotic benefits likely via increasing HDL-C levels. Correspondence: Prof. Xiaochun Tang, E-mail: xiaochuntang@jlu.edu.cn, Tel: (86) 0431-87836175; Fax: (86) 0431-86758018 The authors report no conflicts of interest. This work was financially supported by the National atural Science Foundation of China (Grant No. 31472053 and 31572345). The Program for JLU Science and Technology Innovative Research Team (JLUSTIRT, No. 2017TD-28), the Fundamental Research Funds for the Central Universities. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Real Life Indications to Sacubitril/Valsartan Treatment in Patients with Chronic Systolic Heart Failure Objective. International guidelines recommend the introduction of sacubitril/valsartan in patients with heart failure and reduced ejection fraction who remain symptomatic despite optimal up-titrated therapy. The purpose of the following analysis is to verify the real-life eligibility for sacubitril/valsartan in a population of patients suffering from chronic heart failure, regularly monitored in a single heart failure clinic and treated according to guideline-directed medical therapy. Methods. From a total of 1070 patients regularly monitored in our HF Clinic between January-2011 and September-2017, the clinical records of 224 patients with heart failure and reduced ejection fraction on optimized guidelines directed medical therapy were retrospectively analyzed. Results. Out of 224 analyzed patients, 75 improved their ejection fraction or were asymptomatic after up-titration of guideline-directed medical therapy during follow up; 50 were not on angiotensin converting enzyme inhibitor or angiotensin receptor blocker for different reasons; 13 patients had systolic blood pressure ≤100 mmhg, so they were not eligible for sacubitril/valsartan introduction. The remaining patients were still symptomatic (NYHA ≥2) and therefore sacubitril/valsartan introduction was indicated in these 86 patients (38.4%) out of 224 enrolled. Conclusion. In patients with heart failure and reduced ejection fraction, where guideline-directed medical therapy is appropriately achieved, indication to sacubitril/valsartan treatment is around 38%. Address for correspondence: Gabriele Fragasso, MD Department of Clinical Cardiology, Heart Failure Clinic Istituto Scientifico San Raffaele, Via Olgettina 60, 20132 Milano – Italy e.mail gabriele.fragasso@hsr.it Phone: +390226437366; Fax: +390226437358 Conflicts of Interest: The Authors declare that there are no financial or other relations that could lead to a conflict of interest. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Ligustilide ameliorates the permeability of the blood-brain barrier model in vitro during oxygen-glucose deprivation injury through HIF/VEGF pathway Abstract Chuanxiong rhizome has been widely used for the treatment of cerebral vascular disease in traditional Chinese medicine. The integrity of blood-brain barrier (BBB) is closely linked to the cerebral vascular disease. The protective effects of ligustilide, the major bioactive component in Chuanxiong rhizome, on cerebral blood vessel has been reported previously, but its effects and potential mechanism on BBB has not been entirely clarified. In the current work, the effects of ligustilide on BBB permeability and the underlying molecular mechanisms had been investigated using the model of BBB established by co-culturing astrocytes and brain microvascular endothelial cells isolated from the rat brain. The ischemia-damaged model of BBB has been established with oxygen and glucose deprivation (OGD). Our results indicated that OGD significantly increased the permeability in the co-culture BBB model. This OGD-induced increase in permeability could suppress by ligustilide in a concentration dependent manner. Also, ligustilide promoted both gene and protein expression of tight junction proteins. Ligustilide suppressed the up-regulation of HIF-1α, VEGF and AQP-4 in the BBB model induced by OGD. Collectively, all results have demonstrated that ligustilide is capable of reducing the permeability of BBB in vitro model induced by OGD through HIF-1α/VEGF pathway and AQP-4, which provide a new target for the clinical application of ligustilide on BBB after stroke in future. Corresponding author: Prof. Ning Wang, Department of Pharmacy, Anhui University of Chinese Medicine, NO.1 Qian Jiang Road, Hefei, 230012, China. Tel:+86-551-68128186 Fax: + 86-0551-68129028 E-mail: wnsci123@163.com The authors report no conflicts of interest. The study was supported by the National Natural Science Foundation of China (No. 81773933, 81374005). The key projects of overseas visits of outstanding young backbone talents from universities in Anhui Province (gxfxZD2016117), Academic assistance program for the top-notch innovative talents from universities in 2017 provided by Anhui Province Office of Education (gxbjZD15). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Allopurinol administration for the prevention of contrast-induced nephropathy: a network meta-analysis with trial sequential analysis Contrast-induced nephropathy represents a major source of morbidity in patients undergoing coronary angiography. Various preventive measures have been proposed, although the optimal one remains still unknown. The aim of the present meta-analysis is to accumulate current literature knowledge and evaluate the renoprotective effects of allopurinol administration prior to contrast medium exposure. To achieve this, Medline, Scopus, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov. and Google Scholar databases were searched from inception to November 8, 2018. Statistical meta-analysis was conducted with Review Manager 5.3, TSA 0.9.5.5 and R-3.4.3. Six studies were included with a total of 918 patients. Quantitative synthesis revealed that allopurinol lead to significantly reduced incidence of contrast-induced nephropathy compared to hydration alone (OR: 0.29, 95% CI: [0.09-0.90]). Trial sequential analysis suggested that Z-curve crossed the O'Brien–Fleming significance boundaries, although required information size was not reached. Network meta-analysis indicated that allopurinol had the highest probability (81.2%) to rank as the most effective intervention compared to hydration and N-acetyl cysteine; however, significant overlap with the rest treatments was noted. In conclusion, the present meta-analysis suggests that allopurinol may represent a promising measure for the prevention of acute kidney injury following coronary angiography. Future large-scale randomized controlled trials should verify this finding, while combinations of allopurinol with other novel interventions should be evaluated in order to define the most effective strategy to be implemented in the clinical setting. Corresponding author: Ioannis Bellos, MD, 15Β, Ag. Thoma str., Athens 115 27, Greece, e-mail: bellosg@windowslive.com, Tel: 0030 6947470441 Funding: None Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Effects of low-dose sacubitril/valsartan on different stages of cardiac hypertrophy in salt-loaded hypertensive rats Background: Sacubitril/valsartan was shown to attenuate the development of cardiac hypertrophy with enhanced blood pressure (BP) reduction compared to valsartan alone in animal models. We investigated whether a low dose sacubitril/valsartan has BP-independent effects on cardiac hypertrophy and pulmonary edema using a rat model of hypertension and obesity. Methods and results: In plan 1, male SHR/NDmcr-cp rats fed normal or phased-increased high salt were treated with vehicle, 6 mg/kg sacubitril/valsartan or 3 mg/kg valsartan, for 6 months. In plan 2, after high salt loading for 6 months, drugs were administered for 4 months. Antihypertensive effects of the two drugs were similar during all study periods. In plan 1 with normal salt, there were no differences between treatments in the left ventricle weight/body weight (VW/BW), or lung weight/BW as an index of cardiac hypertrophy or pulmonary edema, respectively. These indexes were smaller in high-salt-fed rats with sacubitril/valsartan than vehicle. In plan 2, both indexes did not differ between vehicle and sacubitril/valsartan. VW/BW was lower in valsartan than sacubitril/valsartan. In plan 2, gene markers of cardiac dysfunction were upregulated by sacubitril/valsartan compared to the other groups. Conclusion: Low-dose Sacubitril/valsartan may have different effects depending on the stage of cardiac hypertrophy in rats. Corresponding author: Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Japan, E-mail: kyamamoto@geriat.med.osaka-u.ac.jp Source of funding: This study was financially supported by Novartis Pharma K.K., Japan. Sacubitril/valsartan and valsartan were provided by Novartis AG. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

ALDH2 activation inhibited cardiac fibroblast-to-myofibroblast transformation via TGF-β1/Smad signaling pathway Pathological stimulus-triggered differentiation of cardiac fibroblasts plays a major role in the development of myocardial fibrosis. Aldehyde dehydrogenase 2 (ALDH2) was reported to exert protective role in cardiovascular disease and whether ALDH2 is involved in cardiac fibroblast differentiation remains unclear. In this study, we employed transforming growth factor-β1 (TGF-β1) to induce the differentiation of human cardiac fibroblasts (HCFs) and adopted ALDH2 activator Alda-1 to verify the influence of ALDH2 on HCF differentiation. Results showed that ALDH2 activity was obviously impaired when treating HCFs with TGF-β1. Activation of ALDH2 with Alda-1 inhibited the transformation of HCFs into myofibroblasts, demonstrated by the decreased α-SMA and periostin expression, reduced HCF derived-myofibroblast proliferation, collagen production and contractility. Moreover, application of Smad2/3 inhibitor alleviated TGF-β1-induced HCF differentiation and improved ALDH2 activity, which was reversed by the application of ALDH2 inhibitor daidzin. Finally, Alda-1-induced HCF alterations alleviated neonatal rat cardiomyocyte hypertrophy, supported by the immunostaining of α-actin. To summarize, activation of ALDH2 enzymatic activity inhibited the differentiation of cardiac fibroblasts via TGF-β1/Smad signaling pathway, which might be a promising strategy to relieve myocardial fibrosis of various causes. 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. Correspondence to: Ping Guo, Qilu Hospital, Shandong University, No. 107 Wenhua Xi Road, Jinan 250012, China; Tel: +86-531-82166844; Fax: +86-531-86927544; E-mail: 13953100732@163.com. The authors declare no conflict of interest. * These authors contributed equally to this work. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Number of ECG Replicates Influences the Estimated QT Prolonging Effect of a Drug Introduction: The present analysis addressed the effect of the number of ECG replicates extracted from a continuous ECG on estimated QT interval prolongation for different QT correction formulas. Methods: For one hundred healthy volunteers, who received a compound prolonging the QT interval, 18 ECG replicates within a 3 minute window were extracted from 12-lead Holter ECGs. Ten QT correction formulas were deployed and the QTc interval was controlled for baseline and placebo and averaged per dose level. Results: The mean prolongation difference was >4 ms for single and > 2 ms for triplicate ECG measurements compared to the 18 ECG replicate mean value. The difference was <0.5ms after 14 replicates. In contrast, concentration-effect analysis was independent of replicate count and also of QT correction formula. Conclusion: The number of ECG replicates impacted the estimated QT interval prolongation for all deployed QT correction formulas. However, concentration-effect analysis was independent of both the replicate number and correction formula. Address for correspondence: Prof. dr. J. Burggraaf Centre for Human Drug Research Zernikedreef 8 2333 CL Leiden E: kb@chdr.nl T: + 31 71 5246 400F: + 31 71 5246 499 Conflict of Interest: No Funding: No Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Prognostic Impact of Angiotensin Converting Enzyme Inhibitors and Receptor Blockers on Recurrent Ventricular Tachyarrhythmias and ICD Therapies This study sought to assess the prognostic impact of treatment with angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) on recurrences of ventricular tachyarrhythmias in recipients of implantable cardioverter defibrillators (ICD). Using a large retrospective registry including consecutive ICD recipients with documented episodes of ventricular tachycardia (VT) or fibrillation (VF) from 2002 to 2016, those patients treated with ACEi/ARB were compared to patients without (non-ACEi/ARB). The primary prognostic endpoint was first recurrences of ventricular tachyarrhythmias and related ICD therapies at 5 years. Multivariable Cox regression analyses were applied within the entire cohort, and thereafter Kaplan-Meier analyses were performed in propensity-matched subgroups. A total of 592 consecutive ICD recipients were included (81% treated with ACEiARB and 19% without). Although ACEi/ARB was associated with no differences of overall recurrence of ventricular tachyarrhythmias, ACEi/ARB was especially associated with improved freedom from appropriate ICD therapy within multivariable Cox regressions (HR=0.666; p=0.043), especially in patients with index episodes of VF, LVEF <35%, coronary artery disease, secondary preventive ICDs and GFR <45 ml/min/1.73m2. In the propensity-matched sub-group, ACEi/ARB still prolonged freedom from appropriate ICD therapies (HR=0.380; 95% CI 0.193-0.747; p=0.005). In conclusion, ACEi/ARB therapy was associated with improved freedom from appropriate ICD therapies. Corresponding author: Michael Behnes, First Department of Medicine, University Medical Center Mannheim (UMM), Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. Phone: (+49) 621-383-6239; E-mail: michael.behnes@umm.de. No conflict of interest for all authors. Supported by the DZHK (Deutsches Zentrum fur Herz-Kreislauf-Forschung - German Centre for Cardiovascular Research). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The NLRP3 Inflammasome Inhibitor, OLT1177 (Dapansutrile), Reduces Infarct Size and Preserves Contractile Function After Ischemia Reperfusion Injury in the Mouse Background: Activation of the NLRP3 inflammasome is a primary driver of sterile inflammation in response to myocardial ischemia reperfusion. Pharmacologic inhibitors of the NLRP3 inflammasome are being developed. We proposed that OLT1177 (dapansutrile), a novel NLRP3 inflammasome inhibitor, could preserve myocardial function after ischemia reperfusion injury in the mouse. Methods: We used an experimental murine model of myocardial ischemia reperfusion injury through transient ligation of the left coronary artery, and measured the effects of OLT1177 (6, 60 or 600 mg/kg intraperitoneal dose) on infarct size at pathology and on systolic cardiac function at echocardiography. To simulate a clinical scenario, we investigated the time window of therapeutic intervention with OLT1177 (60 mg/kg) administered 60, 120, or 180 minutes after reperfusion. Results: OLT1177 was rapidly detectable in the plasma following intraperitoneal injection and had no effect on cardiac function in healthy mice. OLT1177 treatment at reperfusion showed significant dose-dependent reduction in infarct size (-36%, -67% and -62% for 6, 60 and 600 mg/kg, respectively; P<0.001 for linear trend, P=0.010 vs vehicle for 6 mg/kg and P<0.001 vs vehicle for 60 and 600 mg/kg) and preserved cardiac systolic function measured as LV fractional shortening (LVFS) at 24 hour and 7 days after injury (P=0.015 for 6 mg/kg and P<0.01 for 60 and 600 mg/kg). OLT1177 reduced infarct size also when given after 60 minutes of reperfusion (-71%, P<0.001 versus vehicle). Conclusion: OLT1177 (dapansutrile), a NLRP3 inflammasome inhibitor, limits infarct size and prevents LV systolic dysfunction when given within 60 minutes following ischemia reperfusion injury in the mouse. 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. Address for correspondence: Stefano Toldo, PhD Assistant Professor of Medicine Virginia Commonwealth University, VCU Pauley Heart Center, Box 980281, 1200 E. road St., Richmond, VA, 23298 - USA Stefano.toldo@vcuhealth.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Internal Medicine

Editorial M Premanath APIK Journal of Internal Medicine 2019 7(3):59-59

A sneak peek into channelopathies Pratibha Pereira APIK Journal of Internal Medicine 2019 7(3):60-61

Hyponatremia: A clinician's perspective Sudha Vidyasagar APIK Journal of Internal Medicine 2019 7(3):62-68 Hyponatremia is a commonly encountered clinical problem by all physicians. It is classified according to volume status as hypovolemic, euvolemic, or hypervolemic hyponatremia. The clinical presentation depends on the type of hyponatremia and the speed of onset. Acute hyponatremias can result in altered sensorium, convulsions, and coma, making it a medical emergency. Chronic hyponatremias can be due to drugs and several systemic illnesses. The syndrome of inappropriate secretion of antidiuretic hormone is common and can occur in several diseases as euvolemic hyponatremia. Its onset can be deceptively slow but needs attention to prevent complications. Investigations of serum and urine, osmolality and sodium, help in classification of this condition. Apart from intravenous correction with hypertonic saline, which may be urgently needed in acute hyponatremia to prevent mortality, vaptans offer an oral option in chronic hyponatremia. Care must be taken to avoid rapid correction of serum sodium, to prevent osmotic demyelination syndrome.

Medical education in India: Past, present, and future Praveen Kulkarni, K Pushpalatha, Deepa Bhat APIK Journal of Internal Medicine 2019 7(3):69-73 Medical education in global context has evolved over a period of time and so in India. With changing community needs, educational advancements and technological revolutions, we need to update the method of imparting knowledge and skills to the students. Major components of hidden curriculum like communication skills, attitude, empathy, altruism, professionalism, humanities etc need to be uncovered and delivered in a more systematic way. Ever increasing demand of doctors in the country has forced to establish new medical colleges across the country but the quality of Indian Medical Graduates produced out of them needs a lot to think and work upon. Reforms in curriculum Medical Council of India is planning to bring should be taken seriously and all efforts should be made to bring them to reality. In order to bring a competent Indian Medical Graduate in par with global standards should be the MANTRA of every medical education institution.

Secondary hypokalemic periodic paralysis: A study of a case series Vasantha Kamath, Shreyashi Ganguly, BL Avinash, V Vinodh APIK Journal of Internal Medicine 2019 7(3):74-79 Background: Periodic paralysis is a group of heterogeneous disorders of different etiologies, with episodic, short-lived, and hyporeflexic skeletal muscle weakness, with or without myotonia. There is neither sensory deficit nor loss of consciousness. They can be familial (primary) or acquired (secondary). Secondary periodic paralysis is due to demonstrably known causes. The interictal potassium level is abnormal in these cases. Hypokalemic paralysis is more common than hyperkalemic. Materials and Methods: This is a prospective observational study elucidating the clinical profile of the cases of secondary hypokalaemic periodic paralysis seen in our care over a period of 14 months. Results: In this study, we present nine patients with hypokalemic periodic paralysis, in which four were diagnosed with thyrotoxicosis and five with dengue. They were given potassium correction under judicious cardiac monitoring. Antithyroid drugs and beta-blockers were used in thyrotoxicosis. Dengue patient received adequate fluid and antipyretic cover. All the patients made complete recovery, without any neurological sequelae. Conclusion: Secondary hypokalemic periodic paralysis should always be kept in mind as a differential in the setting of acute, painless, flaccid motor paralysis, especially in young patients with no significant family history or risk factors for stroke or Guillain–Barre Syndrome. A clinician must be aware of causes of secondary periodic paralysis as recognition and diagnosis can completely prevent further attacks of periodic paralysis. Routine estimation of thyroid levels should be the initial line of investigation even if features of thyrotoxicosis are absent. In the presence of acute febrile illness, ordering serology for dengue, after ruling out thyrotoxicosis, is the preferred approach in India.

Peripheral limb ischemia with preserved pulses Sangram Biradar, S Sumangala, Manne Nagaraj APIK Journal of Internal Medicine 2019 7(3):80-81 Symmetric peripheral limb gangrene can occur with preserved arterial pulses due to the involvement of microcirculation, including small venules. Various representative disorders, including drug-induced vasculitis have been reported. Presenting a case of a 22-year-old female with symmetric ischemic changes of fingers with preserved pulses secondary to ergot alkaloid-induced secondary Raynaud's phenomena causing vasculitis. This case emphasizes on the importance of drug history and clinical examination and the need for high index of suspicion for drug-induced Raynaud's.

A case of pulmonary thromboembolism secondary to hyperhomocysteinemia Rishika Reddy, Sangram Biradar, Matta Rakesh APIK Journal of Internal Medicine 2019 7(3):82-83 Hyperhomocysteinemia (HHcy) affects hemostasis and shifts its balance in favor of thrombosis. HHcy can be a potential cause of unprovoked pulmonary thromboembolism, which may be a sole manifestation rather than typical multisystem involvement of the disease. Here, we report a rare case of a 56-year-old male presented with sudden onset of breathlessness, unexplained tachycardia, hypoxemia, who was diagnosed as a case of pulmonary embolism secondary to HHcy without any evidence of deep vein thrombosis.

An enigmatic case of pure neuritic leprosy with trophic ulcers Mohd Zeeshan Ali, Sangram Biradar, S Sumangala APIK Journal of Internal Medicine 2019 7(3):84-86 Leprosy is one of the most common diseases of peripheral nerves. In pure neuritic leprosy, skin along the distribution of the affected nerve is usually hypo-anesthetic or anesthetic, and as a rule, no classical leprosy skin lesions/patches should be present. However, depending on the severity of sensory and autonomic dysfunction, there could be a variable degree of hypo/anhidrosis, xerosis, fissuring, and ulcers along its distribution. Diagnosis of leprosy in the absence of typical dermatological features is difficult and requires histopathological confirmation using nerve biopsy. We report a case of leprosy with peripheral neuropathy without skin lesions. Nerve biopsy showed chronic inflammatory cell infiltration, epithelioid-cell granulomas, and the presence of Mycobacterium leprae on Modified Ziehl-Neelson stain. Hence, in leprosy prevalent countries like India, this form of leprosy should be thoroughly investigated, especially in patient without skin changes and presenting with trophic ulcers. It was a diagnostic challenge requiring high degree of clinical suspicion and thorough investigations.

Electrocardiographic diagnosis Suresh V Sagarad, Ashwini , Malavika Rao APIK Journal of Internal Medicine 2019 7(3):87-87

Radiological diagnosis Ragahavendra Bhat APIK Journal of Internal Medicine 2019 7(3):88-89

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com