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Developed by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies: Gregory A. Nuttall, M.D. (Chair), Rochester, Minnesota; Brian C. Brost, M.D., Rochester, Minnesota; Richard T. Connis, Ph.D., Woodinville, Washington; James S. Gessner, M.D., Chestnut Hill, Massachusetts; Chantal R. Harrison M.D., San Antonio, Texas; Ronald D. Miller, M.D., San Francisco, California; David G. Nickinovich, Ph.D., Bellevue, Washington; Nancy A. Nussmeier, M.D., Houston, Texas; Andrew D. Rosenberg, M.D., Roslyn Heights, New York; Richard Spence, M.D., Baltimore, Maryland.Click on the links below to access all the ArticlePlus for this article.Please note that ArticlePlus files may launch a viewer application outside of your web browser.PRACTICE guidelines are systematically developed recommendations that assist the practitioner and patient in making decisions about health care. These recommendations may be adopted, modified, or rejected according to clinical needs and constraints.Practice guidelines are not intended as standards or absolute requirements. The use of practice guidelines cannot guarantee any specific outcome. Practice guidelines are subject to revision as warranted by the evolution of medical knowledge, technology, and practice. They provide basic recommendations that are supported by analysis of the current literature and by a synthesis of expert opinion, open forum commentary, and clinical feasibility data.This update includes data published since the “Practice Guidelines for Blood Component Therapy” were adopted by the American Society of Anesthesiologists (ASA) in 1995; it also includes data and recommendations for a wider range of techniques than was previously addressed.Blood transfusion refers to the perioperative administration of blood and blood components (e.g. , autologous blood, allogeneic whole blood, red blood cells, fresh frozen plasma [FFP], platelets, and cryoprecipitate). Adjuvant therapies refer to drugs and techniques to reduce or prevent blood loss and the need for transfusion of allogeneic blood.The purposes of these Guidelines are to improve the perioperative management of blood transfusion and adjuvant therapies and to reduce the risk of adverse outcomes associated with transfusions, bleeding, or anemia. In addition, these Guidelines provide an update on the relative risks that cause morbidity and mortality associated with blood transfusion and adjuvant therapies.These Guidelines focus on the perioperative management of patients undergoing surgery or other invasive procedures in which significant blood loss occurs or is expected. This includes but is not limited to (1) patients undergoing cardiopulmonary bypass or cardiac surgery, urgent or emergent procedures, obstetric procedures, organ transplantation, and major noncardiac surgery; (2) patients with preexisting blood disorders or acquired deficiency secondary to massive bleeding; (3) critically ill patients; and (4) patients who elect not to undergo transfusion. Excluded from the focus of these Guidelines are neonates, infants, children weighing less than 35 kg, and nonsurgical patients.These Guidelines apply to both inpatient and outpatient surgical settings and to procedures performed in operating rooms as well as in other locations (e.g. , interventional radiology, critical care units) where blood transfusion or other adjuvant therapy is indicated. They are directly applicable to care administered by anesthesiologists and individuals who deliver care under the medical direction or supervision of an anesthesiologist. They are also intended to serve as a resource for other physicians and patient care personnel who are involved in the perioperative care of these patients.The ASA appointed a Task Force of 10 members to (1) review the published evidence, (2) obtain the opinion of a panel of consultants including anesthesiologists and nonanesthesiologist physicians concerned with perioperative blood transfusion, and (3) obtain opinions from practitioners likely to be affected by the Guidelines. The Task Force included anesthesiologists in both private and academic practices from various geographic areas of the United States, a surgeon, a pathologist specializing in transfusion medicine, an obstetrician, and two consulting methodologists from the ASA Committee on Practice Parameters.The Task Force developed the Guidelines by means of a seven-step process. First, they reached consensus on the criteria for evidence of effective blood transfusion and adjuvant therapies. Second, original published research studies from peer-reviewed journals relevant to the perioperative management of patients undergoing blood transfusions were reviewed. Third, the panel of expert consultants was asked to (1) participate in opinion surveys on the effectiveness of various perioperative management strategies and (2) review and comment on a draft of the Guidelines developed by the Task Force. Fourth, opinions about the Guideline recommendations were solicited from random samples of active members of the ASA. Fifth, the Task Force held open forums at two major national meetings to solicit input on its draft recommendations. National organizations representing specialties whose members typically care for patients undergoing perioperative transfusion were invited to participate in the open forums. Sixth, the consultants were surveyed to assess their opinions on the feasibility of implementing the Guidelines. Seventh, all available information was used to build consensus within the Task Force to finalize the Guidelines.Preparation of these Guidelines followed a rigorous methodologic process. To convey the findings in a concise and easy-to-understand fashion, these Guidelines use several descriptive terms.When sufficient numbers of studies are available for evaluation, the following terms describe the strength of the findings.The lack of scientific evidence in the literature is described by the following terms.Formal survey information is collected from consultants and members of the ASA. The following terms describe survey responses for any specified issue. Responses are solicited on a five-point scale; ranging from 1 (strongly disagree) to 5 (strongly agree), with a score of 3 being equivocal. Survey responses are summarized based on median values as follows:Preoperative evaluation of a patient for blood transfusion and adjuvant therapies includes (1) reviewing previous medical records, (2) conducting a patient or family interview, and (3) reviewing laboratory test results. Although comparative studies are insufficient to evaluate the perioperative impact of reviewing medical records or conducting a patient interview, the literature reports certain patient characteristics that may be associated with blood transfusion complications. These characteristics include, but are not limited to, congenital or acquired conditions such as factor VIII deficiency, sickle cell anemia, idiopathic thrombocytopenic purpura, and liver disease. In addition, the literature suggests that some preoperative laboratory tests (e.g. , hemoglobin, hematocrit, coagulation profile) may predict the need for blood transfusion or excessive blood loss. The consultants and ASA members strongly agree that reviewing previous medical records, interviewing the patient, and reviewing hemoglobin/hematocrit test results should be part of a preoperative evaluation.†The consultants strongly agree and the ASA members agree that a coagulation profile should be reviewed.Preoperative evaluation should include reviewing previous medical records, conducting a physical examination of the patient, and an interview of the patient or family to identify risk factors for (1) organ ischemia (e.g. , cardiorespiratory disease), which may influence the ultimate transfusion trigger for red blood cells (e.g. , hemoglobin level), and (2) coagulopathy (e.g. , use of warfarin, clopidogrel, aspirin), which may influence transfusion of non–red blood cell components. In addition, a preoperative evaluation should include checking for the presence of congenital or acquired blood disorders, the use of vitamins or herbal supplements that may affect coagulation (appendix 2), or previous exposure to drugs (e.g. , aprotinin) that may, upon repeat exposure, cause an allergic reaction. Patients should be informed of the potential risks versus benefits of blood transfusion, and their preferences elicited. Available preoperative laboratory results including, but not limited to, hemoglobin, hematocrit, and coagulation profiles should be reviewed if they are appropriate and available. Additional laboratory tests should be ordered based on a patient's condition (e.g. , clinical coagulopathy) or institutional policy.Preoperative patient preparation includes (1) discontinuation or modification of anticoagulation therapy, (2) the prophylactic administration of drugs to promote coagulation and minimize blood loss (e.g. , aprotinin, ϵ-aminocaproic acid, tranexamic acid), and (3) prevention or reduction of allogeneic transfusion requirements.The impact of discontinuing anticoagulation therapy on blood loss has not been sufficiently addressed in the literature. In addition, the literature is insufficient to address the impact of delaying surgery until the effects of anticoagulation drugs have dissipated. The literature supports the use of aprotinin in reducing blood loss and in reducing the number of patients transfused in major surgical procedures (e.g. , selected cardiac and orthopedic procedures). In addition, the literature is supportive of the use of ϵ-aminocaproic acid and tranexamic acid in reducing blood loss; however, the impact of these drugs on reducing the number of patients transfused is equivocal. The literature is insufficient to evaluate the use of these drugs in a nonprophylactic manner. Some literature has reported adverse outcomes associated with the use of antifibrinolytic drugs such as graft thrombosis or closure and rare massive thrombosis. Severe anaphylactic reactions may occur with aprotinin reexposure.The efficacy of erythropoietin in reducing the volume of allogeneic blood transfused per patient as well as reducing the number of patients requiring such transfusions is supported by the literature in select populations (e.g. , renal insufficiency, anemia of chronic disease, refusal of transfusion). The literature is insufficient to address the effects of vitamin K.The efficacy of preadmission blood collection to reduce the volume of allogeneic blood transfused per patient and to reduce the number of patients requiring such transfusions is supported by the literature. However, the literature indicates that certain adverse outcomes (e.g. , transfusion reaction due to clerical errors, bacterial contamination) may still occur with the use of autologous blood.The consultants agree and the ASA members strongly agree that anticoagulation drugs (e.g. , warfarin, clopidogrel, aspirin) should be discontinued before elective or nonemergent surgery, and both agree that such surgery should be delayed until the anticoagulation effects wear off. They agree that, when significant blood loss is expected, antifibrinolytics should be administered. In addition, the consultants and ASA members agree that erythropoietin may be used to reduce the use of allogeneic blood. They agree that vitamin K should be administered preoperatively for reversal of warfarin to potentially avoid transfusion of FFP. The ASA members agree and the consultants are equivocal that preadmission donation of blood should be offered to patients when transfusion of autologous blood is required or preferred. They disagree that autologous blood should be administered to the patient who donated it if his or her hemoglobin is greater than 10 g/dl.If possible, the preoperative evaluation should be done well enough in advance to correct or plan for the management of risk factors associated with transfusions. For elective surgery, patient preparation should include discontinuing anticoagulation therapy for a sufficient time in advance of surgery, if clinically possible. If sufficient time has not elapsed, surgery should be delayed until the effects of these drugs dissipate. The Task Force notes that the effect of clopidogrel may last for approximately a week, and the effects of warfarin may last for several days depending on patient response and the administration of reversal agents (e.g. , vitamin K, prothrombin complex concentrate, recombinant activated factor VII, or FFP). The risk of thrombosis versus the risk of increased bleeding should be considered when altering anticoagulation status. Assure that blood and blood components are available for patients when significant blood loss or transfusion is expected.Antifibrinolytic therapy should not be routinely administered. However, such therapy may be used for reducing the volume of allogeneic blood transfused for patients at high risk of excessive bleeding (e.g. , repeat cardiac surgery). The risks and benefits of instituting antifibrinolytic therapy should be assessed on a case-by-case basis.Erythropoietin should be administered when possible to reduce the need for allogeneic blood in certain selected patient populations (e.g. , renal insufficiency, anemia of chronic disease, refusal of transfusion). The Task Force recognizes that erythropoietin administration is perceived as being expensive and requires time (in weeks) to induce a significant increase in hemoglobin concentration. Vitamin K or another warfarin antagonist should be used for reversal of warfarin to potentially avoid transfusion of FFP.Where autologous blood is required or preferred, the patient may be offered the opportunity to donate blood before However, the Task Force that preoperative anemia may be in to an increase in autologous or allogeneic transfusions, as well as and include red blood cell transfusion, management of and and of adverse effects of and management of potential or blood loss includes (1) the of blood (2) hemoglobin or hematocrit, (3) for the presence of and of (e.g. , blood blood and (4) transfusion of allogeneic red blood cells or autologous blood , and red blood cell literature is insufficient to evaluate the efficacy of specific or techniques for the presence of or of or as for the transfusion of red blood The literature supports the efficacy of as well as red blood cell in reducing the number of allogeneic transfused per patient in certain appropriate surgical procedures (e.g. , cardiac surgery, liver surgery, orthopedic However, the literature is equivocal the of to reduce the number of patients Although the practice is in the United States, the literature suggests that red blood cell reduce the number of patients a volume of that has been published since the last practice the information to when a blood transfusion should be is not available in the literature. Although have transfusion on patient the literature is insufficient to a transfusion trigger in surgical patients with blood consultants and ASA members strongly agree that a of the surgical and with the surgical should be done to assess the presence of excessive bleeding , The consultants and ASA members strongly agree that for the presence of and of should be They strongly agree that red blood cells should be administered when the hemoglobin is less than and strongly agree that red blood cells are when the is than 10 In addition, the consultants and ASA members agree that, when autologous blood is required or preferred, and or red blood cell are The consultants are equivocal and the ASA members agree that red blood cell is a in or allogeneic transfusion. they agree that and other laboratory may be a of significant blood of the surgical should be to assess the presence of excessive bleeding , for of blood loss (e.g. , and should be (e.g. , blood should be used to assess the of and of should be used when appropriate (e.g. , blood hemoglobin or when blood loss or any of organ ischemia blood cells should be administered when the hemoglobin is (e.g. , less than in a when the anemia is blood cells are when the hemoglobin is than 10 These may be in the presence of blood loss. The of hemoglobin , or red blood cell transfusion should be based on any of organ potential or bleeding and the patient's volume and the patient's risk factors for of These risk factors include a cardiopulmonary and high volume and blood with or until the criteria for red blood cell transfusion are of red blood cells should be transfused to organ or blood and other means to blood loss (e.g. , may be may also be and management of potential or coagulopathy includes (1) of the surgical and laboratory for (2) transfusion of platelets, (3) transfusion of (4) transfusion of administration of drugs to excessive bleeding (e.g. , and recombinant activated factor of the surgical is practice and of the presence of bleeding and the of blood includes or In a bleeding patient, coagulation tests is also and the literature suggests that coagulation test results with perioperative blood depending on the of used for volume The literature supports the use of and to excessive Although are insufficient numbers of published clinical the efficacy of recombinant activated factor in excessive bleeding , reports its efficacy as a when therapy has a volume of that has been published since the last practice the information to when transfusion of a blood should occur is not available in the literature. Although have transfusion on patient and transfusion in cardiac surgery, the literature is insufficient to specific transfusion for coagulopathy in surgical patients with blood consultants and ASA members strongly agree that, in to a of the surgical with the surgical should include an of the presence of The consultants and ASA members agree that, in a bleeding patient, should be administered when the is below They also agree that, in a bleeding patient, should be administered when or activated time is and that should be when are less than The consultants agree and the ASA members are equivocal that recombinant activated factor is an appropriate when have been The ASA members agree and the consultants are equivocal that should be administered when excessive bleeding the consultants and ASA members agree that (e.g. , or should be administered for the of excessive of the surgical should be by the and to excessive bleeding , coagulopathy) is for excessive blood loss should also include checking surgical and surgical for coagulopathy should include of prothrombin time or and tests may include of and possible, a should be before transfusion of in a bleeding patient, and a test of should be done in patients with or (e.g. , In surgical or obstetric patients with transfusion is if the is to be greater than and is when the is below in the presence of excessive or procedures associated with limited blood loss may be performed in patients with less than transfusion may be an if is or (e.g. , the presence of cardiopulmonary and of patients with and therapy, including prophylactic therapy, should be based on the potential for or bleeding, and the risk of bleeding a (e.g. , or the cannot be done in a in the presence of excessive bleeding , may be when is is due to increased (e.g. , idiopathic thrombocytopenic purpura, thrombocytopenic prophylactic transfusion is and possible, coagulation tests , or and should be before the administration of in a bleeding Transfusion of is not if and are transfusion is for (1) of excessive bleeding , coagulopathy) in the presence of a greater than or greater than or an greater than (2) of excessive bleeding secondary to coagulation factor deficiency in patients transfused with than blood volume and when or and cannot be in a (3) urgent reversal of warfarin (4) of coagulation factor for which specific are or in a patient requiring is not for of plasma volume or frozen plasma should be in to a of of plasma factor with administration of for urgent reversal of warfarin for which to 1 platelets, or 1 fresh whole a of coagulation factors to that in 1 possible, a should be before the administration of in a bleeding Transfusion of is if is greater than Transfusion of is (1) when the is less than in the presence of excessive bleeding, (2) to correct excessive bleeding in transfused patients when cannot be in a fashion, and (3) for patients with congenital possible, decisions patients with congenital should be in with the patient's The of patients with and therapy should be based on the potential for or bleeding and the risk of bleeding a (e.g. , or patients with should be with specific if available. If are not is indicated. of of it should be that of the of as or such as or should be considered when excessive bleeding for excessive bleeding , coagulopathy) have been recombinant activated factor should be effects of transfusions include, but are not limited to, bacterial of and transfusion of blood platelets, is the cause of from blood transfusions. The increased risk of bacterial is to a of blood are their If a patient a within platelets, from may be a is from of certain a transfusion. and transfusion and are in within and in the may is specific therapy other than transfusion and instituting critical care supportive patients in is of the of transfusion major adverse effect of transfusion therapy is the of For the and deficiency were allogeneic blood These risks are of the major for the in has been the use of acid The and be by this To disease, and cannot be may the of both and transfusion of reactions include and bleeding, but these may be to other in the The of a transfusion reaction in patients include or However, these may not be consultants and ASA members strongly agree that checking for and of a transfusion reaction should be done in the The consultants agree and the ASA members strongly agree that and should be the consultants and ASA members agree that should be assessed to for transfusion for and of bacterial and transfusion including increased and instituting therapy for transfusion the blood transfusion and appropriate scientific of these Guidelines was based on evidence or potential clinical and The below were to assess their impact on a of outcomes to perioperative blood transfusion and adjuvant they are not included in the focus of these areas of research include (1) the use of to improve making and reduce transfusion and (2) or other blood to reduce transfusion requirements. evidence was from research and evidence was from open and other (e.g. , For purposes of literature potentially relevant clinical studies were and of the literature. The and a from than were a of that addressed to the evidence review of the studies not provide evidence and were of reported in a was as an evidence a or equivocal. The results were summarized to obtain a for evidence before conducting a to evidence enough studies with and information sufficient for These were (1) erythropoietin versus (2) preadmission blood donation versus autologous blood (3) antifibrinolytics ϵ-aminocaproic acid tranexamic acid (4) transfusion of autologous blood red blood cell and versus or tests were for and were for tests were as (1) the values based on of the reported values from the and (2) the of the studies by of the by the of the based on the for results was used with was at for of the studies were to the results. were when significant was To for potential a was for studies was and tests for research results were results are reported in To be as significant agree with test results both of data are In the of findings from both the and tests agree with other to be as Task Force members and two methodologists was by a for were as (1) of (2) of (3) evidence and (4) literature for values were (1) (2) of (3) and (4) literature These values to high of was from including (1) survey opinion from consultants who were selected based on their or in perioperative blood transfusion and adjuvant (2) survey opinions from a selected of active members of the (3) from of two held open forums at two national commentary, and Task Force opinion and The survey of was of for and of for of the surveys are reported in and in the of the consultants were asked to if of the evidence their clinical practices if the Guidelines were The of was of The of consultants associated with were as preoperative discontinuation of anticoagulation and of drugs to perioperative drugs to promote coagulation and minimize blood preoperative autologous blood for and for transfusion transfusion of allogeneic red blood transfusion of autologous transfusion of transfusion of transfusion of of excessive and and laboratory for transfusion of the that the Guidelines have effect on the of time on a that be an increase in the of time they on a with the of these Guidelines. The of increased time by these from 5 to 10

Journal of Palliative MedicineVol. 3, No. 1 Innovations in End-of-Life CareTaking a Spiritual History Allows Clinicians to Understand Patients More FullyDr. Christina Puchalski and Anna L. RomerDr. Christina Puchalski and Anna L. RomerPublished Online:19 Apr 2005https://doi.org/10.1089/jpm.2000.3.129AboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byVerbalizing spiritual needs in palliative care: a qualitative interview study on verbal and non-verbal communication in two Danish hospices4 January 2022 | BMC Palliative Care, Vol. 21, No. 1Implementation of an Educational Toolkit to Increase Nurse Competence in Spirituality and Spiritual Care of Oncology Patients8 November 2022 | Journal of Holistic Nursing, Vol. 5Posicionamento sobre a Saúde Cardiovascular nas Mulheres – 2022Arquivos Brasileiros de Cardiologia, Vol. 119, No. 5Experiences of German health care professionals with spiritual history taking in primary care: a mixed-methods process evaluation of the HoPES3 intervention15 October 2022 | Family Practice, Vol. 29Religious and spiritual journeys of LGBT older adults in rural Southern Appalachia25 October 2021 | Journal of Religion, Spirituality & Aging, Vol. 34, No. 4The CASH assessment tool: A window into existential suffering19 May 2021 | Journal of Health Care Chaplaincy, Vol. 28, No. 4Integrating religion/spirituality into professional social work practice27 July 2022 | Journal of Religion & Spirituality in Social Work: Social Thought, Vol. 41, No. 4The Concept of Spirituality in the Health Sector: Contributions from the Study of Religion27 September 2022 | International Journal of Latin American Religions, Vol. 12Systematic review: The relationship between religion, spirituality and mental health in adolescents who identify as transgender13 September 2022 | Journal of Gay & Lesbian Mental Health, Vol. 26„Des Lebens Ruf an uns wird niemals enden“ – Sinnzentrierte Interventionen im Überblick30 August 2022 | Zeitschrift für Palliativmedizin, Vol. 23, No. 05Case discussion: The critically ill older adult in spiritual distressGeriatric Nursing, Vol. 47Australian Patient Preferences for the Introduction of Spirituality into their Healthcare Journey: A Mixed Methods Study3 August 2022 | Journal of Religion and Health, Vol. 27Religion, Spirituality, and Ethics in Psychiatric Practice30 March 2022 | Journal of Nervous & Mental Disease, Vol. 210, No. 8Spiritual distress in dialysis: A case report21 July 2022 | Progress in Palliative Care, Vol. 211Interprofessional communication training to address spiritual aspects of cancer care19 July 2022 | Journal of Health Care Chaplaincy, Vol. 29Spirituality in Serious Illness and HealthJAMA, Vol. 328, No. 2What is the role of spiritual care specialists in teaching generalist spiritual care? 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September | Journal of Palliative Medicine, Vol. 20, No. in Patients with A Qualitative September | Journal of Research in Nursing and Vol. 14, No. theory on the and in an exploratory case study September | Vol. 69, No. of the of Spirituality and Palliative Care Research and of Pain and Symptom Management, Vol. No. of a spiritual care training program for staff on November | Palliative and Supportive Care, Vol. 15, No. 4Spiritual distress and spiritual care in advanced heart July | Reviews, Vol. and Spiritual Patient Simulation in Nursing, Vol. No. Vol. 42, No. 4The impact of a spiritual in patients with and and their support December | Vol. 26, No. 3The Importance of a Spiritual History in Healthcare Vol. No. About Substance Use DisordersJournal of Psychosocial Nursing and Mental Health Services, Vol. No. and Spiritual Beliefs of April | Journal of Religion and Health, Vol. No. Care Perceptions of and With of Hospice & Palliative Nursing, Vol. 19, No. in Substance Use What to Know to Practice30 November | in Mental Health Nursing, Vol. 38, No. End-of-Life Care to Religious and Vol. No. of Social Education, Vol. 53, No. Nursing Care and of Christian Nursing, Vol. 34, No. 1The of taking a religious and spiritual July | Psychiatry, Vol. 24, No. religion and spirituality in Vol. No. the role of religious in the at the of of Vol. No. care spiritual March | Supportive Care in Cancer, Vol. 24, No. Spiritual Care and the Role of An Review of Literature and April | Journal of Religion and Health, Vol. No. of the Spiritual Needs of of with Is in the June | Journal of Palliative Medicine, Vol. 19, No. Impact of a Tool for Comprehensive Assessment of Palliative Care on Assessment at and of Pain and Symptom Management, Vol. No. from Healthcare Students to Understand Spiritual Assessment in Clinical Practice29 October | Journal of Religion and Health, Vol. No. Spirituality in January | Journal of Religion and Health, Vol. No. 3Development and of to Assess Nurse Provision of Spiritual August 2014 | Journal of Holistic Nursing, Vol. 34, No. and Validation of the Practice Assessment September 2014 | Research on Social Practice, Vol. 26, No. and the Medical A of July | Journal of Health Care Chaplaincy, Vol. 22, No. history taking in palliative care: A controlled September | Palliative Medicine, Vol. 30, No. Is Is Using A and the Life With American in Spiritual March | Journal of in Mental Health, Vol. 11, No. and spiritual in September | International Journal of and Mental Health, Vol. No. 1The of Hospital to and Patients’ Spiritual A May | Journal for the Study of Spirituality, Vol. No. 1The and to March End-of-Life Spiritual March in Holistic Patient Journal of Nursing, Vol. No. of spiritual assessment for older September 2014 | and Vol. No. und der der Care, Vol. No. Spirituality and A for Holistic January | Journal of Religion and Health, Vol. No. and Belief, in Care spiritual history tool by C. M. Puchalski as an for an interdisciplinary in January | Journal for of and Social Vol. 21, No. the of Spiritual A Pain and Palliative Care Service Quality of Pain and Symptom Management, Vol. No. of Spiritual Assessment in September | Vol. No. the of Christian Nursing, Vol. 32, No. 4Spiritual care: is the assessment tool for palliative Journal of Palliative Nursing, Vol. 21, No. und Spiritualität in der September | Vol. 60, No. of September of spirituality assessment in palliative care patients in November 2014 | Progress in Palliative Care, Vol. 23, No. 4The for Spiritual A Mixed-Methods July | Oncology Nursing Vol. 42, No. 4The Integration of Religion and Spirituality in Social Practice: A May | Social Vol. 60, No. 3The and Educational of a Spiritual Life Review for Patients with and June 2014 | Journal of Cancer Education, Vol. 30, No. in Geriatric Palliative in Geriatric Medicine, Vol. No. An for Spiritual Well-Being May | Journal of Religion & Spirituality in Social Work: Social Thought, Vol. 34, No. Spiritual Assessment March | Journal of Health Care Chaplaincy, Vol. 21, No. American on Mental Health, and Help April | and Vol. 60, No. of Christian Nursing, Vol. 32, No. the Spiritual Needs and of Oncology Patients in Nursing Practice, Vol. 29, No. Care Training to Healthcare Professionals: A Systematic April | Journal of Pastoral Care & Counseling: Advancing theory and professional practice through scholarly and reflective publications, Vol. 69, No. analysis of spiritual

Brief Report15 September 1991Postmenopausal Estrogen and Prevention BiasElizabeth Barrett-Connor, MDElizabeth Barrett-Connor, MDAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-115-6-455 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptIn the last decade many investigators reported that postmenopausal women taking estrogen were at reduced risk for cardiovascular disease compared with women not taking estrogen (1). Many clinicians in the United States now believe that replacement estrogen prevents heart disease. The results are fairly consistent and biologically plausible. Replacement estrogen lowers low-density lipoprotein (LDL) cholesterol and raises high-density lipoprotein (HDL) cholesterol (2) and may also lower blood pressure, blood glucose, and plasma insulin (3). If estrogen does prevent heart disease, the quantitative benefit would far exceed any known or postulated adverse events, including cancer (4).Observational studies suffer from several...References1. Barrett-ConnorBush ET. Estrogen and coronary heart disease in women. JAMA. 1991;265:1861-7. CrossrefMedlineGoogle Scholar2. TikkanenNikkiläVartiainen MEE. Natural oestrogen as an effective treatment for type-II hyperlipoproteinaemia in postmenopausal women. Lancet. 1978;2:490-1. CrossrefMedlineGoogle Scholar3. Barrett-Connor E. Putative complications of estrogen replacement therapy: hypertension, diabetes, thrombophlebitis, and gallstones. In: Korenman SG, ed. The Menopause. Norwell, Massachusetts: Serono Symposia; 1990:199-209. Google Scholar4. ErnsterBushHugginsHulkaKelseySchottenfeld VTGBJD. Benefits and risks of menopausal estrogen and/or progestin hormone use. Prev Med. 1988;17:201-23. CrossrefMedlineGoogle Scholar5. CauleyCummingsBlackMascioliSeeley JSDSD. Prevalence and determinants of estrogen replacement therapy in elderly women. Am J Obstet Gynecol. 1990;163:1438-44. CrossrefMedlineGoogle Scholar6. Barrett-ConnorWingardCriqui EDM. Postmenopausal estrogen use and heart disease risk factors in the 1980s. JAMA. 1989;261:2095-100. CrossrefMedlineGoogle Scholar7. Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project. New Engl J Med. 1980;303:1038-41. CrossrefMedlineGoogle Scholar8. HorwitzViscoliBerkmanDonaldsonHorwitzMurray RCLRSC. Treatment adherence and risk of death after a myocardial infarction. Lancet. 1990;336:542-5. CrossrefMedlineGoogle Scholar9. BergkvistAdamiPerssonHooverSchairer LHIRC. The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl J Med. 1989;321:293-7. CrossrefMedlineGoogle Scholar10. BergkvistAdamiPerssonBergstromKrusemo LHIRU. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol. 1989;130:221-8. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: From the University of California, San Diego; La Jolla, California. For the current author address, see end of text. 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A follow-up study among 1689 women aged 45–60 yearsEffects of estrogens on lipoprotein metabolism and cardiovascular disease in womenDo women taking hormone replacement therapy have a higher uptake of screening mammograms?CALCIUM, ESTROGEN, AND PROGESTIN IN THE TREATMENT OF OSTEOPOROSISPostmenopausal estrogen replacement: A long-term cohort studyImpact of the menopause on the epidemiology and risk factors of coronary artery heart disease in womenPostmenopausal estrogen and the risk of breast cancerCorrelates of Impaired Function in Older WomenHormonal Treatment of Postmenopausal WomenHormonal treatment for the climacteric: alleviation of symptoms and prevention of postmenopausal diseaseCoronary heart disease, the menopause, and hormone replacement therapy.Epidemiologic Studies on Ert and Cardioprotection: State of the Art on HRT and Cardiovascular DiseaseSex steroids and lipoprotein metabolismHormone replacement therapy: the need for reconsideration.Editor's note: Estrogen therapy for the prevention of coronary heart disease: What are the facts?Endocrine disordersThe Menopause: Health Implications and Clinical ManagementGender, Health, and Responsible ResearchThe epidemiology of osteoporosis5 Oestrogens and atherosclerotic vascular disease—lipid factors6 Epidemiological overview of oestrogen replacement and cardiovascular disease7 Hormone replacement therapy and cancerWinner of the Young Clinical investigater Manuscript Award: Hysterectomy Status and Preventive Health Behaviors in Older WomenPostmenopausal hormone replacement therapy.Do current regimes of hormone replacement therapy protect against subsequent fractures?The Prevention and Treatment of OsteoporosisEstrogen Therapy for Osteoporosis—Even in the ElderlySusan M. Ott, MDSafety of post-menopausal hormone replacementPostmenopausal Estrogen Therapy and Cardiovascular DiseasePostmenopausal Estrogen and Prevention BiasMaryann NapoliEvidence-Based Medicine and GeriatricsSpezielle therapeutische Probleme im höheren AlterPromoting Informed Decision Making: Hormone Replacement TherapyA Summary of the Evidence Relating Postmenopausal Hormone Use and Large Bowel Cancer Risk 15 September 1991Volume 115, Issue 6Page: 455-456KeywordsBlood plasmaCardiovascular therapyCholesterolEstrogensGlucoseHigh density lipoproteinInsulinLow density lipoproteinObservational studiesRisk management Issue Published: 15 September 1991 PDF DownloadLoading ...

* Developed by the American Society of Anesthesiologists Task Force on Perioperative Transesophageal Echocardiography: Daniel M. Thys, M.D., Chair, New York, New York; Martin D. Abel, M.B.B.Ch., Rochester, Minnesota; Robert F. Brooker, M.D., Wausau, Wisconsin; Michael K. Cahalan, M.D., Salt Lake City, Utah; Richard T. Connis, Ph.D., Woodinville, Washington; Peggy G. Duke, M.D., Atlanta, Georgia; David G. Nickinovich, Ph.D., Bellevue, Washington; Scott T. Reeves, M.D., Charleston, South Carolina; Marc A. Rozner, Ph.D., M.D., Houston, Texas; Isobel A. Russell, M.D., San Francisco, California; Scott C. Streckenbach, M.D., Boston, Massachusetts; Pamela Sears-Rogan, M.D., Washington, DC (American Society of Echocardiography); and William J. Stewart, M.D., Cleveland, Ohio (American College of Cardiology).PRACTICE Guidelines are systematically developed recommendations that assist the practitioner and the patient in making decisions about health care. These recommendations may be adopted, modified, or rejected according to clinical needs and constraints and are not intended to replace local institutional policies. In addition, Practice Guidelines developed by the American Society of Anesthesiologists (ASA) are not intended as standards or absolute requirements, and their use cannot guarantee any specific outcome. Practice Guidelines are subject to revision as warranted by the evolution of medical knowledge, technology, and practice. They provide basic recommendations that are supported by a synthesis and analysis of the current literature, expert and practitioner opinion, open forum commentary, and clinical feasibility data.This update includes data published since the Practice Guidelines for Perioperative Transesophageal Echocardiography were adopted by the ASA and the Society of Cardiovascular Anesthesiologists in 1995 and published in 1996.1For these Guidelines, perioperative transesophageal echocardiography (TEE) refers to TEE performed on surgical patients before, during, or immediately after surgery, including the critical care setting. Evidence of effectiveness is discussed relative to specific settings where perioperative TEE is customarily used (e.g. , cardiac surgery, noncardiac surgery, and critical care).The purposes of these Guidelines are (1) to assist the physician in determining the appropriate application of TEE and (2) to improve the outcomes of surgical patients by defining the utility of perioperative TEE based on the strength of supporting evidence.These Guidelines focus on the application of TEE in surgical patients and potential surgical patients in the setting of cardiac surgery, noncardiac surgery, and postoperative critical care. The Guidelines do not apply to the assessment of nonsurgical patients or to postdischarge follow-up assessment of surgical patients.The Task Force believes that physician proficiency in the use of perioperative TEE is of paramount importance due to the risk of adverse outcomes resulting from incorrect interpretation. The Guidelines do not address training, certification, credentialing, and quality assurance, which are addressed elsewhere.2–5These Guidelines are intended for anesthesiologists and other physicians (e.g. , cardiologists, surgeons, and intensivists) who use TEE in the perioperative setting. Recommen- dations to perform TEE are not applicable when the procedure cannot be performed properly or safely nor do they apply when TEE equipment or skilled examiners are unavailable. The recommendations in this report are based on consideration of the risk benefit ratio for individual patients.The ASA and Society of Cardiovascular Anesthesiologists jointly appointed a task force of 13 members, including anesthesiologists in both private and academic practice from various geographic areas of the United States, two cardiologists (one representing the American College of Cardiology and the other representing the American Society of Echocardiography), and two consulting methodologists from the ASA Committee on Standards and Practice Parameters.The Task Force developed the Guidelines by means of a seven-step process. First, they reached consensus on the criteria for evidence. Second, original published research studies from peer-reviewed journals relevant to TEE were reviewed and evaluated. Third, expert consultants were asked (1) to participate in opinion surveys on the effectiveness of TEE imaging and (2) to review and comment on a draft of the Guidelines developed by the Task Force. Fourth, opinions about the Guidelines recommendations were solicited from a sample of active members of the ASA who personally perform TEE as a part of their practice. Fifth, the Task Force held an open forum at a major international meeting†to solicit input on its draft recommendations. Sixth, the consultants were surveyed to assess their opinions on the feasibility of implementing the Guidelines. Seventh, all available information was used to build consensus within the Task Force to finalize the Guidelines (appendix 1).Preparation of these Guidelines followed a rigorous methodologic process (appendix 2). Evidence was obtained from two principal sources: scientific evidence and opinion-based evidence.Study findings from scientific literature published after 1994 (not excluding sentinel articles published prior to 1994) were aggregated and reported in summary form by evidence category, as described later. All literature (e.g. , randomized controlled trials, observational studies, and case reports) relevant to each topic was considered when evaluating the findings. For reporting purposes in this document, only the highest level of evidence (i.e. , levels 1, 2, or 3 identified below) within each category (i.e. , A, B, or C) is included in the summary.Randomized controlled trials report statistically significant (P < 0.01) differences between clinical interventions for a specified clinical outcome.Information from observational studies permits inference of beneficial or harmful relationships among clinical interventions and clinical outcomes.The literature cannot determine whether there are beneficial or harmful relationships among clinical interventions and clinical outcomes.The lack of scientific evidence in the literature is described by the following conditions.All opinion-based evidence relevant to each topic (e.g. , survey data, open-forum testimony, Internet-based comments, letters, and editorials) was considered in the development of these Guidelines. However, only the findings obtained from formal surveys are reported.Opinion surveys were developed by the Task Force to address each clinical intervention identified in the document. Identical surveys were distributed to two groups of respondents: expert consultants and ASA members.Survey responses from Task Force–appointed expert consultants are reported in summary form in the text. A complete listing of consultant survey responses is reported in a table in appendix 2.Survey responses from a sample of members of the ASA are reported in summary form in the text. A complete listing of ASA member survey responses is reported in a table in appendix 2.Expert consultant and ASA membership survey responses are recorded using a 5-point scale and summarized based on median values.§Open-forum testimony, Internet-based comments, letters, and editorials are all informally evaluated and discussed during the development of Guidelines recommendations. When warranted, the Task Force may add educational information or cautionary notes based on this information.Cardiac and thoracic aortic procedures consist of cardiac and thoracic aortic surgery, and catheter-based intracardiac procedures.Cardiac and thoracic aortic surgery: For cardiac or thoracic aortic surgery patients, the literature reports variations in sensitivity, specificity, or positive and negative predictive values for the detection of abnormalities relating to valvular, coronary, aortic, congenital, and other cardiovascular disease (table 1in appendix 2). Examples of these abnormalities include mitral valve abnormalities, valvular abscesses, myocardial ischemia, aortic dissection, and atrial septal defect (Category B2 evidence ). The literature also reports a range of sensitivity, specificity, and positive and negative predictive values for the confirmation or refinement by TEE of the preoperative diagnosis (table 1in appendix 2). Examples include aortic dissection, aortic intramural hemorrhage, and valvular or mural infective endocarditis lesions (Category B2 evidence ). The ASA members agree and the consultants strongly agree that TEE should be used for all cardiac or thoracic aortic surgery patients.For adult patients without contraindications, TEE should be used in all open heart (e.g. , valvular procedures) and thoracic aortic surgical procedures and should be considered in coronary artery bypass graft surgeries to: (1) confirm and refine the preoperative diagnosis, (2) detect new or unsuspected pathology, (3) adjust the anesthetic and surgical plan accordingly, and (4) assess the results of surgical intervention. In small children, the use of TEE should be considered on a case-by-case basis because of risks unique to these patients (e.g. , bronchial obstruction).Catheter-based intracardiac procedures: Studies with observational findings confirm the utility of TEE or intracardiac echocardiography for guiding management of catheter-based intracardiac procedures (e.g. , occluder device placement, percutaneous valvular procedures, and intracardiac ablation procedures) (Category B2 evidence ). In addition, studies with observational findings report the detection of unsuspected abnormalities by TEE, such as aortic root abscess, atrial thrombi, atrial septal aneurysm, shunting, mitral valve/annular calcification and regurgitation, wall motion abnormalities, and tamponade (Category B2 evidence ). The detection of pericardial effusion is also reported (Category B3 evidence ).Both the consultants and ASA members agree that TEE should be used for patients undergoing transcatheter intracardiac procedures when general anesthesia is provided and intracardiac ultrasound is not used. The ASA members agree and the consultants strongly agree that TEE should be used for septal defect closure or atrial appendage obliteration. Both the consultants and ASA members strongly agree that TEE should be used during catheter-based valve replacement and repair. Finally, both the consultants and ASA members are equivocal regarding the use of TEE during dysrhythmia treatment.For patients undergoing transcatheter intracardiac procedures, TEE may be used.For noncardiac surgery patients, studies with observational findings or case reports note the detection of the following abnormalities by TEE: (1) venous air embolism and patent foramen ovale in neurosurgery (Category B2 evidence ); (2) pericardial effusion and compression of the cardiac chambers in liver transplantation (Category B3 evidence ); (3) intracardiac emboli and patent foramen ovale (Category B2 evidence ), mitral regurgitation, left ventricular hypertrophy, and left ventricular outflow tract obstruction in orthopedic surgery (Category B3 evidence ), (4) left ventricular segmental wall motion abnormalities (Category B2 evidence ), aortic lesions and atrial tumors in vascular surgery (Category B3 evidence ), and (5) atrial septal defect, myocardial ischemia, hypovolemia, pericardial tamponade, thromboembolic events (Category B2 evidence ), pericardial effusion, tamponade, and intrapulmonary emboli in other major surgery (i.e. , lung, renal, abdominal, and head/neck/chest wall surgeries) (Category B3 evidence ).The consultants and ASA members agree that TEE should be used for noncardiac surgical patients when the patient has known or suspected cardiovascular pathology that might result in hemodynamic, pulmonary, or neurologic compromise. The consultants and ASA members both strongly agree that TEE should be used during unexplained persistent hypotension. Further, both the consultants and ASA members agree that TEE should be used when persistent unexplained hypoxemia occurs. The ASA members agree and the consultants strongly agree that TEE should be used when life-threatening hypotension is anticipated.Both the consultants and ASA members agree that TEE should be used during either lung transplantation or major abdominal or thoracic trauma. The consultants agree although the ASA members are equivocal regarding the use of TEE during open abdominal aortic procedures and liver transplantation. Both the consultants and ASA members are equivocal regarding the use of TEE during: (1) endovascular aortic procedures, (2) neurosurgery in the sitting position, and (3) percutaneous cardiovascular interventions (e.g. , femoral artery stenting). Finally, the consultants and ASA members both disagree with the assertion that TEE should be used during orthopedic surgery.TEE may be used when the nature of the planned surgery or the patient's known or suspected cardiovascular pathology might result in severe hemodynamic, pulmonary, or neurologic compromise. If equipment and expertise are available, TEE should be used when unexplained life-threatening circulatory instability persists despite corrective therapy.Studies with observational findings for critically ill patients with an unexplained adverse postoperative clinical course report TEE detection for the following abnormalities: regurgitant valvular lesions, aortic or mitral valve vegetation, aortic dissection, intracardiac mass, tamponade, ventricular failure, and hypovolemia (Category B2 evidence ). Case reports of critically ill postoperative patients indicate that TEE detects abnormalities such as aortic root abscess, pericardial hematoma, atherosclerotic debris in the thoracic aorta, left ventricular hypertrophy, wall motion abnormalities, and ventricular masses (Category B3 evidence ).Both the consultants and ASA members strongly agree that TEE should be used for critical care patients when diagnostic information expected to alter management cannot be obtained by transthoracic echocardiography or other modalities in a timely manner. The ASA members agree and the consultants strongly agree that TEE should be used during unexplained persistent hypotension. They both agree that TEE should be used when persistent unexplained hypoxemia occurs.For critical care patients, TEE should be used when diagnostic information that is expected to alter management cannot be obtained by transthoracic echocardiography or other modalities in a timely manner.Studies with observational findings and case reports indicate that, although rare, potential complications associated with TEE may include esophageal perforation, esophageal injury, hematoma, laryngeal palsy, dysphagia, dental injury, or death (Category B2 evidence ). However, there is insufficient literature to assess whether there are contraindications for the use of TEE (Category D evidence ).Both the consultants and ASA members are equivocal with regard to whether there are no absolute contraindications to TEE other than previous esophagectomy or esophagogastrectomy. Those consultants and ASA members who do not agree that there are no absolute contraindications other than previous esophagectomy or esophagogastrectomy do agree that the following four conditions should be absolute contraindications to TEE: esophageal stricture, tracheoesophageal fistula, postesophageal surgery, and esophageal trauma. Both the consultants and ASA members disagree that the following four conditions should be absolute contraindications to TEE: Barrett esophagus, hiatal hernia, large descending aortic aneurysm, and unilateral vocal cord paralysis. Finally, both the consultants and ASA members are equivocal with regard to whether the following three conditions should be absolute contraindications to TEE: esophageal varices, postradiation therapy, and previous bariatric surgery. The consultants agree but the ASA members are equivocal that Zenker diverticulum and colonic interposition are absolute contraindications. Finally, the ASA members disagree and the consultants are equivocal that dysphagia is an absolute contraindication to TEE.TEE may be used for patients with oral, esophageal, or gastric disease, if the expected benefit outweighs the potential risk, provided the appropriate precautions are applied. These precautions may include the following: considering other imaging modalities (e.g. , epicardial echocardiography), obtaining a gastroenterology consultation using a smaller probe, limiting the examination, avoiding unnecessary probe manipulation, and using the most experienced operator.For these Guidelines, a literature review was used in combination with opinions obtained from expert consultants and other sources (e.g. , ASA members, open forums, Internet postings). Both the literature review and opinion data were based on evidence linkages or statements regarding potential relationships between clinical interventions and outcomes. The efficacy and outcomes from the use of TEE were examined for the following procedures:The impact of the use of perioperative TEE was assessed on the basis of the following:For the literature review, potentially relevant clinical studies published after 1994 were identified via electronic and manual searches of the literature. The electronic and manual searches covered a 16-yr period from 1994 through 2009. More than 8000 citations were initially identified, yielding a total of 861 nonoverlapping articles that addressed topics related to the evidence linkages. After review of the articles, 404 studies did not provide direct evidence and were subsequently eliminated. A total of 457 articles contained direct linkage-related evidence. A complete bibliography used to develop these Guidelines, organized by section, is available as Supplemental Digital Content 2, http://links.lww.com/ALN/A568.Literature reporting the detection of new abnormalities by TEE was summarized, followed by a summary of literature reporting the confirmation of previously diagnosed abnormalities by TEE. The sensitivity, specificity, and positive and negative predictive values for the efficacy of TEE in detecting new abnormalities and in confirming or redefining previous diagnoses were also obtained (table 1). Study findings reporting the misdiagnosis or limited effectiveness of TEE to detect pathology are also listed in table 1.Interobserver agreement among Task Force members and two methodologists was established by interrater reliability testing. Agreement levels using a κ statistic for two-rater agreement pairs were as follows: (1) type of study design, κ= 0.50–1.00; (2) type of analysis, κ= 0.50–0.83; (3) evidence linkage assignment, κ= 0.75–1.00; and (4) literature inclusion for database, κ= 0.78–1.00. Three-rater chance-corrected agreement values were as follows: (1) study design, Sav = 0.66, Var (Sav) = 0.006; (2) type of analysis, Sav = 0.66, Var (Sav) = 0.007; (3) linkage assignment, Sav = 0.83, Var (Sav) = 0.005; and (4) literature database inclusion, Sav = 0.84, Var (Sav) = 0.046. These values represent moderate to high levels of agreement.Consensus was obtained from multiple sources, including (1) survey opinion from consultants who were selected based on their knowledge or expertise in the perioperative use of TEE, (2) survey opinions solicited from active members of the ASA who personally perform TEE as part of their practice, (3) testimony from attendees of a publicly held open forum at an international anesthesia meeting, (4) Internet commentary, and (5) Task Force opinion and interpretation. The survey rate of return was 53% (n = 55 of 103) for the consultants, and 818 surveys were received from active ASA members who indicated that they personally performed TEE as part of their practice. Results of the surveys are reported in tables 2 and 3and summarized in the text of the Guidelines.The consultants were asked to indicate which, if any, of the recommendations would change their clinical practices if the Guidelines were instituted. The rate of return was 14% (n = 14 of 103). The percent of responding consultants expecting a change in their practice associated with each linkage topic was as follows: (1) major cardiac and thoracic aortic surgery, 7%; (2) transcatheter intracardiac procedures, 0%; (3) pacemaker and implanted cardioverter defibrillator lead extraction, 7% (4); neurosurgery, 7% (5); liver transplantation, 0% (6); orthopedic surgery, 7% (7); vascular/endovascular surgery, 7%, (8) other major surgery (i.e. , lung, renal, abdominal, and head/neck/chest wall), 14%; and (9) postoperative critical care, 21%. Eighty-six percent indicated that their clinical practice will not need new equipment, supplies, or training to implement the Practice Guidelines. Eighty-six percent indicated that the Guidelines would not require ongoing changes in their practice which will affect costs. One hundred percent of the respondents indicated that the Guidelines would have no effect on the amount of time spent on a typical case.

POINT-COUNTERPOINTThe major limitation to exercise performance in COPD is lower limb muscle dysfunctionRichard Debigaré, and François MaltaisRichard Debigaré, and François MaltaisPublished Online:01 Aug 2008https://doi.org/10.1152/japplphysiol.90336.2008aMoreSectionsPDF (152 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations Exercise intolerance is ubiquitous in patients suffering from chronic obstructive pulmonary disease (COPD). Functional impairment can be evidenced by a lower walking capacity and cycling endurance compared with age-matched healthy controls (26). Reduced functional status and low level of daily physical activity predict poor quality of life (24), high health care use (7), and mortality (9) in these patients. A comprehensive understanding of the mechanisms of exercise intolerance is therefore of utmost importance to impact on these adverse outcomes and modify the evolution of the functional impairment associated with COPD.Respiratory impairment is not sufficient in itself to explain exercise intolerance in COPD. The weak correlation between FEV1 or inspiratory capacity and exercise tolerance implies that other factors must be involved (21, 14). In 1992, Killian and collaborators (15) published a landmark paper that draws attention to the impact of the lower limb muscles on exercise intolerance in COPD. They reported that leg discomfort was a frequent exercise-limiting symptom invoked by these patients after a standardized cycling protocol. This report was the foundation of the rationale used by scientists to investigate lower limb muscle dysfunction in COPD. At that time, no one could have predicted how vast this research area would develop.Although the ventilatory system is clearly dysfunctional in COPD, we will demonstrate that peripheral limitation to exercise tolerance is frequent in patients with COPD. To persuade the reader, morphological, biochemical, and clinical evidences demonstrating causal relationship between lower limb muscle dysfunction and exercise limitation will be exposed. We will focus on the tolerance to submaximal exercises, which are particularly influenced by the function and aerobic capacity of the lower limb muscles (3).Morphological and biochemical evidences of lower limb muscle dysfunction in COPD.The prevalence of lower limb muscle atrophy in COPD ranges from 21 to 45% depending on the population being investigated and its operational definition (23, 27). Unexpectedly, muscle atrophy can even be present in patients with normal body weight (27). Given that muscle strength is mostly determined by muscle mass, muscle weakness is therefore highly prevalent in COPD (4, 11). Patients with COPD also have a poor resistance to isolated leg exercises and increased susceptibility to muscle fatigue (16), two correlates of impaired exercise capacity (1). In parallel, altered muscle energy metabolism as assessed by 31phosphorus magnetic resonance spectroscopy (30) has also been correlated to reduced exercise capacity in patients with COPD (30).Muscle atrophy and impaired energy production are accountable for muscle weakness and increased susceptibility to fatigue, two strong determinants of exercise capacity (13). The physiological link between weakness, leg fatigue, and exercise intolerance was elegantly illustrated by Hamilton and colleagues (12). They evaluated the relationship between the perception of leg fatigue, work capacity, and muscle strength in normal individuals and patients with lung diseases, most of whom had COPD. Three interrelated observations, valid in healthy individuals and patients with lung diseases, were made 1) for a given power output, the perception of leg fatigue was greater in weaker compared with stronger individuals, 2) peak exercise capacity was reduced in weak individuals, and 3) the strength of the quadriceps was a key determinant of exercise capacity, independent of the impairment in lung function.Convincing biochemical data also support the thesis that lower limb muscle dysfunction is a major contributor to exercise intolerance in COPD. At the cellular level, several morphological and structural modifications have been observed in the quadriceps of patients with moderate to severe COPD (2). These changes substantially compromise the metabolic performance and work output of activated muscles during exercise. Specifically, the morphological changes observed include reduction in type I fiber proportion (28) as well as reduction in cross-sectional area (CSA) for type I and II fibers (10, 28) that is proportional to the reported reduction in mid-thigh cross-sectional area (4). This former observation suggests that contractile protein deficit is largely responsible for both muscle atrophy and weakness and thus contribute to impaired exercise capacity.The muscle structural and energetic changes described in COPD involve a reduction in myosin heavy chain I proportion (19) and a decrease in oxidative enzyme activities (10, 17, 18), a strong determinant of muscle endurance (1). Reduced oxidative metabolism correlates significantly with peak exercise capacity independently of lung function impairment (17). Early reliance on glycolytic activity for the energy production results in higher accumulation of inorganic phosphate (30) and premature muscle acidosis from lactate production (18), two biochemical events compromising the ability to sustain repeated muscle contractions and exercise performance. These adaptations seen in COPD are indicative of a muscle tissue that is inappropriately adapted to sustain the metabolic and mechanical requirements of submaximal exercises as seen in daily functional activities and provide a strong muscular basis to lower limb muscle dysfunction and exercise intolerance in COPD.Clinical evidences of lower limb muscle dysfunction in COPD.Exercise intolerance in COPD is the result of a complex interplay between central (ventilation, dynamic hyperinflation, dyspnea) and peripheral (muscle atrophy and weakness, fatigue) factors. Although the relative contribution of these components to exercise intolerance is difficult to sort out within a single patient, clinical models illustrating the role of the lower limb muscles are available.Undisputable evidences of peripheral limitation in exercising patients with COPD were provided by Williams and collaborators (29), who found that exercise limitation persisted in single and double lung transplant recipients years after the surgery despite complete restoration of their ventilatory capacity.Direct role of lower limb muscle dysfunction on exercise intolerance was evidenced by a study evaluating the impact of muscle fatigue on the exercise response to bronchodilation (22). In that study, the occurrence of contractile fatigue of the quadriceps after constant work rate cycling exercise prevented acute bronchodilation to translate into further improvement in exercise capacity. Patients with COPD complaining of leg fatigue as the main exercise-limiting symptom are also less likely to improve exercise tolerance following bronchodilation compared with those stopping because of dyspnea (8). These studies, together with the observation described above in lung transplantation, nicely illustrate how proximal peripheral limitation to exercise prevents interventions aimed at improving lung function to translate into better functional status.Pulmonary rehabilitation exemplifies how an intervention aimed at improving muscle function has a direct and significant positive impact on exercise tolerance. The consistent improvement in exercise tolerance reported with rehabilitation cannot be attributed to changes in respiratory function but rather to its global effects on lower limb muscle function characterized by improved strength, lesser susceptibility to fatigue, and better aerobic capacity (20). To some extent, these muscular physiological benefits also contribute to the reduction in ventilatory requirements, dynamic hyperinflation, and dyspnea often seen after exercise training (5, 6). In fact, better lower limb muscle function represents the physiological foundation of exercise training in COPD (25).Conclusion.Lower limb muscles in COPD are atrophied, weak, fatigable, and metabolically inefficient. These unfavorable muscle characteristics concur to limit exercise capacity, a most debilitating feature in COPD. Taken as a whole, clinical observation and research work performed in several laboratories support the notion that lower limb muscle dysfunction is largely responsible for exercise limitation in COPD. Denying this obvious concept and omitting this relevant component of the disease will disservice our patients since lower limb muscle dysfunction can be, in contrast to lung impairment, amenable to therapy by rehabilitative strategies.GRANTSF. Maltais and R. 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An Official American Thoracic Society/Thoracic Society of Australia and New Zealand/Canadian Thoracic Society/British Thoracic Society Workshop ReportAnnals of the American Thoracic Society, Vol. 15, No. 7Exercise Training in Pulmonary Rehabilitation22 December 2017Inspiratory Muscle Training6 October 2017Prevalence and risk factors of chronic obstructive pulmonary diseases in a Hlai community in Hainan Island of China21 June 2016 | The Clinical Respiratory Journal, Vol. 12, No. 1Place de l'éducation thérapeutique du patient atteint de BPCO en réhabilitation respiratoireRevue de Pneumologie Clinique, Vol. 73, No. 6Cardiorespiratory Responses to Short Bouts of Resistance Training Exercises in Individuals With Chronic Obstructive Pulmonary DiseaseJournal of Cardiopulmonary Rehabilitation and Prevention, Vol. 37, No. 5Respiratory Muscle Strength in Patients With Chronic Obstructive Pulmonary DiseaseAnnals of Rehabilitation Medicine, Vol. 41, No. 4Skeletal muscle power and fatigue at the tolerable limit of ramp-incremental exercise in COPDDaniel T. 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January | American Journal of and Physiology, Vol. No. in vastus lateralis muscle of patients with chronic obstructive pulmonary | Respiratory Research, Vol. 15, No. function and reduced of the quadriceps in patients with January | Respiratory Research, Vol. 15, No. between peripheral muscle strength, exercise and physical activity in daily life in patients with Chronic Obstructive Pulmonary July | Respiratory Medicine, Vol. 9, No. in Chronic Obstructive Pulmonary Disease Patients at an of and and A October | COPD: Journal of Chronic Obstructive Pulmonary Disease, Vol. 11, No. en de muscles en Vol. No. 3Chronic Obstructive Pulmonary in Chest Medicine, Vol. No. of exercise testing in COPD patients with and & Vol. No. Obstructive Pulmonary Disease10 January Official American Thoracic Society/European Respiratory Society and in Pulmonary Journal of Respiratory and Care Medicine, Vol. No. isolated leg exercises improve dyspnea during exercise in chronic obstructive pulmonary Physiology, and Vol. 38, No. of an in Chronic Obstructive Pulmonary Journal of Respiratory and Care Medicine, Vol. No. to and Exercise in Chronic Obstructive Pulmonary Journal of Respiratory and Care Medicine, Vol. No. and COPD: and | The and Vol. 41, No. of limb muscle dysfunction in patients with chronic obstructive pulmonary disease to a pulmonary rehabilitation Vol. No. and Exercise in Vol. No. quadriceps muscle oxygen during exercise in COPD patients with and dynamic Louvaris, Spyros Zakynthinos, Helmut Habazettl, Harrieth Wagner, Peter Wagner, and Ioannis October | Journal of Applied Physiology, Vol. No. of on Exercise in Patients with Chronic Obstructive Pulmonary Journal of Respiratory and Care Medicine, Vol. No. Exercise in Chronic July of lower limb and training on exercise quality of life and in Journal of Chest and Vol. No. in Muscle of Patients with June | Vol. No. on of and Pulmonary Vol. No. a de Vol. 38, No. en de Vol. No. Exercise in COPD: of July | COPD: Journal of Chronic Obstructive Pulmonary Disease, Vol. 8, No. that a higher of muscular to the lower mechanical efficiency associated with COPD: J. and | American Journal of and Physiology, Vol. No. Exercise in the Clinical of Patients With Heart and Vol. No. of bronchodilators on exercise tolerance in COPD & Vol. 24, No. en Vol. No. metabolism during constant cycling exercise in chronic obstructive pulmonary B. Richard Debigaré, and François January | Journal of Applied Physiology, Vol. No. of the Test With Muscle Strength and Functional in With Chronic Obstructive Pulmonary A Vol. No. Muscle Limitation during Exercise in Chronic Obstructive Pulmonary Journal of Respiratory and Care Medicine, Vol. No. during daily life activities in COPD Medicine, Vol. No. of pulmonary system on muscle fatigue in patients with F. and July | American Journal of and Physiology, Vol. No. of on exercise performance in chronic obstructive pulmonary disease: A & Vol. No. to Total a for Chronic Obstructive Pulmonary Disease American Journal of the Vol. No. exercise capacity in COPD patients with and pulmonary Medicine, Vol. No. of the respiratory muscles to rehabilitation in September | Journal of Applied Physiology, Vol. No. and during Dynamic Exercise in Patients with Chronic Obstructive Pulmonary Journal of Respiratory and Care Medicine, Vol. No. de la du de la Vol. 38, No. major limitation to exercise performance in COPD is energy to the respiratory and muscles lower limb muscle dysfunction dynamic B. | Journal of Applied Physiology, Vol. No. from this & the American Physiological in

HomeCirculationVol. 141, No. 22Will Complement Inhibition Be the New Target in Treating COVID-19–Related Systemic Thrombosis? Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBWill Complement Inhibition Be the New Target in Treating COVID-19–Related Systemic Thrombosis? Courtney M. Campbell and Rami Kahwash Courtney M. CampbellCourtney M. Campbell Courtney M. Campbell, MD, PhD, Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Suite 200, 473 W 12th Ave, Columbus, OH 43210. Email E-mail Address: [email protected] Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus. and Rami KahwashRami Kahwash Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus. Originally published9 Apr 2020https://doi.org/10.1161/CIRCULATIONAHA.120.047419Circulation. 2020;141:1739–1741Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: April 9, 2020: Ahead of Print SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel coronavirus responsible for the current pandemic, resulting in an escalating number of cases and fatalities worldwide. Despite a high infection rate of coronavirus disease 2019 (COVID-19), only an estimated 15% of patients require hospitalization, with 5% requiring intensive care. Nearly half (49%) of patients requiring intensive care died. How and why patients succumb to SARS-CoV-2 infection is not well understood. A poignant New York Times article described the sudden decompensation and death of a young physician after she had documented viral clearance and was preparing to go home.Several early publications from the Wuhan region of China focused on describing clinical characteristics of hospitalized patients with severe COVID-19 illness. These initial observational studies demonstrate in severe cases evidence of coagulation dysfunction through elevated D-dimer, elevated lactate dehydrogenase, elevated total bilirubin, and decreased platelets with slight or no changes in partial thromboplastin time or activated partial thromboplastin time. In patients with severe or fatal COVD-19, there is also evidence of end-organ damage with acute kidney injury and primarily mildly elevated troponin. In the study by Shi et al,1 a significantly higher percentage of patients with cardiac injury (average troponin I 0.19 µg/L) died compared with those patients without cardiac injury (51.2% versus 4.5%, respectively).The mechanism of cardiac injury for COVID-19 is uncertain. No series of cardiac imaging data, such as echocardiography or cardiac magnetic resonance imaging, has been published for patients with COVID-19. Theories include direct viral damage via the angiotensin-converting enzyme 2 receptor, myocarditis, systemic inflammatory response with cytokine storm, destabilized coronary plaques, and aggravated hypoxia. In case reports of COVID-19–related myocarditis, patients had minimal pulmonary involvement and significant cardiac involvement and recovered from COVID-19. Cardiac biomarkers in the myocarditis cases were much higher than the average values of cardiac injury in patients with COVID-19 reported in the observational studies. Whether myocarditis as a COVID-19 mechanism applies broadly is uncertain. Excessive cytokine release has also been observed in patients with COVID-19. High cytokines were also found in patients with SARS-CoV and MERS-CoV (Middle East respiratory syndrome coronavirus), but subsequent studies demonstrated that corticosteroids did not improve mortality and delayed viral clearance. Tocilizumab, an interleukin-6 inhibitor, is being studied as a potential treatment option. However, elevated cytokines in this context could be a biomarker of critical illness with COVID-19 rather than the pathogenic mediator.In a joint webinar between the Chinese Cardiology Association and the American College of Cardiology on March 28, 2020, the Chinese cardiologists described diffuse microvascular thrombi in multiple organs on autopsy review of COVID-19 nonsurvivors. Given this diffuse thrombosis, Chinese physicians recommended treatment of patients with COVID-19 with systemic anticoagulation, but no trials or publications have evaluated this approach. Similar findings of diffuse multiorgan microvascular thrombosis without viral infiltrates were seen in an autopsy case report for a patient who died of SARS.2Thrombotic microangiopathy (TMA) can occur in many different clinical scenarios, including pathogenic complement activation. The complement system is a mediator of the innate immune response that promotes inflammation, defends against bacterial infections, and often neutralizes infectious viruses. In brief, the complement cascade can be activated via the classical pathway, triggered by antibody-antigen complexes; the alternative pathway, stimulated by specific surface antigens; and the lectin pathway, initiated by binding mannose residues on the pathogen surface. These pathways converge on the common pathway. The common pathway includes production of C3a and C5a inflammatory mediators and C3b-initiated pathogen opsonization and ends in formation of the C5b-9 membrane attack complex, which lyses target cells, resulting in cell death (Figure [A]). Two murine studies directly investigated complement activation in coronavirus infections and asked whether activation of the system would be protective or pathogenic. In a murine model lacking C3 and thus unable to activate the common complement pathway, SARS-CoV infection severity was decreased, with less respiratory dysfunction and lower cytokine levels despite equal viral loads (Figure [C]).2 The authors suggest that a significant portion of SARS-mediated disease is likely immune mediated. In a murine model of MERS-CoV infection, increased concentrations of C5a and C5b-9 were found in sera and lung tissues.4 Blocking C5a with a murine antibody alleviated lung and spleen damage, with decreased cytokine response and viral replication (Figure [D]).Download figureDownload PowerPointFigure. Coronavirus and complement.A, Simplified diagram of the common complement pathway. Eculizumab inhibits C5, preventing breakdown into C5a and C5b, which is an integral component of the membrane attack complex (MAC). B, In humans, overactivation of the complement pathway can lead to thrombotic microangiopathy, resulting in renal and cardiac dysfunction. In atypical hemolytic-uremic syndrome (aHUS), early treatment with eculizumab reverses organ dysfunction. C, On the basis of the mouse model of SARS-CoV (severe acute respiratory syndrome coronavirus)infection described by Gralinski et al,2 lack of the C3 protein results in improved lung function, less cytokine release, and no change in viral load compared with mice with an intact complement system. D, On the basis of the mouse model of MERS-CoV (Middle East respiratory syndrome coronavirus) infection described by Jiang et al,3 antibody blockade of C5 results in improved lung function, less cytokine release, and less viral load compared with untreated mice.In humans, excessive complement activation occurs in a number of pathological settings, leading to diffuse TMA and end-organ dysfunction (Figure [B]). Atypical hemolytic-uremic syndrome (aHUS) is a rare disorder of uncontrolled complement activation characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. TMA in aHUS results in renal dysfunction and, in rare cases, cardiac dysfunction.5 Patients often have an underlying genetic predisposition, with variants in the complement cascade. Alternatively, infection, pregnancy, and certain medications and autoimmune disorders can trigger complement-activating autoantibodies. Importantly, aHUS is treatable with a C5 complement inhibitor, eculizumab. If given early, eculizumab therapy can reverse both renal and cardiac dysfunction.5 Before the introduction of eculizumab, the prognosis of aHUS was poor, with 67% of adults dying within 5 years.Transplant-associated TMA is also thought to be initiated by excessive complement activation, trigged by endothelial injury from chemotherapy, radiation, or viral infection. A recent study showed that 78% of patients with transplant-associated TMA had a pathogenic or likely pathogenic variant in TMA and complement-associated genes.6 Importantly, endothelial injury is a hallmark of COVID-19. Like SARS-CoV, COVID-19 acts primarily through the angiotensin-converting enzyme 2 receptor, which is expressed widely in vascular tissues, including alveolar epithelium and cardiac pericytes.Complement inhibition may be a promising treatment for severe COVID-19 by reducing the innate immune-mediated consequences of severe coronavirus infection, and it would pair well with direct antiviral therapy. The published clinical observations of severe COVID-19 are consistent with excessive complement activation: elevated lactate dehydrogenase, D-dimer, and bilirubin; decreased platelets; mild anemia; renal and cardiac injury; and reportedly diffuse TMA. Patients with severe and fatal cases of COVID-19 might have increased susceptibility to TMA through a genetic predisposition to pathogenic complement activation. Complement inhibition was associated with favorable outcomes in SARS-CoV and MERS-CoV murine models and reversed cardiac dysfunction in aHUS-TMA, which mimics the pathological findings seen in COVID-19. Complement inhibition might be a new target in treating COVID-19–related systemic thrombosis. This approach is worthy of further investigation with a randomized, controlled clinical trial to investigate whether complement inhibition could improve the clinical course for COVID-19 patients with severe disease.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circCourtney M. Campbell, MD, PhD, Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Suite 200, 473 W 12th Ave, Columbus, OH 43210. Email courtney.campbell@osumc.eduReferences1. Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W, Liu X, Liang J, Zhao Q, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China [published online March 25, 2020].JAMA Cardiol. doi: 10.1001/jamacardio.2020.0950. https://jamanetwork.com/journals/jamacardiology/fullarticle/2763524.Google Scholar2. Xiang-Hua Y, Le-Min W, Ai-Bin L, Zhu G, Riquan L, Xu-You Z, Wei-Wei R, Ye-Nan W. Severe acute respiratory syndrome and venous thromboembolism in multiple organs.Am J Respir Crit Care Med. 2010; 182:436–437. doi: 10.1164/ajrccm.182.3.436CrossrefMedlineGoogle Scholar3. Gralinski LE, Sheahan TP, Morrison TE, Menachery VD, Jensen K, Leist SR, Whitmore A, Heise MT, Baric RS. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis.mBio. 2018; 9:e01753-18. doi: 10.1128/mBio.01753-18CrossrefMedlineGoogle Scholar4. Jiang Y, Zhao G, Song N, Li P, Chen Y, Guo Y, Li J, Du L, Jiang S, Guo R, et al. Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV.Emerg Microbes Infect. 2018; 7:77. doi: 10.1038/s41426-018-0063-8CrossrefMedlineGoogle Scholar5. Campbell CM, Cassol C, Cataland SR, Kahwash R. Atypical haemolytic uraemic syndrome: a case report of a rare cause of reversible cardiomyopathy.Eur Heart J Case Rep. 2020; 4:1–6. doi: 10.1093/ehjcr/ytaa050CrossrefMedlineGoogle Scholar6. Gavriilaki E, Touloumenidou T, Sakellari I, Batsis I, Mallouri D, Psomopoulos F, Tsagiopoulou M, Koutra M, Yannaki E, Papalexandri A, et al. Pretransplant genetic susceptibility: clinical relevance in transplant-associated thrombotic microangiopathy.Thromb Haemost. March 4, 2020; 120:638–646. doi: 10.1055/s-0040-1702225CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. 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Kutlutürk I, Tokuç E, Karabaş L, Rückert R, Kaya M, Karagöz A and Munk M (2023) How the immune response to the structural proteins of SARS-CoV-2 affects the retinal vascular endothelial cells: an immune thrombotic and/or endotheliopathy process with in silico modeling, Immunologic Research, 10.1007/s12026-023-09412-1, 72:1, (50-71), Online publication date: 1-Feb-2024. Khokhlov R, Yarmonova M and Tribuntseva L (2024) Lesions of the heart and parenchymatous organs in patients with COVID-19 and other acute respiratory infections, Russian Family Doctor, 10.17816/RFD622794, 27:4, (21-32) Rizoli S, Peralta R, Al-Thani H, Ramzee A, El-Menyar A, Asim M, Shahid F, Fino A, Ata Y, El Baba H, Nair A and Al Maslamani M (2023) Descriptive Analysis of Thromboembolic Events in COVID-19 Patients in Qatar, Panamerican Journal of Trauma, Critical Care & Emergency Surgery, 10.5005/jp-journals-10030-1436, 12:3, (120-130), Online publication date: 30-Dec-2023. 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POINT-COUNTERPOINTThe major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor musclesAndrea Aliverti, and Peter T. MacklemAndrea Aliverti, and Peter T. MacklemPublished Online:01 Aug 2008https://doi.org/10.1152/japplphysiol.90336.2008This is the final version - click for previous versionMoreSectionsPDF (139 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations No doubt dynamic hyperinflation and lack of oxidative capacity of skeletal muscles are important causes of exercise limitation in COPD. O'Donnell and Webb and Debigaré and Maltais will convince the reader of this by the elegant experiments they have performed. The thesis we will put forward is that during the natural history of COPD the primary factors leading to impairment of exercise performance are an increase in energy demands combined with a decrease in supplies and that both of these result from excessive recruitment of expiratory muscles. We argue that both dynamic hyperinflation and reduced oxidative capacity are secondary adaptations resulting from this primary abnormality.Increased energy demands during exercise in COPD.Energy demands are increased in COPD because of the high O2 cost of breathing (V̇o2resp). In health, V̇o2resp is only 1–3 ml O2/l breathed, whereas in COPD it has been reported variously to average 6.3, 9.7, and 16.4 ml/l breathed with individual values ranging from 3.0 to 19.5 ml/l (8, 17).The large between patient range in V̇o2resp probably reflects variation in the work of breathing (Wresp). During exercise, a large variation in Wresp certainly exists. In two studies, COPD patients formed two distinct groups: those that strongly recruited abdominal muscles and those that did not (5, 10). In the first (5), at an exercise workload of 10 W the work performed on the lung averaged 754 cmH2O·l−1·min−1 in recruiters but only 277 cmH2O·l−1·min−1 in nonrecruiters, although ventilation was similar. Expiratory muscle activation is the normal response to exercise (1) so the recruiters behaved normally. The problem is that in COPD, it fails to increase ventilation, because expiratory flow becomes limited by high pleural pressures. While abdominal muscle recruitment is beneficial during exercise in health (1), it is definitely harmful in COPD (4, 5).Because Wresp was 2.7-fold greater in recruiters, we can assume that their V̇o2resp was twice as high as the nonrecruiters. Let's also assume that it was 12 ml O2/l in the former and 6 ml/l in the latter. The maximal exercise workload (Wmax) was 20 and 35 W in recruiters and nonrecruiters (P < 0.05), while V̇e at Wmax was 35.9 and 37.9 l/min, respectively (5). Thus the estimated V̇o2resp was 430.8 ml/min in recruiters but only 227.4 ml/min in nonrecruiters. From the measured values of V̇o2 at rest and during 10 W exercise and assuming that V̇o2 increased linearly (dV̇o2/dwatt is constant) the V̇o2 at maximal exercise workload (V̇o2max) was 830.0 and 1,327.5 ml O2/min, respectively, in recruiters and nonrecruiters. Subtracting V̇o2resp from V̇o2max reveals that if the respiratory muscles received all their demands there was only 399.2 ml O2 available to locomotor muscles and other body tissues in recruiters but 1,100.1 ml in nonrecruiters. The respiratory muscles demanded 53% of V̇o2max in recruiters but only 17%, a value close to normal (6), in nonrecruiters.The nonrecruiters' breathing pattern was abnormal because abdominal muscles were not recruited during exercise. As a result, their exercise performance was better. However, their resting lung function was worse. Both the FEV1 and FEV1/FVC were significantly lower in nonrecruiters. This strongly suggests that as COPD progresses, patients eventually realize that abdominal muscles recruitment is bad and somehow they learn to derecruit them. Alas, without abdominal muscle contraction they dynamically hyperinflate. They can exercise a bit more, but not much (15). Thus we believe that dynamic hyperinflation results from a learned response to an inadequate supply of energy to meet demands.Decreased energy supplies during exercise with expiratory flow limitation.When normal subjects breathe with a Starling resistor in the expiratory line, which limits expiratory flow to ∼1 l/s, exercise is limited by severe dyspnea; abdominal pressure (Pab) increases abnormally; duty cycle decreases; CO2 retention occurs, increasing Pab even more (3, 13, 14); the high expiratory pressures and short duty cycle act like a Valsalva maneuver and decrease cardiac output (Q′c) (2); as a result, O2 debt is increased by 52% (22). Expiratory flow limitation (EFL) decreases the shortening velocity of abdominal muscles, and, in accordance with their force velocity characteristics Pab increases (3). Expiratory muscle recruitment can account for 66% of the variation in Borg scale ratings of difficulty in breathing (14). None of these abnormalities can be attributed to either dynamic hyperinflation or impaired oxidative capacity of skeletal muscles.Does this scenario occur in COPD? There is strong evidence that it does. First, there is uniform agreement that lactic acid production occurs at a very low exercise level in COPD. This suggests an imbalance between energy supply and demand, resulting in competition between respiratory and locomotor muscles for limited energy supplies (9, 12, 20). Administration of O2 improves exercise performance probably by decreasing V̇o2resp (7), thereby releasing more energy for locomotor muscles. This improvement should not occur if skeletal muscles were unable to use the energy available to them. Richardson et al. (19) showed that in small muscle mass exercise in COPD there was a 2.2-fold greater mass-specific power output than during whole body exercise. Locomotor muscles have a greater maximal power output in the absence of respiratory-locomotor muscle competition, Oelberg et al. (18) reported a Q′c of only 39% of predicted during exercise in COPD and when heliox was breathed, decreasing V̇o2resp and increasing the energy available to locomotor muscles, V̇o2 increased by 15% without any change in Q′c (18). If the respiratory muscles in recruiters demand 53% of V̇o2max, they probably demand the same share of Q′c (6), and if Q′c is only 39% predicted, locomotor muscles must be pretty ischemic. Finally Francois (21) himself reported a plateau in lower limb perfusion while exercise workload increased in COPD.If inadequate energy to meet demands limits exercise in COPD, why is the oxidative capacity of skeletal muscles reduced? The obvious answer is that disuse and lack of energy supplies (tissue hypoxia) cause the enzymatic changes and mitochondrial abnormalities responsible for decreasing oxidative capacity. Again there is strong evidence that this is so [see Gosker et al. (11) for an outstanding review]. The myopathic changes in congestive heart failure and COPD are almost identical. They do not occur in the diaphragm because there is no disuse of this muscle. There is no reason to believe that myopathy is a primary abnormality in COPD and congestive heart failure and every reason to believe that it is secondary to disuse and tissue hypoxia. Francois refers to this when he states "…a comparable disorder has been described in chronic heart failure. Chronic reduction in oxygen availability at the cellular level…could contribute to…skeletal muscle dysfunction" (16). Francois also recognized the potential importance of respiratory-locomotor muscle competition when he wrote that in COPD "…the respiratory muscles, with [high] V̇o2 during exercise…might…compete with lower limb muscles for the available blood flow and O2" (21). Yes, reduced oxidative capacity, like dynamic hyperinflation, can limit exercise performance in COPD, but it is secondary to a longstanding imbalance between energy supply and demand.We believe the long natural history of COPD results in the sequence of events during exercise shown in Fig. 1. The primary event, EFL during exercise, probably occurs when the disease is still mild and exercise is not seriously impaired. This in turn leads to an increase in force generation of expiratory muscles increasing expiratory pressures from which all the pathophysiology described above derives.Fig. 1.Natural history of COPD and its results in the sequence of events during exercise.Download figureDownload PowerPointREFERENCES1 Aliverti A, Cala SJ, Duranti R, Ferrigno G, Kenyon CM, Pedotti A, Scano G, Sliwinski P, Macklem PT, Yan S. Human respiratory muscle actions and control during exercise. J Appl Physiol 83: 1256–1269, 1997.Link | ISI | Google Scholar2 Aliverti A, Dellaca RL, Lotti P, Bertini S, Duranti R, Scano G, Heyman J, Lo MA, Pedotti A, Macklem PT. Influence of expiratory flow-limitation during exercise on systemic oxygen delivery in humans. Eur J Appl Physiol 95: 229–242, 2005.Crossref | ISI | Google Scholar3 Aliverti A, Iandelli I, Duranti R, Cala SJ, Kayser B, Kelly S, Misuri G, Pedotti A, Scano G, Sliwinski P, Yan S, Macklem PT. 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Eur J Appl Physiol 99: 265–274, 2007.Crossref | ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByBlood shifts between body compartments during submaximal exercise with induced expiratory flow limitation in healthy humans29 November 2022 | The Journal of Physiology, Vol. 601, No. 1Association of Pulmonary Function With Motor Function Trajectories and Disability Progression Among Older Adults: A Long-Term Community-Based Cohort Study4 May 2022 | The Journals of Gerontology: Series A, Vol. 77, No. 12Impact of chronic obstructive pulmonary disease on passive viscoelastic components of the musculoarticular system10 September 2021 | Scientific Reports, Vol. 11, No. 1Effect of counselling during pulmonary rehabilitation on self-determined motivation to be physically active for people with chronic obstructive pulmonary disease: a pragmatic RCT12 October 2021 | BMC Pulmonary Medicine, Vol. 21, No. 1Acute Cardiopulmonary and Muscle Oxygenation Responses to Normocapnic Hyperpnea Exercise in COPDMedicine & Science in Sports & Exercise, Vol. Publish Ahead of PrintHigh-intensity exercise impairs extradiaphragmatic respiratory muscle perfusion in patients with COPDZafeiris Louvaris, Antenor Rodrigues, Sauwaluk Dacha, Tin Gojevic, Wim Janssens, Ioannis Vogiatzis, Rik Gosselink, and Daniel Langer9 February 2021 | Journal of Applied Physiology, Vol. 130, No. 2Assessment of knowledge, attitude, and practice towards pulmonary rehabilitation among COPD patients: A multicenter and cross-sectional survey in ChinaRespiratory Medicine, Vol. 174Pulmonary Rehabilitation of Chronic Obstructive Pulmonary Diseases (Review of Clinical Trials, National and International Recommendations)29 October 2020 | Bulletin of Restorative Medicine, Vol. 99, No. 5Physical activity and exercise: Strategies to manage frailtyRedox Biology, Vol. 35Pectoralis muscle area is associated with bone mineral density and lung function in lung transplant candidates13 March 2020 | Osteoporosis International, Vol. 31, No. 7Mechanical cardiopulmonary interactions during exercise in health and diseaseWilliam S. 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HomeCirculationVol. 83, No. 1An updated coronary risk profile. A statement for health professionals. Free AccessAbstractPDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessAbstractPDF/EPUBAn updated coronary risk profile. A statement for health professionals. K M Anderson, P W Wilson, P M Odell and W B Kannel K M AndersonK M Anderson Office of Scientific Affairs, American Heart Association, Dallas, TX 75231. , P W WilsonP W Wilson Office of Scientific Affairs, American Heart Association, Dallas, TX 75231. , P M OdellP M Odell Office of Scientific Affairs, American Heart Association, Dallas, TX 75231. and W B KannelW B Kannel Office of Scientific Affairs, American Heart Association, Dallas, TX 75231. Originally published1 Jan 1991https://doi.org/10.1161/01.CIR.83.1.356Circulation. 1991;83:356–362 Previous Back to top Next FiguresReferencesRelatedDetailsCited By Hespe C, Giskes K, Harris M and Peiris D (2022) Findings and lessons learnt implementing a cardiovascular disease quality improvement program in Australian primary care: a mixed method evaluation, BMC Health Services Research, 10.1186/s12913-021-07310-6, 22:1, Online publication date: 1-Dec-2022. Lemke E, Vetter V, Berger N, Banszerus V, König M and Demuth I (2022) Cardiovascular health is associated with the epigenetic clock in the Berlin Aging Study II (BASE-II), Mechanisms of Ageing and Development, 10.1016/j.mad.2021.111616, 201, (111616), Online publication date: 1-Jan-2022. 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HomeCirculationVol. 142, No. 1Obesity Is a Risk Factor for Severe COVID-19 Infection Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBObesity Is a Risk Factor for Severe COVID-19 InfectionMultiple Potential Mechanisms Naveed Sattar, Iain B. McInnes and John J.V. McMurray Naveed SattarNaveed Sattar Naveed Sattar, MD, Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom. Email E-mail Address: [email protected] https://orcid.org/0000-0002-1604-2593 Institute of Cardiovascular and Medical Sciences (N.S., J.J.V.M.), University of Glasgow, United Kingdom. , Iain B. McInnesIain B. McInnes Institute of Infection, Immunity and Inflammation (I.B.M.), University of Glasgow, United Kingdom. and John J.V. McMurrayJohn J.V. McMurray Institute of Cardiovascular and Medical Sciences (N.S., J.J.V.M.), University of Glasgow, United Kingdom. Originally published22 Apr 2020https://doi.org/10.1161/CIRCULATIONAHA.120.047659Circulation. 2020;142:4–6Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: April 22, 2020: Ahead of Print The coronavirus disease 2019 (COVID-19) pandemic has led to worldwide research efforts to identify people at greatest risk of developing critical illness and dying. Initial data pointed toward older individuals being particularly vulnerable, as well as those with diabetes mellitus or cardiovascular (including hypertension), respiratory, or kidney disease. These problems are often concentrated in certain racial groups (eg, African Americans and Asians), which also appear to be more prone to worse COVID-19 outcomes.1 Increasing numbers of reports have linked obesity to more severe COVID-19 illness and death.1–3 In a French study, the risk for invasive mechanical ventilation in patients with COVID-19 infection admitted to the intensive treatment unit was more than 7-fold higher for those with body mass index (BMI) >35 compared with BMI <25 kg/m2.2 Among individuals with COVID-19 who were <60 years of age in New York City, those with a BMI between 30 to 34 kg/m2 and >35 kg/m2 were 1.8 times and 3.6 times more likely to be admitted to critical care, respectively, than individuals with a BMI <30 kg/m2.3We suggest obesity or excess ectopic fat deposition may be a unifying risk factor for severe COVID-19 infection, reducing protective cardiorespiratory reserve as well as potentiating the immune dysregulation that appears, at least in part, to mediate the progression to critical illness and organ failure in a proportion of patients with COVID-19 (Figure). Whether obesity is an independent risk factor for susceptibility to infection requires further research.Download figureDownload PowerPointFigure. Pathways potentially linking obesity or excess ectopic fat to more severe coronavirus disease 2019 (COVID-19) illness. There are multiple pathways by which obesity (or excess ectopic fat) may increase the effect of COVID-19 infection. These include underlying impairments in cardiovascular, respiratory, metabolic, and thrombotic pathways in relation to obesity, all of which reduce reserve and ability to cope with COVID-19 infection and the secondary immune reaction to it. At the same time, there are several reasons why obese individuals may have amplified or dysregulated immune response, linked both to greater viral exposure, as well as the possibility that excess adipose tissue potentiates the immune response. BP indicates blood pressure; COVID-19, coronavirus disease 2019; CV, cardiovascular; FEV1, forced expiratory volume; FVC, forced vital capacity; and SES, socioeconomic status.From a cardiovascular perspective, trial and genetic evidence conclusively show that obesity (and excess fat mass) are causally related to hypertension, diabetes mellitus, coronary heart disease, stroke, atrial fibrillation, renal disease, and heart failure. Obesity potentiates multiple cardiovascular risk factors, the premature development of cardiovascular disease, and adverse cardiorenal outcomes. There is also a metabolic concern. In individuals with diabetes mellitus, or at high risk of diabetes mellitus, obesity and excess ectopic fat lead to impairment of insulin resistance and reduced β-cell function. Both the latter limit ability to evoke an appropriate metabolic response on immunologic challenge, leading some patients with diabetes mellitus to require substantial amounts of insulin during severe infections. Overall, the integrated regulation of metabolism required for the complex cellular interactions, and for effective host defense, is lost, leading to functional immunologic deficit. COVID-19 may also directly disrupt pancreatic β-cell function through an interaction with angiotensin-converting enzyme 2. Furthermore, obesity enhances thrombosis, which is relevant given the association between severe COVID-19 and prothrombotic disseminated intravascular coagulation and high rates of venous thromboembolism.Beyond cardiometabolic and thrombotic consequences, obesity has detrimental effects on lung function, diminishing forced expiratory volume and forced vital capacity (Figure). Higher relative fat mass is also linked to such adverse changes, perhaps relevant to emerging reports of greater critical illness from COVID-19 in certain ethnicities, eg, Asians.1 Asians often display lower cardiorespiratory fitness and carry proportionally more fat tissue at lower BMIs. With extreme obesity (eg, BMI >40 kg/m2), care for individuals admitted to intensive therapy units is often impeded as these patients are more difficult to image, ventilate, nurse, and rehabilitate.With respect to the immune response, there is a clear association between obesity and basal inflammatory status characterized by higher circulating interleukin 6 and C-reactive protein levels. Adipose tissue in obesity is "proinflammatory," with increased expression of cytokines and particularly adipokines. There is also dysregulated tissue leukocyte expression, and inflammatory macrophage (and innate lymphoid) subsets replace tissue regulatory (M2) phenotypic cells. Obesity per se is an independent and causal risk factor for the development of immune-mediated disease, eg, psoriasis,4 suggesting that such adipose state may have systemic immune consequence on additional environmental provocation. In terms of host defense, obesity impairs adaptive immune responses to influenza virus5 and conceivably could do so in COVID-19. Obese individuals may exhibit greater viral shedding, suggesting potential for great viral exposure, especially if several family members are overweight. This may be aggravated in overcrowded multigenerational households, which are more common in the socioeconomically deprived communities in which obesity is prevalent. All these observations point toward a potential for obesity to give rise to a more adverse virus versus host immune response relationship in COVID-19. Poorer nutritional status and hyperglycemia may further aggravate the situation in some obese individuals.Much of the focus of COVID-19 has been on older people. However, it is important to remember that weight and muscle mass start to decline at advanced age but relative fat mass increases, particularly in those with comorbid diseases such as cardiovascular and respiratory conditions. Older age is also associated with more hypertension and diabetes mellitus because of stiffer vessels and impaired metabolic efficiency, respectively. People who are older (eg, >70 years of age), similar to younger obese individuals, have less cardiorespiratory reserve to cope with COVID-19 infection. Immune senescence is well recognized, as is the concept of inflammaging, and both may influence virus–host dynamics in the elderly and infection outcomes.What are the implications of these emerging observations for future research and public health messaging? With respect to research, predictive instruments for those most at risk of severe outcomes should consider BMI. Mechanistic understanding of the relationship between obesity and COVID-19 may suggest therapeutic interventions (eg, proven weight loss drugs, low-calorie diets) to potentially reduce the risk of developing severe COVID-19 illness. With respect to public health, it is important to communicate risks without causing anxiety. People worldwide should be encouraged to improve their lifestyle to lessen risk both in the current and subsequent waves of COVID-19. In addition to increasing activity levels, there should be improved messaging on better diet, focusing on simpler advice to help people adopt sustainable changes. This is particularly challenging with current stay-at-home rules limiting activity levels—the lockdown cost of weight gain. Even more worrying is that the resultant economic downturn may worsen obesity, especially in the most vulnerable individuals, a risk that governments need to address after the current pandemic. Indeed, this pandemic has highlighted that more—not less—must be done to tackle and prevent obesity in societies for the prevention of chronic disease and greater adverse reactions to viral pandemics.AcknowledgmentsThe authors thank Liz Coyle from the University of Glasgow for her excellent technical assistance in the preparation of this article.Sources of FundingThe work in this study is supported by the British Heart Foundation Center of Research Excellence Grant RE/18/6/34217.DisclosuresDr Sattar reports personal fees from Amgen, AstraZeneca, Eli Lilly, Novo Nordisk, Pfizer, and Sanofi and personal fees and research grants from Boehringer Ingelheim outside the submitted work. Drs McInnes and McMurray report no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circNaveed Sattar, MD, Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom. Email naveed.sattar@glasgow.ac.ukReferences1. Petrilli CM, Jones SA, Yang J, Rajagopalan H, O'Donnell LF, Chernyak Y, Tobin K, Cerfolio RJ, Francois F, Horwitz LI. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study.BMJ2020; 369:m1966. doi: 10.1136/bmj.m1966CrossrefMedlineGoogle Scholar2. Simonnet A, Chetboun M, Poissy J, Raverdy V, Noulette J, Duhamel A, Labreuche J, Mathieu D, Pattou F, Jourdain M, Lille Intensive Care COVID-19 and Obesity Study Group. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation [published online April 9, 2020].Obesity (Silver Spring). doi: 10.1002/oby.22831. https://onlinelibrary.wiley.com/doi/10.1002/oby.22831Google Scholar3. Lighter J, Phillips M, Hochman S, Sterling S, Johnson D, Francois F, Stachel A. Obesity in patients younger than 60 years is a risk factor for COVID-19 hospital admission [published online April 9, 2020].Clin Infect Dis. 2020. doi:10.1093/cid/ciaa415. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa415/5818333CrossrefGoogle Scholar4. Budu-Aggrey A, Brumpton B, Tyrrell J, Watkins S, Modalsli EH, Celis-Morales C, Ferguson LD, Vie GÅ, Palmer T, Fritsche LG, et al. Evidence of a causal relationship between body mass index and psoriasis: a mendelian randomization study.PLoS Med. 2019; 16:e1002739. doi: 10.1371/journal.pmed.1002739CrossrefMedlineGoogle Scholar5. Green WD, Beck MA. Obesity impairs the adaptive immune response to influenza virus.Ann Am Thorac Soc. 2017; 14(suppl 5):S406–S409. doi: 10.1513/AnnalsATS.201706-447AWCrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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Ramos T and Adhikary D (2024) Genome Designing for Nutritional Quality in Amaranthus Compendium of Crop Genome Designing for Nutraceuticals, 10.1007/978-981-19-3627-2_56-2, (1-33), . Aktiz Bıçak E and Oğlak S (2023) Clinical characterisation and management outcome of obstetric patients following intensive care unit admission for COVID-19 pneumonia, Journal of Obstetrics and Gynaecology, 10.1080/01443615.2023.2218915, 43:2, Online publication date: 8-Dec-2023. Nganabashaka J, Niyibizi J, Umwali G, Rulisa S, M. Bavuma C, Byiringiro J, Ntawuyirushintege S, Niyomugabo P, Izerimana L, Tumusiime D and Keetile M (2023) The effects of COVID-19 mitigation measures on physical activity (PA) participation among adults in Rwanda: An online cross-sectional survey, PLOS ONE, 10.1371/journal.pone.0293231, 18:11, (e0293231) Moll-Bernardes R, Ferreira J, Sousa A, Tortelly M, Pimentel A, Figueiredo A, Schaustz E, Secco J, Sales A, Terzi F, Xavier de Brito A, Sarmento R, Noya-Rabelo M, Fortier S, Matos e Silva F, Vera N, Conde L, Cabral-Castro M, Albuquerque D, Rosado de-Castro P, Camargo G, Pinheiro M, Souza O, Bozza F, Luiz R and Medei E (2023) Impact of the immune profiles of hypertensive patients with and without obesity on COVID-19 severity, International Journal of Obesity, 10.1038/s41366-023-01407-0 Onyango T, Zhou F, Bredholt G, Brokstad K, Lartey S, Mohn K, Özgümüs T, Kittang B, Linchausen D, Shafiani S, Elyanow R, Blomberg B, Langeland N and Cox R (2023) SARS-CoV-2 specific immune responses in overweight and obese COVID-19 patients, Frontiers in Immunology, 10.3389/fimmu.2023.1287388, 14 Chenchula S, Sharma S, Tripathi M, Chavan M, Misra A and Rangari G (2023) Prevalence of overweight and obesity and their effect on COVID‐19 severity and hospitalization among younger than 50 years versus older than 50 years population: A systematic review and meta‐analysis, Obesity Reviews, 10.1111/obr.13616, 24:11, Online publication date: 1-Nov-2023. Boutari C, Kokkorakis M, Stefanakis K, Valenzuela-Vallejo L, Axarloglou E, Volčanšek Š, Chakhtoura M and Mantzoros C (2023) Recent research advances in metabolism, clinical and experimental, Metabolism, 10.1016/j.metabol.2023.155722, (155722), Online publication date: 1-Nov-2023. Woodward-Lopez G, Esaryk E, Rauzon S, Hewawitharana S, Thompson H, Cordon I and Whetstone L (2023) Associations between Changes in Food Acquisition Behaviors, Dietary Intake, and Bodyweight during the COVID-19 Pandemic among Low-Income Parents in California, Nutrients, 10.3390/nu15214618, 15:21, (4618) Zhang Y, Li J, Feng L, Luo Y, Pang W, Qiu K, Mao M, Song Y, Cheng D, Rao Y, Wang X, Hu Y, Ying Z, Pu X, Lin S, Huang S, Liu G, Zhang W, Xu W, Zhao Y and Ren J (2023) A Population-Based Outcome-Wide Association Study of the Comorbidities and Sequelae Following COVID-19 Infection, Journal of Epidemiology and Global Health, 10.1007/s44197-023-00161-w Jeong S, Yun S, Park S and Mun S (2023) Understanding cross-data dynamics of individual and social/environmental factors through a public health lens: explainable machine learning approaches, Frontiers in Public Health, 10.3389/fpubh.2023.1257861, 11 Cosentino F, Verma S, Ambery P, Treppendahl M, van Eickels M, Anker S, Cecchini M, Fioretto P, Groop P, Hess D, Khunti K, Lam C, Richard-Lordereau I, Lund L, McGreavy P, Newsome P, Sattar N, Solomon S, Weidinger F, Zannad F and Zeiher A (2023) Cardiometabolic risk management: insights from a European Society of Cardiology Cardiovascular Round Table, European Heart Journal, 10.1093/eurheartj/ehad445, 44:39, (4141-4156), Online publication date: 14-Oct-2023. ATUK KAHRAMAN T and YILMAZ M (2023) Comparison of The Nutritional Habits of Individuals With and Without a COVID-19 Diagnosis: An Online Cross-Sectional Study From TürkiyeCOVID-19 Tanısı Alan ve Almayan Bireylerin Beslenme Alışkanlıklarının Karşılaştırılması: Türkiye'den Çevrimiçi Kesitsel Bir Çalışma, İzmir Katip Çelebi Üniversitesi Sağlık Bilimleri Fakültesi Dergisi, 10.61399/ikcusbfd.1244702, 8:3, (1009-1017) Sprockel Díaz J, Coral Zuñiga V, Angarita Gonzalez E, Tabares Rodríguez S, Carrillo Ayerbe M, Acuña Cortes I, Montoya Rumpf R, Martínez Arias L, Parra J and Diaztagle Fernández J (2023) Obesity and the obesity paradox in patients with severe COVID-19, Medicina Intensiva (English Edition), 10.1016/j.medine.2023.03.009, 47:10, Online publication date: Sprockel Díaz J, Coral Zuñiga V, Angarita Gonzalez E, Tabares Rodríguez S, Carrillo Ayerbe M, Acuña Cortes I, Montoya Rumpf R, Martínez Arias L, Parra J and Diaztagle Fernández J (2023) Obesity and the obesity paradox in patients 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The goal of this task force was to examine the 1992 definition of the intensivist, identify gaps, and initiate a path forward to define a concise and practical definition that could be applied globally. A modified Delphi technique was used to develop a revised definition and roles of the intensivist. We determined a priori that 75% or greater participant agreement for the definition and essential roles of the intensivist was required. A task force consisting of physicians, a respiratory therapist, advanced practice providers, and a pharmacist that practice in critical/intensive care medicine, in various settings, was established with the goal of evaluating and revising the previous definition considering evolving healthcare. The task force participated in online questionnaires related to the definition and roles of the intensivist. None. The task force agreed on the following definition of an intensivist: "A physician who has successfully completed an accredited program or equivalent critical care/intensive care medicine training and maintains advanced certification (if available); and shows dedication to the area of critical/intensive care medicine in the way of professional work." Additionally, the task force determined a list of essential roles of the intensivist categorized into Direct Clinical Care, Unit Management/Unit Involvement, Responsibility to the Community, and Administration and Leadership. The revised definition of the intensivist seeks to integrate the intensivist in the current realm of team-based healthcare. The intensivist is a physician who provides care to critically ill patients in collaboration with an interprofessional team. Establishment of a single, revised definition is intended to render clarity of an intensivist's role and responsibilities for patients, families, and the interprofessional team.

For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310&#x2008;000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120&#x2008;000 sources were used for estimation of disease and injury burden and 59&#x2008;000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100&#x2008;000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2&#xb7;5th and 97&#xb7;5th percentile ordered values from a 250-draw distribution. Total numbers of global DALYs grew 6&#xb7;1% (95% UI 4&#xb7;0-8&#xb7;1), from 2&#xb7;64 billion (2&#xb7;46-2&#xb7;86) in 2010 to 2&#xb7;80 billion (2&#xb7;57-3&#xb7;08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12&#xb7;6% (11&#xb7;0-14&#xb7;1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1&#xb7;45 billion (1&#xb7;31-1&#xb7;61) global DALYs in 2010, increasing to 1&#xb7;80 billion (1&#xb7;63-2&#xb7;03) in 2023, alongside a concurrent 4&#xb7;1% (1&#xb7;9-6&#xb7;3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90&#xb7;2 million [75&#xb7;2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62&#xb7;8% [34&#xb7;0-107&#xb7;5]), depressive disorders (26&#xb7;3% [11&#xb7;6-42&#xb7;9]), and diabetes (14&#xb7;9% [7&#xb7;5-25&#xb7;6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25&#xb7;8% (22&#xb7;6-28&#xb7;7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49&#xb7;1% (32&#xb7;7-61&#xb7;0) for diarrhoeal diseases, 42&#xb7;9% (38&#xb7;0-48&#xb7;0) for HIV/AIDS, and 42&#xb7;2% (23&#xb7;6-56&#xb7;6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16&#xb7;5% (10&#xb7;6-22&#xb7;0) and 24&#xb7;8% (7&#xb7;4-36&#xb7;7), respectively. Injury-related age-standardised DALY rates decreased by 15&#xb7;6% (10&#xb7;7-19&#xb7;8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1&#xb7;27 billion [1&#xb7;18-1&#xb7;38]) of the roughly 2&#xb7;80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8&#xb7;4% (6&#xb7;9-10&#xb7;0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30&#xb7;7% (24&#xb7;8-37&#xb7;3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6&#xb7;7% (2&#xb7;0-11&#xb7;0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54&#xb7;4% (38&#xb7;7-65&#xb7;3) for unsafe sanitation, 50&#xb7;5% (33&#xb7;3-63&#xb7;1) for unsafe water source, and 45&#xb7;2% (25&#xb7;6-72&#xb7;0) for no access to handwashing facility, and by 44&#xb7;9% (37&#xb7;3-53&#xb7;5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10&#xb7;5% [0&#xb7;1 to 20&#xb7;9]), drug use (8&#xb7;4% [2&#xb7;6 to 15&#xb7;3]), and high FPG (6&#xb7;2% [-2&#xb7;7 to 15&#xb7;6]; non-significant). Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. Gates Foundation and Bloomberg Philanthropies.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is one of the most prevalent liver diseases globally, contributing to both economic and health-related challenges. We aimed to evaluate the global, regional, and national burden of MASLD from 1990 to 2023, quantify the contribution of identified modifiable risk factors, and project future prevalence up to the year 2050. Estimates of MASLD prevalence and disability-adjusted life-years (DALYs) were produced by age, sex, region, Socio-demographic Index (SDI), and Healthcare Access and Quality (HAQ) index across 204 countries and territories from 1990 to 2023 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023. The MASLD burden attributable to three risk factors (smoking, high BMI, and high fasting plasma glucose) was assessed as part of the GBD comparative risk assessment. As a secondary analysis, we used these estimates to forecast MASLD prevalence up to 2050 using fasting plasma glucose and mean BMI as predictors. Furthermore, to examine the relative contributions of population ageing, population growth, and changes in MASLD prevalence rate to the forecasted changes in case counts from 2023 to 2050, we conducted a decomposition analysis. In 2023, approximately 1&#xb7;3 billion (95% uncertainty interval [UI] 1&#xb7;2 to 1&#xb7;4) individuals were estimated to be living with MASLD (ie, 16&#xb7;1% of the global population), with an age-standardised prevalence rate of 14&#x2009;429&#xb7;3 (95% UI 13&#x2009;268&#xb7;3 to 15&#x2009;990&#xb7;6) per 100&#x2009;000 population, representing a percentage increase of 142&#xb7;7% (95% UI 139&#xb7;2 to 146&#xb7;7) in crude numbers from 1990 (0&#xb7;5 billion [0&#xb7;5 to 0&#xb7;6]) and of 28&#xb7;6% (27&#xb7;8 to 29&#xb7;5) in the rate (11&#x2009;217&#xb7;2 [10&#x2009;276&#xb7;8 to 12&#x2009;467&#xb7;0] per 100&#x2009;000 in 1990). An estimated 3&#xb7;6 million (2&#xb7;8 to 4&#xb7;5) total DALYs were attributable to MASLD worldwide in 2023, corresponding to an age-standardised DALY rate of 39&#xb7;6 (31&#xb7;2 to 49&#xb7;9) per 100&#x2009;000 population. Despite a 116&#xb7;3% (93&#xb7;3 to 139&#xb7;4) increase in crude DALYs (from 1&#xb7;7 million [1&#xb7;3 to 2&#xb7;1] in 1990), its age-standardised estimate remained consistent (1&#xb7;8% [-8&#xb7;6 to 12&#xb7;8]) from 1990 (38&#xb7;9 [30&#xb7;1 to 49&#xb7;8] per 100&#x2009;000) to 2023. There was substantial variation in age-standardised estimates across regions. North Africa and the Middle East had the highest prevalence rate (29&#x2009;246&#xb7;1 [26&#x2009;848&#xb7;3 to 32&#x2009;048&#xb7;7] per 100&#x2009;000) and Andean Latin America showed the highest DALY rate (152&#xb7;3 [114&#xb7;1 to 194&#xb7;7] per 100&#x2009;000). By contrast, the high-income Asia Pacific region had the lowest prevalence rate (8653&#xb7;5 [7923&#xb7;7 to 9592&#xb7;8] per 100&#x2009;000) and east Asia had the lowest DALY rate (16&#xb7;3 [13&#xb7;5 to 19&#xb7;9] per 100&#x2009;000) among all GBD regions. North Africa and the Middle East showed disproportionately higher prevalence rates relative to other regions with similar SDIs. Lower SDIs and HAQs were associated with higher age-standardised DALY rates. The age-standardised prevalence rate was consistently higher in males (15&#x2009;616&#xb7;4 [14&#x2009;349&#xb7;2 to 17&#x2009;263&#xb7;3] per 100&#x2009;000 people in 2023) than in females (13&#x2009;245&#xb7;2 [12&#x2009;132&#xb7;0 to 14&#x2009;692&#xb7;6] per 100&#x2009;000 people), and peaked at age 80-84 years in both sexes. The number of MASLD prevalent cases was the highest in younger adults, peaking at age 35-39 years for males and age 55-59 years for females. Among the risk factors for MASLD, high fasting plasma glucose presented the largest contribution to the age-standardised DALY rate of total MASLD in 2023 (2&#xb7;2 [95% UI 1&#xb7;6 to 3&#xb7;1] per 100&#x2009;000 people), followed by high BMI (1&#xb7;4 [0&#xb7;6 to 2&#xb7;4] per 100&#x2009;000 people) and smoking (1&#xb7;0 [0&#xb7;3 to 1&#xb7;8] per 100&#x2009;000 people). Our forecasting model estimates that 1&#xb7;8 billion (95% UI 1&#xb7;6 to 2&#xb7;0) individuals are likely to have MASLD by 2050, representing a 42&#xb7;0% increase from 2023. The age-standardised prevalence rate is expected to increase to 15&#x2009;774&#xb7;9 (95% UI 14&#x2009;613&#xb7;9 to 17&#x2009;336&#xb7;2) per 100&#x2009;000 people in 2050, representing an average annual percentage change of 0&#xb7;3% (95% UI 0&#xb7;3-0&#xb7;3). According to our decomposition analysis, this change will be primarily due to population growth, particularly in sub-Saharan Africa and North Africa and Middle East, and less by population ageing or epidemiological change. With a global prevalence of 16&#xb7;1% and approximately 1&#xb7;3 billion people already living with MASLD in 2023, the condition has and will continue to have substantial health and economic impacts worldwide. An inverse association between the HAQ Index and age-standardised DALY rates suggests that countries with lower health-care access and quality might be less well positioned to manage the growing MASLD burden, underscoring the need for strengthened health-system capacity in these settings. Gates Foundation.

Comprehensive, comparable, and timely estimates of demographic metrics-including life expectancy and age-specific mortality-are essential for evaluating, understanding, and addressing trends in population health. The COVID-19 pandemic highlighted the importance of timely and all-cause mortality estimates for being able to respond to changing trends in health outcomes, showing a strong need for demographic analysis tools that can produce all-cause mortality estimates more rapidly with more readily available all-age vital registration (VR) data. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) is an ongoing research effort that quantifies human health by estimating a range of epidemiological quantities of interest across time, age, sex, location, cause, and risk. This study-part of the latest GBD release, GBD 2023-aims to provide new and updated estimates of all-cause mortality and life expectancy for 1950 to 2023 using a novel statistical model that accounts for complex correlation structures in demographic data across age and time. We used 24&#x2008;025 data sources from VR, sample registration, surveys, censuses, and other sources to estimate all-cause mortality for males, females, and all sexes combined across 25 age groups in 204 countries and territories as well as 660 subnational units in 20 countries and territories, for the years 1950-2023. For the first time, we used complete birth history data for ages 5-14 years, age-specific sibling history data for ages 15-49 years, and age-specific mortality data from Health and Demographic Surveillance Systems. We developed a single statistical model that incorporates both parametric and non-parametric methods, referred to as OneMod, to produce estimates of all-cause mortality for each age-sex-location group. OneMod includes two main steps: a detailed regression analysis with a generalised linear modelling tool that accounts for age-specific covariate effects such as the Socio-demographic Index (SDI) and a population attributable fraction (PAF) for all risk factors combined; and a non-parametric analysis of residuals using a multivariate kernel regression model that smooths across age and time to adaptably follow trends in the data without overfitting. We calibrated asymptotic uncertainty estimates using Pearson residuals to produce 95% uncertainty intervals (UIs) and corresponding 1000 draws. Life expectancy was calculated from age-specific mortality rates with standard demographic methods. For each measure, 95% UIs were calculated with the 25th and 975th ordered values from a 1000-draw posterior distribution. In 2023, 60&#xb7;1 million (95% UI 59&#xb7;0-61&#xb7;1) deaths occurred globally, of which 4&#xb7;67 million (4&#xb7;59-4&#xb7;75) were in children younger than 5 years. Due to considerable population growth and ageing since 1950, the number of annual deaths globally increased by 35&#xb7;2% (32&#xb7;2-38&#xb7;4) over the 1950-2023 study period, during which the global age-standardised all-cause mortality rate declined by 66&#xb7;6% (65&#xb7;8-67&#xb7;3). Trends in age-specific mortality rates between 2011 and 2023 varied by age group and location, with the largest decline in under-5 mortality occurring in east Asia (67&#xb7;7% decrease); the largest increases in mortality for those aged 5-14 years, 25-29 years, and 30-39 years occurring in high-income North America (11&#xb7;5%, 31&#xb7;7%, and 49&#xb7;9%, respectively); and the largest increases in mortality for those aged 15-19 years and 20-24 years occurring in Eastern Europe (53&#xb7;9% and 40&#xb7;1%, respectively). We also identified higher than previously estimated mortality rates in sub-Saharan Africa for all sexes combined aged 5-14 years (87&#xb7;3% higher in GBD 2023 than GBD 2021 on average across countries and territories over the 1950-2021 period) and for females aged 15-29 years (61&#xb7;2% higher), as well as lower than previously estimated mortality rates in sub-Saharan Africa for all sexes combined aged 50 years and older (13&#xb7;2% lower), reflecting advances in our modelling approach. Global life expectancy followed three distinct trends over the study period. First, between 1950 and 2019, there were considerable improvements, from 51&#xb7;2 (50&#xb7;6-51&#xb7;7) years for females and 47&#xb7;9 (47&#xb7;4-48&#xb7;4) years for males in 1950 to 76&#xb7;3 (76&#xb7;2-76&#xb7;4) years for females and 71&#xb7;4 (71&#xb7;3-71&#xb7;5) years for males in 2019. Second, this period was followed by a decrease in life expectancy during the COVID-19 pandemic, to 74&#xb7;7 (74&#xb7;6-74&#xb7;8) years for females and 69&#xb7;3 (69&#xb7;2-69&#xb7;4) years for males in 2021. Finally, the world experienced a period of post-pandemic recovery in 2022 and 2023, wherein life expectancy generally returned to pre-pandemic (2019) levels in 2023 (76&#xb7;3 [76&#xb7;0-76&#xb7;6] years for females and 71&#xb7;5 [71&#xb7;2-71&#xb7;8] years for males). 194 (95&#xb7;1%) of 204 countries and territories experienced at least partial post-pandemic recovery in age-standardised mortality rates by 2023, with 61&#xb7;8% (126 of 204) recovering to or falling below pre-pandemic levels. There were several mortality trajectories during and following the pandemic across countries and territories. Long-term mortality trends also varied considerably between age groups and locations, demonstrating the diverse landscape of health outcomes globally. This analysis identified several key differences in mortality trends from previous estimates, including higher rates of adolescent mortality, higher rates of young adult mortality in females, and lower rates of mortality in older age groups in much of sub-Saharan Africa. The findings also highlight stark differences across countries and territories in the timing and scale of changes in all-cause mortality trends during and following the COVID-19 pandemic (2020-23). Our estimates of evolving trends in mortality and life expectancy across locations, ages, sexes, and SDI levels in recent years as well as over the entire 1950-2023 study period provide crucial information for governments, policy makers, and the public to ensure that health-care systems, economies, and societies are prepared to address the world's health needs, particularly in populations with higher rates of mortality than previously known. The estimates from this study provide a robust framework for GBD and a valuable foundation for policy development, implementation, and evaluation around the world. Gates Foundation.

Breast cancer is a leading cause of mortality and morbidity among females worldwide. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, we provided an updated comprehensive assessment of the epidemiological trends, disease burden, and risk factors associated with breast cancer globally, regionally, and nationally from 1990 to 2023. Breast cancer incidence, mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) were estimated by age and sex for 204 countries and territories from 1990 to 2023. Mortality estimates were generated using GBD Cause of Death Ensemble models, leveraging data from population-based cancer registration systems, vital registration systems, and verbal autopsies. Mortality-to-incidence ratios were calculated to derive both mortality and incidence estimates. Prevalence was calculated by combining incidence and modelled survival estimates. YLLs were established by multiplying age-specific deaths with the GBD standard life expectancy at the age of death. YLDs were estimated by applying disability weights to prevalence estimates. The sum of YLLs and YLDs equalled the number of DALYs. Breast cancer burden attributable to seven risk factors was examined through the comparative risk assessment framework. The GBD forecasting framework was used to forecast breast cancer incidence and mortality from 2024 to 2050. Age-standardised rates were calculated for each metric using the GBD 2023 world standard population. In 2023, there were an estimated 2&#xb7;30 million (95% uncertainty interval [UI] 2&#xb7;01 to 2&#xb7;61) breast cancer incident cases, 764&#x2008;000 deaths (672&#x2008;000 to 854&#x2008;000), and 24&#xb7;1 million (21&#xb7;3 to 27&#xb7;5) DALYs among females globally. In the World Bank low-income group, where a low age-standardised incidence rate (ASIR) was estimated (44&#xb7;2 per 100&#x2008;000 person-years [31&#xb7;2 to 58&#xb7;4]), the age-standardised mortality rate (ASMR) was the highest (24&#xb7;1 per 100&#x2008;000 [16&#xb7;8 to 31&#xb7;9]). The highest ASIR was in the high-income group (75&#xb7;7 per 100&#x2008;000 [67&#xb7;1 to 84&#xb7;0]), and the lowest ASMR was in the upper-middle-income group (11&#xb7;2 per 100&#x2008;000 [10&#xb7;2 to 12&#xb7;3]). Between 1990 and 2023, the ASIR in the low-income group increased by 147&#xb7;2% (38&#xb7;1 to 271&#xb7;7), compared with a 1&#xb7;2% (-11&#xb7;5 to 17&#xb7;2) change in the high-income group. The ASMR decreased in the high-income group, changing by -29&#xb7;9% (-33&#xb7;6 to -25&#xb7;9), but increased by 99&#xb7;3% (12&#xb7;5 to 202&#xb7;9) in the low-income group. The increase in age-standardised DALY rates followed that of ASMRs. Risk factors such as dietary risks, tobacco use, and high fasting plasma glucose contributed to 28&#xb7;3% (16&#xb7;6 to 38&#xb7;9) of breast cancer DALYs in 2023. The risk factors with a decrease in attributable DALYs between 1990 and 2023 were high alcohol use and tobacco. By 2050, the global incident cases of breast cancer among females were forecast to reach 3&#xb7;56 million (2&#xb7;29 to 4&#xb7;83), with 1&#xb7;37 million (0&#xb7;841 to 2&#xb7;02) deaths. The stable incidence and declining mortality rates of female breast cancer in high-income nations reflect success in screening, diagnosis, and treatment. In contrast, the concurrent rise in incidence and mortality in other regions signals health system deficits. Without effective interventions, many countries will fall short of the WHO Global Breast Cancer Initiative's ambitious target of achieving an annual reduction of 2&#xb7;5% in age-standardised mortality rates by 2040. The mounting breast cancer burden, disproportionately affecting some of the world's most vulnerable populations, will further exacerbate health inequalities across the globe without decisive immediate action. Gates Foundation, St Jude Children's Research Hospital.

This special article is the 18th in an annual series for the Journal of Cardiothoracic and Vascular Anesthesia. The authors thank the editor-in-chief, Dr. Kaplan, Dr. Augoustides, and the editorial board for the opportunity to continue this series, namely, the research highlights of the past year in the specialty of cardiothoracic and vascular anesthesiology. The major themes selected for 2025 are outlined in this introduction, and each highlight is reviewed in detail in the main article. The literature highlights in the specialty for 2025 begin with an update on perioperative rehabilitation and enhanced recovery in cardiothoracic surgery, with a focus on prehabilitation and the impact of implementing enhanced recovery care models on outcomes. The second major theme is focused on cardiac surgery, with the authors discussing new insights into blood conservation methods and updates on coronary artery bypass grafting. The third theme is focused on cardiothoracic transplantation, with discussions focusing on techniques related to lung transplantation including extracorporeal life support. The fourth theme is focused on mechanical circulatory support, with discussions exploring advancements in left ventricular assist devices, highlighting the evolving landscape of mechanical circulatory support in cardiogenic shock and discussing anticoagulation practices. The fifth and final theme is an update on medical cardiology, with a focus on outcomes of transcatheter management of aortic valve pathology, tricuspid valve regurgitation, and surgical versus transcatheter management of mitral valve disease. The themes selected for this article are only a few of the diverse advances in the specialty during 2025. These highlights will inform the reader of key updates on a variety of topics, leading to the improvement of perioperative outcomes for patients with cardiothoracic and vascular disease.

Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. To estimate the worldwide burden of SAH. Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. SAH and 14 modifiable risk factors. Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor-specific population attributable fractions (PAFs). In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100&#x202f;000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF]&#x2009;=&#x2009;51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF&#x2009;=&#x2009;14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

Donor lung procurement and preservation is critical for lung transplantation&#xa0;success. Unfortunately, the large variability in techniques impacts organ utilization rates and transplantation outcomes. Compounding this variation, recent developments in cold static preservation and new technological advances with machine perfusion have increased the complexity of the procedure. The objective of the American Association for Thoracic Surgery (AATS) Clinical Practice Standards Committee (CPSC) expert panel was to make evidence-based recommendations for best practices in donor lung procurement and preservation&#xa0;based on review of the existing literature. The AATS CPSC assembled an expert panel of 16 lung transplantation surgeons from 14 centers who developed a consensus document of recommendations. The panel was divided into 7 subgroups covering (1) intraoperative donor assessment, (2) surgical techniques, (3) ex situ static lung preservation methods, (4) hypothermic preservation, (5) normothermic ex&#xa0;vivo lung perfusion (EVLP), (6) donation after circulatory death (DCD) and normothermic regional perfusion, and (7) donor management centers, organ assessment centers, and third-party procurement&#xa0;teams. Following a focused literature review, each subgroup formulated recommendation statements for each subtopic, which were reviewed and further refined using a Delphi process until a 75% consensus was achieved on each final statement by the voting group. The expert panel achieved consensus on 34 recommendations for current best practices in donor lung procurement and preservation both in brain-dead as well as DCD donation. The use of new methods of cold preservation, the role of EVLP, and DCD with and without concomitant heart donation are described in detail. Consistent and best practices in donor lung procurement and preservation&#xa0;are critical to improve both lung transplantation numbers as well as recipient outcomes. The recommendations described here provide guidance for&#xa0;professionals involved in the care of patients with end-stage lung disease considered for transplantation.

During early months of the COVID-19 pandemic, presentations for acute myocardial infarction (AMI) declined significantly, and outcomes worsened. However, the full extent and long-term sequelae of changes in AMI epidemiology during the pandemic remain uncertain, as does whether these patterns differed by rurality. To describe the epidemiology of AMI-related hospitalizations, interventions, and outcomes among Medicare beneficiaries throughout the COVID-19 pandemic, focusing on differences in urban and rural populations. This retrospective cohort study included all Medicare fee-for-service beneficiaries with AMI between January 1, 2018, and December 31, 2023, in the analysis. Data were analyzed from March 19 to July 9, 2025. Time period (prepandemic [January 1, 2018, to December 31, 2019], pandemic [January 1, 2020, to December 31, 2021], and postpandemic [January 1, 2022, to December 31, 2023]) and beneficiary-level rurality. The primary outcome was in-hospital death, defined as death within 1 day of discharge from the index episode of AMI. Secondary outcomes included death within 90 days of the index admission date and postdischarge outcomes. AMI episodes were defined as any emergency department (ED), observational, or inpatient stay with a primary ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) diagnosis or a primary cardiogenic shock and secondary STEMI or NSTEMI diagnosis. Generalized estimating equations clustering on hospitals were used to compare pandemic and postpandemic outcomes with the prepandemic period, adjusting for beneficiary characteristics. A total of 1&#x202f;152&#x202f;851 AMI episodes among 1&#x202f;032&#x202f;212 beneficiaries were identified between 2018 and 2023, of which 75.6% were NSTEMI. Most AMI episodes were among male (57.6%) beneficiaries aged 65 to 80 years (56.8%). The unadjusted quarterly incidence of AMI decreased from 17.2 to 13.0 episodes per million beneficiary days at risk (quarter 1 of 2018 to quarter 4 of 2023). In-hospital (adjusted odds ratio [AOR], 1.09; 95% CI, 1.07-1.11]) and 90-day mortality (AOR, 1.10; 95% CI, 1.09-1.12) increased during the pandemic and then returned to baseline or lower (AORs, 0.99 [95% CI, 0.97-1.01] and 0.96 [95% CI, 0.95-0.98], respectively). After the pandemic, beneficiaries were less likely to discharge to a skilled nursing facility (AOR, 0.67; 95% CI, 0.66-0.68), utilize the ED (adjusted incidence rate ratio [AIRR], 0.93; 95% CI, 0.92-0.94), or experience readmission (AIRR, 0.90; 95% CI, 0.90-0.92) within 90 days of their index episode of AMI. Patterns were largely similar by rurality. In this retrospective cohort study of fee-for-service Medicare beneficiaries, the incidence of AMI decreased during and after the pandemic. Beneficiaries experienced greater in-hospital and 90-day mortality during the pandemic. After the pandemic, in-hospital and 90-day mortality returned to baseline among micropolitan and rural beneficiaries and was lower than baseline among urban beneficiaries.

BioTechniquesVol. 30, No. 1 BenchmarksOpen AccessMicroplate Assay for the Measurement of Hydroxyproline in Acid-Hydrolyzed Tissue SamplesSharon Brown, Michael Worsfold & Christopher SharpSharon Brown*Address correspondence to Ms. Sharon Brown, Charles Salt Centre, Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, Shropshire SY10 7AG, UK. e-mail: E-mail Address: sharon.rowbotham@rjahoh-tr.wmids.nhs.ukRobert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, ShropshireUniversity College Chester, Chester, Cheshire, UK, Michael WorsfoldRobert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, Shropshire & Christopher SharpRobert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, ShropshirePublished Online:5 Sep 2018https://doi.org/10.2144/01301bm06AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInReddit FiguresReferencesRelatedDetailsCited ByCollagen fibrils from both positional and energy-storing tendons exhibit 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