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INTRODUCTION: Healthcare systems are complex and challenging for all stakeholders, but artificial intelligence (AI) has transformed various fields, including healthcare, with the potential to improve patient care and quality of life. Rapid AI advancements can revolutionize healthcare by integrating it into clinical practice. Reporting AI's role in clinical practice is crucial for successful implementation by equipping healthcare providers with essential knowledge and tools. RESEARCH SIGNIFICANCE: This review article provides a comprehensive and up-to-date overview of the current state of AI in clinical practice, including its potential applications in disease diagnosis, treatment recommendations, and patient engagement. It also discusses the associated challenges, covering ethical and legal considerations and the need for human expertise. By doing so, it enhances understanding of AI's significance in healthcare and supports healthcare organizations in effectively adopting AI technologies. MATERIALS AND METHODS: The current investigation analyzed the use of AI in the healthcare system with a comprehensive review of relevant indexed literature, such as PubMed/Medline, Scopus, and EMBASE, with no time constraints but limited to articles published in English. The focused question explores the impact of applying AI in healthcare settings and the potential outcomes of this application. RESULTS: Integrating AI into healthcare holds excellent potential for improving disease diagnosis, treatment selection, and clinical laboratory testing. AI tools can leverage large datasets and identify patterns to surpass human performance in several healthcare aspects. AI offers increased accuracy, reduced costs, and time savings while minimizing human errors. It can revolutionize personalized medicine, optimize medication dosages, enhance population health management, establish guidelines, provide virtual health assistants, support mental health care, improve patient education, and influence patient-physician trust. CONCLUSION: AI can be used to diagnose diseases, develop personalized treatment plans, and assist clinicians with decision-making. Rather than simply automating tasks, AI is about developing technologies that can enhance patient care across healthcare settings. However, challenges related to data privacy, bias, and the need for human expertise must be addressed for the responsible and effective implementation of AI in healthcare.

INTRODUCTION Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection (1). Sepsis and septic shock are major healthcare problems, impacting millions of people around the world each year and killing between one in three and one in six of those it affects (2–4). Early identification and appropriate management in the initial hours after the development of sepsis improve outcomes. The recommendations in this document are intended to provide guidance for the clinician caring for adult patients with sepsis or septic shock in the hospital setting. Recommendations from these guidelines cannot replace the clinician’s decision-making capability when presented with a unique patient’s clinical variables. These guidelines are intended to reflect best practice (Table 1). TABLE 1. - Table of Current Recommendations and Changes From Previous 2016 Recommendations Recommendations 2021 Recommendation Strength and Quality of Evidence Changes From 2016 Recommendations 1. For hospitals and health systems, we recommend using a performance improvement program for sepsis, including sepsis screening for acutely ill, high-risk patients and standard operating procedures for treatment. Strong , moderate-quality evidence (for screening) Changed from Best practice statement “We recommend that hospitals and hospital systems have a performance improvement program for sepsis including sepsis screening for acutely ill, high-risk patients.” Strong , very low-quality evidence (for standard operating procedures) 2. We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a single-screening tool for sepsis or septic shock. Strong , moderate-quality evidence NEW 3. For adults suspected of having sepsis, we suggest measuring blood lactate. Weak , low quality of evidence INITIAL RESUSCITATION 4. Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately. Best practice statement 5. For patients with sepsis induced hypoperfusion or septic shock we suggest that at least 30 mL/kg of IV crystalloid fluid should be given within the first 3 hr of resuscitation. Weak, low quality of evidence DOWNGRADE from Strong , low quality of evidence “We recommend that in the initial resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid be given within the first 3 hr” 6. For adults with sepsis or septic shock, we suggest using dynamic measures to guide fluid resuscitation, over physical examination, or static parameters alone. Weak , very low quality of evidence 7. For adults with sepsis or septic shock, we suggest guiding resuscitation to decrease serum lactate in patients with elevated lactate level, over not using serum lactate. Weak , low quality of evidence 8. For adults with septic shock, we suggest using capillary refill time to guide resuscitation as an adjunct to other measures of perfusion. Weak , low quality of evidence NEW MEAN ARTERIAL PRESSURE 9. For adults with septic shock on vasopressors, we recommend an initial target mean arterial pressure (MAP) of 65 mm Hg over higher MAP targets. Strong , moderate-quality evidence ADMISSION TO INTENSIVE CARE 10. For adults with sepsis or septic shock who require we suggest the patients to the within Weak , low quality of evidence For adults with suspected sepsis or septic shock we recommend and for and an of is or Best practice statement For adults with septic shock or a for sepsis, we recommend within hr of Strong , low quality of evidence from “We recommend that of should be as as after and within one for septic shock and sepsis Strong , very low quality of evidence , quality of evidence For adults with sepsis shock, we recommend of the of of Best practice statement For adults with sepsis shock, we suggest a of and for infection the of within 3 hr from the time when sepsis first Weak , very low quality of evidence NEW from “We recommend that of IV should be as as after and within hr for septic shock and sepsis , quality of evidence For adults with a low of infection and shock, we suggest to the Weak , very low quality of evidence NEW from “We recommend that of IV should be as as after and within hr for septic shock and sepsis , quality of evidence For adults with suspected sepsis or septic shock, we suggest against using clinical to when to as compared to clinical alone. Weak , very low quality of evidence For adults with sepsis or septic shock at of we recommend using with over using Best practice statement NEW from “We recommend with one or for patients with sepsis or septic shock to and or Strong , quality of evidence For adults with sepsis or septic shock at low of we suggest against using with as compared with using Weak , low quality of evidence NEW from “We recommend with one or for patients with sepsis or septic shock to and or Strong , quality of evidence For adults with sepsis or septic shock and for we suggest using with for treatment over one Weak , very low quality of evidence For adults with sepsis or septic shock and low for we suggest against using for as compared to one Weak , very low quality of evidence For adults with sepsis or septic shock, we suggest against using the and the are Weak , very low quality of evidence For adults with sepsis or septic shock at of we suggest using over Weak , low quality of evidence NEW from “We recommend with one or for patients with sepsis or septic shock to and or Strong , quality of evidence For adults with sepsis or septic shock at low of we suggest against of Weak , low quality of evidence NEW from “We recommend with one or for patients with sepsis or septic shock to and or Strong , quality of evidence We on the of For adults with sepsis or septic shock, we suggest using of for an initial over Weak , moderate-quality evidence For adults with sepsis or septic shock, we recommend of on and Best practice statement For adults with sepsis or septic shock, we recommend or a of infection that and as as and Best practice statement For adults with sepsis or septic shock, we recommend of that are a of sepsis or septic shock after other Best practice statement For adults with sepsis or septic shock, we suggest for of over using of for Weak , very low quality of evidence For adults with an initial of sepsis or septic shock and we suggest using over of Weak , very low quality of evidence For adults with an initial of sepsis or septic shock and of is we suggest using clinical to when to over clinical alone. Weak , low quality of evidence For adults with sepsis or septic shock, we recommend using as fluid for resuscitation. Strong , moderate-quality evidence For adults with sepsis or septic shock, we suggest using of for resuscitation. Weak , low quality of evidence from , low quality of “We suggest using or for fluid resuscitation of patients with sepsis or septic For adults with sepsis or septic shock, we suggest using in patients who of Weak , moderate-quality evidence For adults with sepsis or septic shock, we recommend against using for resuscitation. Strong , evidence For adults with sepsis and septic shock, we suggest against using for resuscitation. Weak , moderate-quality evidence from , low quality of evidence “We suggest using over when patients with sepsis or septic For adults with septic shock, we recommend using as the over other Strong evidence evidence quality of evidence quality of evidence low-quality evidence For adults with septic shock on with mean arterial pressure we suggest of the of Weak , quality evidence For adults with septic shock and mean arterial pressure and we suggest Weak , low quality of evidence For adults with septic shock, we suggest against using Weak , low quality of evidence For adults with septic shock and dysfunction with hypoperfusion and arterial blood we suggest to or using alone. Weak , low quality of evidence For adults with septic shock and dysfunction with hypoperfusion and arterial blood we suggest against using Weak , low quality of evidence NEW For adults with septic shock, we suggest of arterial blood pressure over as as and are Weak , very low quality of evidence For adults with septic shock, we suggest to mean arterial pressure a is Weak , very low quality of evidence NEW is evidence to a on the of fluid in the first hr of resuscitation in patients with sepsis and septic shock who have of hypoperfusion and after the initial resuscitation. NEW “We suggest using or for fluid resuscitation of patients with sepsis or septic Weak , low quality of evidence “We suggest using over when patients with sepsis or septic Weak , low quality of evidence is evidence to a on the of in adults with sepsis-induced For adults with sepsis-induced we suggest the of over Weak , low quality of evidence NEW is evidence to a on the of in to for adults with sepsis-induced For adults with sepsis-induced we recommend using a low over a Strong , evidence For adults with sepsis-induced we recommend using an for of 30 over higher Strong , moderate-quality evidence For adults with to sepsis-induced we suggest using higher over Weak , moderate-quality evidence For adults with sepsis-induced we suggest using low as compared with Weak , low quality of evidence For adults with sepsis-induced we suggest using Weak , moderate-quality evidence using we recommend against using Strong , moderate-quality evidence For adults with sepsis-induced we recommend using for hr Strong , moderate-quality evidence For adults with sepsis induced we suggest using over Weak , moderate-quality evidence For adults with sepsis-induced we suggest using when in with the in to Weak , low quality of evidence NEW For adults with septic shock and an for we suggest using IV Weak , moderate-quality evidence from Weak , low quality of evidence “We suggest against using IV to septic shock patients fluid resuscitation and are to for this is not we suggest IV at a of For adults with sepsis or septic shock we suggest against using Weak , low quality of evidence NEW from “We the of blood is evidence to a on the of other blood For adults with sepsis or septic shock we recommend using a Strong , moderate-quality evidence For adults with sepsis or septic shock we suggest against using IV Weak , low quality of evidence For adults with sepsis or septic shock, and who have for we suggest using Weak , moderate-quality evidence For adults with sepsis or septic shock, we recommend using a to Strong , moderate-quality evidence For adults with sepsis or septic shock, we recommend using low over for Strong , moderate-quality evidence For adults with sepsis or septic shock, we suggest against using in to over alone. Weak , low quality of evidence adults with sepsis or septic shock and we suggest using or Weak , low quality of evidence adults with sepsis or septic shock and with for we suggest against using Weak , moderate-quality evidence For adults with sepsis or septic shock, we recommend at a of Strong , moderate-quality evidence For adults with sepsis or septic shock we suggest against using IV Weak , low quality of evidence NEW For adults with septic shock and we suggest against using to improve or to Weak , low quality of evidence For adults with septic shock and and or we suggest using Weak , low quality of evidence For adult patients with sepsis or septic shock who be we suggest of Weak , very low quality of evidence CARE For adults with sepsis or septic shock, we recommend of and with patients and over Best practice statement For adults with sepsis or septic shock, we suggest of over hr or Weak , low quality of evidence For adults with sepsis or septic shock, is evidence to a on to of For adults with sepsis or septic shock, we recommend that the of on clinician be the treatment when to and and Best practice statement For adults with sepsis or septic shock, we suggest against for patients over on clinician Weak , low quality of evidence For adult of sepsis or septic shock and we suggest to over Weak , very low quality of evidence For adults with sepsis or septic shock, we suggest using a of at of over Weak , very low quality of evidence For adults with sepsis or septic shock, is evidence to a on the of tool over For adults with sepsis or septic shock and we recommend screening for and and and to these Best practice statement For adults with sepsis or septic shock and we suggest and sepsis and to hospital and in the setting. Weak , very low quality of evidence For adults with sepsis or septic shock and we recommend the clinical provide the to in in and hospital to are and Best practice statement For adults with sepsis and septic shock and we suggest using a compared with to the Weak , very low quality of evidence For adults with sepsis and septic shock, we recommend at and hospital Best practice statement For adult of sepsis and septic shock and we recommend including the sepsis and and after sepsis in the and hospital Best practice statement For adults with sepsis or septic shock who we recommend hospital with to and and Best practice statement For adults with sepsis or septic shock and is evidence to a on compared with For adults with sepsis or septic shock, is evidence to a for or against For adult of sepsis or septic shock, we recommend and for and after hospital Best practice statement For adult of sepsis or septic shock, we suggest to a program Weak , very low quality of evidence For adult of sepsis or septic shock for or an of we suggest to a Weak , very low quality of evidence are to in the be at for Sepsis and - Recommendation 1. For hospitals and health systems, we recommend using a performance improvement program for sepsis, including sepsis screening for acutely ill, high-risk patients and standard operating procedures for treatment. Strong quality of evidence for Strong very low-quality evidence for standard operating Sepsis performance improvement of sepsis of sepsis and for a of on the of performance improvement that these with to sepsis with a in in patients with sepsis and septic shock The of performance improvement not to be as as the of a program that sepsis screening and Sepsis screening are to identification of sepsis and of or of the health is in of these with having the of with in of clinical and are for sepsis as response of or Early or Early improve performance of screening and in a of patients from for hospital sepsis the the operating and higher for the for screening as MEWS and target patients in as or of three not a of screening is in and of sepsis screening are an of sepsis for operating procedures are a of that a response to clinical Sepsis standard operating as Early have to a standard with of the sepsis and the between of sepsis and of sepsis to hospitals in the in a and after of sepsis with a from other this time in hospitals with higher with the sepsis a of in higher with standard operating procedures compared with it in one - Recommendation 2. We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a screening tool for sepsis or septic shock. Strong moderate-quality The qSOFA three to and in patients with or suspected a a and a blood pressure mm of these are the is qSOFA to the recommendations of the on the of Sepsis qSOFA as a of in patients with or suspected to as a screening tool that time have the of the qSOFA as a screening tool for sepsis The have as to have that qSOFA is having of for identification of infection induced organ dysfunction qSOFA are screening for sepsis and the clinician to the of the that of patients a qSOFA or these patients for of have when against the Early and the Early the of a qSOFA should the clinician to the of sepsis in given the of the the a against as a screening - Recommendation 3. For adults suspected of having sepsis, we suggest measuring blood lactate. Weak low-quality The of lactate with in patients with suspected infection and sepsis is is as of the sepsis for those patients with sepsis and an elevated lactate is of the of septic shock that lactate be to for the of sepsis adult patients with suspected not have the of lactate in this The lactate an elevated from of the from with from and from the three are and an between the of lactate at and the are the of an elevated or lactate or the of a of sepsis in patients with suspected lactate is to or the on not be in we a the of serum lactate as an to the of sepsis in patients with suspected not - Recommendations 4. Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately. Best practice 5. For patients with sepsis induced hypoperfusion or septic shock we suggest that at least 30 mL/kg of IV crystalloid fluid should be given within the first 3 hours of resuscitation. Weak low-quality 6. For adults with sepsis or septic shock, we suggest using dynamic measures to guide fluid resuscitation over physical or static parameters alone. Weak very low-quality parameters response to a or a fluid using pressure or 7. For adults with sepsis or septic shock, we suggest guiding resuscitation to decrease serum lactate in patients with elevated lactate level, over not using serum lactate. Weak low-quality resuscitation, serum lactate should be the clinical and other of elevated lactate. 8. For adults with septic shock, we suggest using capillary refill time to guide resuscitation as an adjunct to other measures of perfusion. Weak low-quality fluid resuscitation is for the of sepsis-induced hypoperfusion in sepsis and septic shock. Previous guidelines recommend appropriate resuscitation of sepsis or septic shock and having a low for it in those patients sepsis is not is the evidence from this is a best practice and are that a is The 2016 a for using a of 30 mL/kg of IV in initial fluid resuscitation. of initial resuscitation on evidence are for initial resuscitation in sepsis or septic shock. of adults to an with sepsis or septic shock that to 30 mL/kg of crystalloid fluid within 3 hours of sepsis with of of and of in of including and the and the of fluid in the of 30 that this fluid in clinical practice patients require fluid initial resuscitation. to be with the of fluid and with fluid of and of the of septic patients is the for a initial and of the response to treatment. and fluid the initial resuscitation should be by of and organ perfusion. pressure and blood pressure are of fluid measures have at fluid compared with static measures with fluid against pressure or and of in response to in a and dynamic to guide fluid with to of to and of to in one other in between septic patients with a compared with standard from and a of evidence in to guide of fluid resuscitation as as the appropriate in patients with sepsis and in that resuscitation with of IV by and arterial with fluid in the first hours and higher hospital standard fluid the initial 30 mL/kg is by measures of fluid of mL/kg compared to to 3 mL/kg the of fluid and on of of or not be a in pressure that the is fluid a for lactate is an of and is not a of of septic shock in lactate as evidence of to (1). Previous of these guidelines have using lactate as a target of resuscitation in the of sepsis and septic shock, on to and of in serum lactate in with or in The that serum lactate are not in patients with septic shock, these that decrease lactate lactate should be the clinical and other of elevated lactate. with sepsis lactate not be in is not measures of organ be to the and of of the and capillary refill time have and to be of The a resuscitation a resuscitation at or lactate by hours in the first hours of septic shock the organ dysfunction as by in the and in the lactate this not the of a on using resuscitation and is and this should be by and to or fluid are of the or to the should management - Recommendation 9. For adults with septic shock on vasopressors, we recommend an initial target mean arterial pressure (MAP) of 65 mm Hg over higher MAP targets. Strong moderate-quality MAP is a of mean in is the major of and MAP in blood and the of perfusion. as the and have the to blood a to be mm are with organ with MAP Previous guidelines a MAP of 65 mm Hg for initial resuscitation. The on a in septic shock patients who given to target a MAP of mm a target of mm Hg in a a in with higher MAP patients with higher MAP with with a higher of of this that the MAP in the of on this that higher MAP not improve in septic shock to and MAP target compared a mm with a that and MAP by the in patients 65 and with septic shock The in this a mean MAP of mm compared with mm Hg in the to in the by of and in in the and the of with higher MAP and the of patients with MAP of mm the a MAP of 65 mm Hg in the initial resuscitation of patients with septic shock who require to - Recommendation 10. For adults with sepsis or septic shock who require we suggest the patients to the within Weak low-quality The of patients on of in an appropriate the septic patients are in the and hospital of patients from are with sepsis and and and hospital of on the time for to the from and an of an in of for each of to of patients in the a higher hospital for the higher to time hr and compared with the to time for of an to time hr with hospital in patients with higher of with sepsis not patients to when hours hospital the a hospital higher and higher of and of patients in hospitals in the that to to higher and on of patients to an in outcomes. is evidence of and are best in an are of patients with sepsis to an not be in in and be this and appropriate treatment should not be of of - Recommendation For adults with suspected sepsis or septic shock we recommend and for and an of is or Best practice of these we the of a for to it is to in a a best practice we that appropriate should be in patients with suspected sepsis and septic shock it in in the of not in this as as The and of sepsis are and other is to sepsis, the cannot have a of sepsis in a with organ a or of patients with sepsis to have Best practice is to the to other are or a patient’s clinical after hospital or the of a of this be in when it is to or major is a that to on the that the is each as in and of the that by or in each in of or that the for a in the or a We not or evidence this are to a an that not from is or this is not of the should the of patients and patients that is not to - Recommendations For adults with septic shock or a for sepsis, we recommend within one of Strong low quality of evidence very low quality of evidence For adults with sepsis shock, we recommend of the of of Best practice and clinical examination, for and of and treatment for that this should be within 3 hours of that a be as to the of an of the patient’s and the of sepsis is to be For adults with sepsis shock, we suggest a of and for infection the of within 3 hours from the time when sepsis first Weak very low quality of For adults with a low of infection and shock, we suggest to the Weak very low quality of Early of appropriate is one of the to in patients with sepsis to patients with sepsis or septic shock should be as an The to provide as as be against the with to patients infection These a of as or and sepsis is as sepsis in and that first to be sepsis to be the of infection and of for each with suspected sepsis should the and of The with in patients with septic shock, have a between time to and in patients with septic shock in patients septic shock a of patients at each of time from to of with of for patients for patients not on a of patients at each of time from to of with of for patients with sepsis at least one of or or organ and for patients with septic to a for sepsis and a for septic shock in a of patients in each in time from to of with of and of in patients with in patients not an between and should be that the and at of to the of with or other patients with sepsis shock, the between time to and within the first hours from is have one to a in between and the other in a in time to suggest that after hours from hospital sepsis We suggest in patients with sepsis shock as as sepsis to be the and 3 hours after sepsis first suspected for sepsis at that given the of with septic shock and the of and the a to and within one in patients with septic shock. for patients with sepsis, we recommend be 1). For patients with sepsis shock, we recommend a of and of be to within 3 should be or should be to the Recommendations on of from suggest that of in patients with sepsis and septic shock is and and of a of in The and time for by and the of and of on is to recommendations to the of in patients with sepsis and septic shock in are in with the recommendations to - Recommendation For adults with suspected sepsis or septic shock, we suggest against using clinical to when to as compared to clinical alone. Weak very low quality of is in in response to in with clinical the of and of a of 30 a of and of for sepsis in patients We evidence from three that compared for of the three in to of to or of to and not in of the and on the with of the and the quality of evidence very guidelines for the management of recommend of for patients with of and in including the a against using to guide in to clinical - Recommendations For adults with sepsis or septic shock at of we recommend using with over using Best practice For adults with sepsis or septic shock at low of we suggest against using with as compared with using Weak low quality of The on to an against in an treatment for sepsis and septic shock the that the patient’s infection is caused by the of with treatment for in a with and the of with treatment in a for of patients and be to The of by from in to in and by for of infection or IV of or of hospital and of on the of including in on patients with the of in patients with of hours are with in not in patients with or sepsis, including against with higher patients The with are by an between of and in patients with or to for in a with be in a be from including the of to for are and on and clinical for are - Recommendations For adults with sepsis or septic shock and for we suggest using with for treatment over one Weak very low quality of For adults with sepsis or septic shock and low for we suggest against using for compared with one Weak very low quality of For adults with sepsis or septic shock, we suggest against using the and the are Weak very low quality of the of in of the world and between in and the initial of is to the at least one that is against the the and are the of on the of for and the of the and are is for patients with in a with of in or other between in adult patients with sepsis or septic shock when from the in the of of and in a low with the from the Recommendations the of one for treatment over one are given clinical including of and the of the of sepsis is to the appropriate For this we from recommendations in patients with sepsis or septic shock recommend the of on of to guide this infection or with within the of within the to a within the and within the the and are is not for patients with with and quality of evidence very and the of with the of for treatment. have an in in patients at for we suggest using for treatment to the of in patients with a low for we suggest using a for as are of using and the a of including infection and development of of is in patients at for with septic shock. - Recommendations For adults with sepsis or septic shock at of we suggest using over Weak low quality of For adults with sepsis or septic shock at low of we suggest against of Weak low quality of Sepsis and septic shock to are in and are with that of appropriate

The genetics underlying severe COVID-19 The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science , this issue p. eabd4570 , p. eabd4585 ; see also p. 404

BACKGROUND: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. METHODS: We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. RESULTS: The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which four are best practice statements, nine are strong recommendations, and 35 are weak recommendations. No recommendation was provided for six questions. The topics were: 1) infection control, 2) laboratory diagnosis and specimens, 3) hemodynamic support, 4) ventilatory support, and 5) COVID-19 therapy. CONCLUSION: The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new evidence in further releases of these guidelines.

The development of nanoparticle-based drug formulations has yielded the opportunities to address and treat challenging diseases. Nanoparticles vary in size but are generally ranging from 100 to 500 nm. Through the manipulation of size, surface characteristics and material used, the nanoparticles can be developed into smart systems, encasing therapeutic and imaging agents as well as bearing stealth property. Further, these systems can deliver drug to specific tissues and provide controlled release therapy. This targeted and sustained drug delivery decreases the drug related toxicity and increase patient's compliance with less frequent dosing. Nanotechnology has proven beneficial in the treatment of cancer, AIDS and many other disease, also providing advancement in diagnostic testing.

RATIONALE: Corticosteroid therapy is commonly used among critically ill patients with Middle East Respiratory Syndrome (MERS), but its impact on outcomes is uncertain. Analyses of observational studies often do not account for patients' clinical condition at the time of corticosteroid therapy initiation. OBJECTIVES: To investigate the association of corticosteroid therapy on mortality and on MERS coronavirus RNA clearance in critically ill patients with MERS. METHODS: ICU patients with MERs were included from 14 Saudi Arabian centers between September 2012 and October 2015. We performed marginal structural modeling to account for baseline and time-varying confounders. MEASUREMENTS AND MAIN RESULTS: Of 309 patients, 151 received corticosteroids. Corticosteroids were initiated at a median of 3.0 days (quartile 1 [Q1]-Q3, 1.0-7.0) from ICU admission. Patients who received corticosteroids were more likely to receive invasive ventilation (141 of 151 [93.4%] vs. 121 of 158 [76.6%]; P < 0.0001) and had higher 90-day crude mortality (112 of 151 [74.2%] vs. 91 of 158 [57.6%]; P = 0.002). Using marginal structural modeling, corticosteroid therapy was not significantly associated with 90-day mortality (adjusted odds ratio, 0.75; 95% confidence interval, 0.52-1.07; P = 0.12) but was associated with delay in MERS coronavirus RNA clearance (adjusted hazard ratio, 0.35; 95% CI, 0.17-0.72; P = 0.005). CONCLUSIONS: Corticosteroid therapy in patients with MERS was not associated with a difference in mortality after adjustment for time-varying confounders but was associated with delayed MERS coronavirus RNA clearance. These findings highlight the challenges and importance of adjusting for baseline and time-varying confounders when estimating clinical effects of treatments using observational studies.

The aim of these guidelines is to update the 2017 clinical practice guideline (CPG) of the European Society of Intensive Care Medicine (ESICM). The scope of this CPG is limited to adult patients and to non-pharmacological respiratory support strategies across different aspects of acute respiratory distress syndrome (ARDS), including ARDS due to coronavirus disease 2019 (COVID-19). These guidelines were formulated by an international panel of clinical experts, one methodologist and patients' representatives on behalf of the ESICM. The review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations and the quality of reporting of each study based on the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network guidelines. The CPG addressed 21 questions and formulates 21 recommendations on the following domains: (1) definition; (2) phenotyping, and respiratory support strategies including (3) high-flow nasal cannula oxygen (HFNO); (4) non-invasive ventilation (NIV); (5) tidal volume setting; (6) positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM); (7) prone positioning; (8) neuromuscular blockade, and (9) extracorporeal life support (ECLS). In addition, the CPG includes expert opinion on clinical practice and identifies the areas of future research.

BACKGROUND: The need for reintubation after extubation and discontinuation of mechanical ventilation is not uncommon and is associated with increased mortality. Noninvasive positive-pressure ventilation has been suggested as a promising therapy for patients with respiratory failure after extubation, but a single-center, randomized trial recently found no benefit. We conducted a multicenter, randomized trial to evaluate the effect of noninvasive positive-pressure ventilation on mortality in this clinical setting. METHODS: Patients in 37 centers in eight countries who were electively extubated after at least 48 hours of mechanical ventilation and who had respiratory failure within the subsequent 48 hours were randomly assigned to either noninvasive positive-pressure ventilation by face mask or standard medical therapy. RESULTS: A total of 221 patients with similar baseline characteristics had been randomly assigned to either noninvasive ventilation (114 patients) or standard medical therapy (107 patients) when the trial was stopped early, after an interim analysis. There was no difference between the noninvasive-ventilation group and the standard-therapy group in the need for reintubation (rate of reintubation, 48 percent in both groups; relative risk in the noninvasive-ventilation group, 0.99; 95 percent confidence interval, 0.76 to 1.30). The rate of death in the intensive care unit was higher in the noninvasive-ventilation group than in the standard-therapy group (25 percent vs. 14 percent; relative risk, 1.78; 95 percent confidence interval, 1.03 to 3.20; P=0.048), and the median time from respiratory failure to reintubation was longer in the noninvasive-ventilation group (12 hours vs. 2 hours 30 minutes, P=0.02). CONCLUSIONS: Noninvasive positive-pressure ventilation does not prevent the need for reintubation or reduce mortality in unselected patients who have respiratory failure after extubation.

RATIONALE: Recent literature in mechanical ventilation includes strong evidence from randomized trials. Little information is available regarding the influence of these trials on usual clinical practice. OBJECTIVES: To describe current mechanical ventilation practices and to assess the influence of interval randomized trials when compared with findings from a 1998 cohort. METHODS: A prospective international observational cohort study, with a nested comparative study performed in 349 intensive care units in 23 countries. We enrolled 4,968 consecutive patients receiving mechanical ventilation over a 1-month period. We recorded demographics and daily data related to mechanical ventilation for the duration of ventilation. We systematically reviewed the literature and developed 11 practice-change hypotheses for the comparative cohort study before seeing these results. In assessing practice changes, we only compared data from the 107 intensive care units (1,675 patients) that also participated in the 1998 cohort (1,383 patients). MEASUREMENTS AND MAIN RESULTS: In 2004 compared with 1998, the use of noninvasive ventilation increased (11.1 vs. 4.4%, P < 0.001). Among patients with acute respiratory distress syndrome, tidal volumes decreased (7.4 vs. 9.1 ml/kg, P < 0.001) and positive end-expiratory pressure levels increased slightly (8.7 vs. 7.7 cm H(2)O, P = 0.02). More patients were successfully extubated after their first attempt of spontaneous breathing (77 vs. 62%, P < 0.001). Use of synchronized intermittent mandatory ventilation fell dramatically (1.6 vs. 11%, P < 0.001). Observations confirmed 10 of our 11 practice-change hypotheses. CONCLUSIONS: The strong concordance of predicted and observed practice changes suggests that randomized trial results have advanced mechanical ventilation practices internationally.

Diabetes mellitus is a chronic heterogeneous metabolic disorder with complex pathogenesis. It is characterized by elevated blood glucose levels or hyperglycemia, which results from abnormalities in either insulin secretion or insulin action or both. Hyperglycemia manifests in various forms with a varied presentation and results in carbohydrate, fat, and protein metabolic dysfunctions. Long-term hyperglycemia often leads to various microvascular and macrovascular diabetic complications, which are mainly responsible for diabetes-associated morbidity and mortality. Hyperglycemia serves as the primary biomarker for the diagnosis of diabetes as well. In this review, we would be focusing on the classification of diabetes and its pathophysiology including that of its various types.

BACKGROUND/PURPOSE: Artificial intelligence (AI) has made deep inroads into dentistry in the last few years. The aim of this systematic review was to identify the development of AI applications that are widely employed in dentistry and evaluate their performance in terms of diagnosis, clinical decision-making, and predicting the prognosis of the treatment. MATERIALS AND METHODS: The literature for this paper was identified and selected by performing a thorough search in the electronic data bases like PubMed, Medline, Embase, Cochrane, Google scholar, Scopus, Web of science, and Saudi digital library published over the past two decades (January 2000-March 15, 2020).After applying inclusion and exclusion criteria, 43 articles were read in full and critically analyzed. Quality analysis was performed using QUADAS-2. RESULTS: AI technologies are widely implemented in a wide range of dentistry specialties. Most of the documented work is focused on AI models that rely on convolutional neural networks (CNNs) and artificial neural networks (ANNs). These AI models have been used in detection and diagnosis of dental caries, vertical root fractures, apical lesions, salivary gland diseases, maxillary sinusitis, maxillofacial cysts, cervical lymph nodes metastasis, osteoporosis, cancerous lesions, alveolar bone loss, predicting orthodontic extractions, need for orthodontic treatments, cephalometric analysis, age and gender determination. CONCLUSION: These studies indicate that the performance of an AI based automated system is excellent. They mimic the precision and accuracy of trained specialists, in some studies it was found that these systems were even able to outmatch dental specialists in terms of performance and accuracy.

Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life threatening complication that can develop after hematopoietic cell transplantation. Although SOS/VOD progressively resolves within a few weeks in most patients, the most severe forms result in multi-organ dysfunction and are associated with a high mortality rate (>80%). Therefore, careful attention must be paid to allow an early detection of SOS/VOD, particularly as drugs have now proven to be effective and licensed for its treatment. Unfortunately, current criteria lack sensitivity and specificity, making early identification and severity assessment of SOS/VOD difficult. The aim of this work is to propose a new definition for diagnosis, and a severity-grading system for SOS/VOD in adult patients, on behalf of the European Society for Blood and Marrow Transplantation.

The Surviving Sepsis Campaign (SSC) International Guidelines for the Management of Sepsis and Septic Shock provide guidance on the care of hospitalized adult patients with (or at risk for) sepsis, based on systematic summary and assessment of relevant literature. This executive summary reviews the history, scope, methodology, and major recommendations of the guidelines, focusing on aspects that are new or different compared with the 2016 guidelines that were published in 2017. Full description of the guidelines process and recommendations are provided in the complete guidelines document. HISTORY AND SCOPE OF THE GUIDELINES The SSC first published guidelines for the management of severe sepsis and septic shock in 2004. Updates were published in 2008, 2012, and 2017. The guidelines are sponsored by the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM), with methodological support by the Guidelines in Intensive Care Development and Evaluation (GUIDE) group, and endorsement by 24 additional societies. There is no funding from any industry partner. Panel membership, patient involvement, and conflict of interest management are discussed in the complete guidelines document. The guidelines provide recommendations on the management of sepsis, focusing on aspects of care specific to sepsis and limiting duplication with other guidelines wherever possible. It is not intended to replace clinical judgement, which must account for the unique circumstances of an individual patient. Following the recommendation of SCCM and ESICM, there are now separate guidelines for sepsis in children (1). The SSC also published separate guidelines specific to the management of COVID (2,3). The 2021 guidelines largely apply to high-resource settings but discuss applicability of the recommendations to lower-resource settings as data allow. The SSC also creates sepsis bundles (4) (a selected set of interventions or processes of care distilled from evidence-based practice guidelines) to facilitate quality improvement and implementation of guidelines recommendations. However, the bundles are developed via a separate process and published separately from the guidelines. Definitions The guidelines recognize sepsis as life-threatening organ dysfunction secondary to a dysregulated host response to infection consistent with the Sepsis-3 consensus definition (5). However, studies were not required to use a particular sepsis definition to be considered as relevant evidence for the guidelines. Question Development and Outcome Prioritization Guidelines questions were selected based on panel rating, clinical practice variability, and inclusion in prior SSC guidelines, and then assigned to one of six SSC adult guidelines working groups: screening and initial resuscitation; infection; hemodynamics; ventilation; additional therapies; and goals of care and long-term outcomes. Clinical practice variation was identified through a global survey of SCCM and ESICM members regarding their current practice and how it related to previous recommendations. All questions were structured in the Population, Intervention, Control, and Outcomes (PICO) format. For each question, relevant outcomes were enumerated and ranked prior to the literature search. Search Strategy and Evidence Summation Professional librarians drafted and executed the search strategy for each PICO question (or group of similar questions), with input from subgroup members. Only English language studies published before May 2019 were included (the lag was the result of the guideline review and approval process coupled with the COVID-19 pandemic). For PICO questions addressed in the 2016 guidelines, the search strategy was revised and updated. Reviewers in the systematic review team, with input from methodologists and experts, screened article titles and abstracts to identify the highest quality evidence, particularly recent randomized controlled trials and high-quality systematic reviews. When new or updated meta-analyses were required, relevant data were abstracted with emphasis on intention-to-treat data where possible and conventional meta-analytic techniques were used to produce pooled estimates. Quality of Evidence and Formulation of Recommendations Using the GRADE approach, methodologists and panelists assessed the quality of evidence for each PICO question as high, moderate, low, or very low. Using the Evidence-to-Decision (EtD) framework (6), each subgroup drafted preliminary recommendations for their assigned PICO questions. The EtD framework took into account not only the magnitude of effect and quality of evidence, but also patient values, resources and cost, equity, acceptability, and feasibility (6). The strength of each recommendation was informed by the quality of the evidence and other components of the EtD framework. Strong recommendations (signified by “we recommend”) reflect high confidence that the desirable effects of adhering to a recommendation clearly outweigh undesirable effects. Weak recommendations (signified by “we suggest”) indicate that desirable effects likely outweigh undesirable effects. Best practice statements (BPSs) reflect ungraded strong recommendations and are used sparingly when benefit or harm is unequivocal, but evidence is difficult to summarize or assess according to GRADE methodology (7). Voting Progress Preliminary recommendations were discussed during face-to-face meetings and revised based on panel feedback prior to electronic voting by panel members who had no conflicts of interest. The a priori threshold for acceptance was having votes cast by at least 75% of the panel and 80% agreement among those who cast a vote. Up to three rounds of voting were allowed per PICO question. RECOMMENDATIONS The recommendations of the SSC 2021 guidelines update are summarized in Table 1 of the full guidelines document. There are 93 total statements, which address screening and initial resuscitation (n = 10 statements), infection (n = 21), hemodynamics (n = 14), ventilation (n = 12), additional therapies (n = 16), and goals of care and long-term outcomes (n = 20). Of the 93 statements, 15 are strong (16%) and 54 are weak (58%) recommendations, 15 are best practice statements (16%), and 9 are statements declaring ‘no recommendation’ (10%). Of the 15 strong recommendations, all but one are based on moderate or high-quality evidence. Selected recommendations that are new or revised from the 2016 guidelines are shown in Table 1. TABLE 1. - Selected New and/or Revised Recommendations in the 2021 Surviving Sepsis Campaign International Guidelines for the Management of Sepsis and Septic Shock 2016 Recommendation 2021 Recommendation Rationale for Change We recommend that in the resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid be given within the first 3 hours. For patients with sepsis-induced hypoperfusion or septic shock we suggest that at least 30 mL/kg of IV crystalloid fluid should be given within the first 3 hours of resuscitation. This panel downgraded this recommendation from a strong recommendation to a weak recommendation based on the low quality of the evidence. There are no prospective intervention studies comparing different volumes for initial resuscitation in sepsis or septic shock. However, a retrospective analysis of adults presenting to an emergency department with sepsis or septic shock showed that failure to receive 30mL/kg of crystalloid fluid therapy within 3 hours of sepsis onset was associated with higher in-hospital mortality (10). Furthermore, the average volume of fluid received pre-randomization the PROCESS (11), PROMISE (12), and ARISE (13) trials was in the range of 30 mL/kg, suggesting this fluid volume has been adopted in routine clinical practice (14). We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock. For adults with sepsis or septic shock, we suggest using balanced crystalloid instead of normal saline for resuscitation. There are many, increasingly recognized potential adverse effects of normal saline including hyperchloremic metabolic acidosis. A network meta-analysis showed in an indirect comparison that balanced fluids were associated with decreased mortality compared with saline (15). In the 2018 SMART single-center cluster-randomized RCT comparing saline to balance fluid, the pre-specified subgroup of patients admitted with sepsis experienced lower 30-day mortality when randomized to balanced fluids versus saline (OR, 0.90; 95% CI, 0.67, 0.94) (16). Not addressed For adults with septic shock, we suggest starting vasopressors peripherally to restore mean arterial pressure rather than delaying initiation until a central venous access is secured. Prompt initiation of vasopressors is an integral component of septic shock management. Vasopressors have been traditionally administered via central venous access due to concerns of extravasation and local tissue injury and ischemia. However, placement of central venous access requires specialized expertise and is time consuming, potentially leading to delays in administration. A recent systematic review showed that peripheral administration of vasopressors is generally safe, particularly if infused distally to the antecubital fossa and for short periods of time (< 6 hr) (17, 18). Peripheral administration of vasopressors is associated with shorter time to administration and faster time to achieving a MAP > 65 mm Hg (19). Not addressed For adults with sepsis or septic shock we suggest against using IV vitamin C. A 2017 single center before and after study reported reduced mortality with administration of high-dose Vitamin C, hydrocortisone, and thiamine among patients with sepsis and sepsis shock (20). However, an updated meta-analysis by the guideline panel found no association between vitamin C and reduced mortality. We suggest against using IV hydrocortisone to treat patients with septic shock if adequate fluid resuscitation and vasopressor therapy can restore hemodynamic stability. If this is not achievable, we suggest IV hydrocortisone at a dose of 200 mg/day. For adults with septic shock and an ongoing requirement for vasopressor therapy we suggest using IVcorticosteroids. Since the 2016 guideline, three large RCTs have been published (21–23). An updated meta-analysis found systemic corticosteroid to accelerate resolution of shock (MD, 1.52 days; 95% CI, 1.71 to 1.32) and increase vasopressor-free days (MD, 1.5 days; 95% CI, 0.8 to 3.11 days) (24). However, corticosteroid use increased neuromuscular weakness (RR, 1.21; 95% CI, 1.01 to 1.45), without a clear effect on short- or long-term mortality (24). The overall quality of evidence was moderate. The panel judged the desirable effects (shock resolution, vasopressor-free days) to outweigh the undesirable effects. This observation, combined with consideration of the resources required, cost of the intervention, and feasibility supported a weak recommendation in favor of using low-dose corticosteroid therapy in septic shock. Not addressed For adult survivors of sepsis or septic shock, we recommend assessment and follow-up for physical, cognitive, and emotional problems after hospital discharge. Given the prevalence of new and worsening physical, cognitive, and emotional problems experienced by sepsis survivors, we recommend assessment and follow-up of these problems after discharge. Screening and Initial Resuscitation The guidelines recommend that hospitals use a performance improvement program for sepsis, including screening of high-risk patients and standard operating procedures for management. The guidelines recognize sepsis as a medical emergency and recommend that treatment and resuscitation begin immediately. For initial resuscitation in patients with sepsis-induced hypoperfusion or septic shock, the guidelines suggest 30 mL/kg IV crystalloid. This recommendation was downgraded from a strong recommendation to a weak recommendation based on the low quality of evidence. Additionally, the guidelines suggest resuscitation be guided by dynamic over static measures, target a decrease in serum lactate, and use capillary refill as an adjunct measure of perfusion. New to this update, the guidelines recommend against qSOFA as a sole screening tool and suggest that patients who are determined to need intensive care be admitted to an ICU within 6 hours. Infection As in the 2016 guidelines, the 2021 guidelines again recommend delivering antimicrobials as soon as possible, ideally within 1 hour of sepsis recognition. The 2021 guidelines provide additional guidance on initiation of antimicrobials, recognizing the challenge of diagnostic uncertainty early in a patient’s presentation. The guidelines now stratify antimicrobial timing recommendations based on the likelihood of sepsis and presence of shock (Figure 1). For patients with probable sepsis or with shock resulting from possible or probable sepsis, the guidelines recommend administering antimicrobials immediately, ideally within 1 hour of recognition. For patients with possible sepsis but without shock, the guidelines recommend rapid assessment of the likelihood of infection versus non-infectious illness. If concern for infection persists after a time-limited course of rapid investigation, then antimicrobials should be administered within 3 hours from when sepsis was first recognized. Finally, for patients with a low likelihood of infection and without shock, the guidelines suggest deferring antimicrobials while continuing to closely monitor the patient.Figure 1.: 2021 Recommendations of the initiation of antimicrobials.The guidelines include several additional recommendations regarding antimicrobial therapy for sepsis. Given the heterogeneity of infectious pathogens, sites of infection, severity of illness, local resistance patterns, and other patient and contextual factors, specific treatment recommendations are beyond the scope of the guidelines. However, the guidelines provide a framework for approaching antimicrobial therapy. They suggest that use of empiric coverage for methicillin-resistant Staphylococcus aureus (MRSA), empiric double-coverage for gram-negative pathogens, and empiric coverage for fungal pathogens be determined based on patient and contextual risk factors. The guidelines provide several recommendations for optimizing antibiotic dosing, addressing source control, and determining duration of antimicrobial therapy. Hemodynamics The guidelines recommend crystalloid fluids as a first line for resuscitation, and new in this update, suggest balanced crystalloids over normal saline. For patients with septic shock, the guidelines recommend norepinephrine as the first-line vasopressor and suggest that vasopressors be started peripherally to avoid delays in administration in the absence of central venous access. There was insufficient evidence to make a recommendation regarding the use of a restrictive versus liberal fluid strategy after the initial fluid resuscitation, and this remains an important area for future research. As in the 2016 guidelines, albumin is suggested in patients who have received large volumes of crystalloid. Ventilation The guidelines recommend a low tidal volume ventilation strategy with limitation of plateau pressure for patients with sepsis-associated ARDS and the use of prone positioning in moderate-to-severe ARDS, and suggest a low tidal volume approach for all patients with sepsis-induced respiratory failure. The guidelines suggest using traditional recruitment maneuvers but recommend against an incremental PEEP strategy. There was insufficient evidence to make a recommendation regarding use of liberal versus conservative oxygen targets; this remains an important area for future research. Additional Therapies To limit overlap with other guidelines and create space for a new section focused on long-term outcomes, PICOs on additional therapies were reduced from prior SSC guidelines. However, there are some noteworthy new recommendations regarding adjunctive therapies. In contrast to the 2016 guidelines, the 2021 guidelines suggest the use of IV corticosteroids for patients with an ongoing need for vasopressor therapy based on newer clinical trial data. Additionally, the guidelines suggest against using IV vitamin C for sepsis or septic shock based on recent randomized controlled trials and an updated meta-analysis showing no impact on mortality. Goals of Care and Long-Term Outcomes As acute survival from sepsis has improved, a growing number of sepsis survivors leave the hospital alive—many of whom experience long-term morbidity and a heightened risk for adverse health outcomes including mortality in the months and years following sepsis (8). Indeed, the 2017 World Health Organization resolution on sepsis called for improving outcomes of sepsis survivors and addressing survivors’ access to rehabilitation (9). Given the burden of long-term morbidity and mortality stemming from sepsis, the SSC guidelines now include a section dedicated to the longer-term recovery from sepsis. To enhance recovery, the guidelines recommend screening for economic and social support for patient and families, involving patients and families in shared decision-making regarding discharge planning, reconciling medications at both ICU and hospital discharge, including information about sepsis and common impairment after sepsis in the discharge summary, and assessing for physical, cognitive, and emotional problems after hospital discharge. The guidelines suggest having a critical care transitional program during ICU stay to floor transitions, using a handoff process during transitions of care, offering verbal and written sepsis education, and referring patients to peer support programs, post-critical illness follow-up programs (if available), and post-hospital rehabilitation programs (for selected survivors). There was insufficient evidence to make a recommendation regarding early cognitive rehabilitation or timing of post-hospital follow up. While many of these recommendations are generally applicable to critically ill and hospitalized patients, the panel deemed them necessary to include in the sepsis guidelines given the burden of long-term morbidity and mortality due to sepsis. CONCLUSIONS This executive summary highlights the most novel aspects of the Surviving Sepsis Campaign International Guidelines for the Management of Sepsis and Septic Shock 2021 that clinicians and stakeholders should consider when caring for adult patients with (or at risk for) sepsis. The recommendation rationales, informed by rigorous data evaluation, discussion by panelists, and input from patients, provide deeper insight into each recommendation. We believe that the 2021 SSC guidelines will foster the delivery of best practices for sepsis evaluation and management, as well as highlight aspects of management where additional evidence is needed most urgently.

OBJECTIVE: To establish evidence-based guidelines for the use of bedside ultrasound by intensivists and specialists in the ICU and equivalent care sites for diagnostic and therapeutic purposes for organs of the chest, abdomen, pelvis, neck, and extremities. METHODS: The Grading of Recommendations, Assessment, Development and Evaluation system was used to determine the strength of recommendations as either strong or conditional/weak and to rank the "levels" of quality of evidence into high (A), moderate (B), or low (C) and thus generating six "grades" of recommendation (1A-1B-1C-2A-2B-2C). Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used for all questions with clinically relevant outcomes. RAND appropriateness method, incorporating modified Delphi technique, was used in steps of GRADE that required panel judgment and for those based purely on expert consensus. The process was conducted by teleconference and electronic-based discussion, following clear rules for establishing consensus and agreement/disagreement. Individual panel members provided full disclosure and were judged to be free of any commercial bias. The process was conducted independent of industry funding. RESULTS: Twenty-four statements regarding the use of ultrasound were considered-three did not achieve agreement and nine were approved as conditional recommendations (strength class 2). The remaining 12 statements were approved as strong recommendations (strength class 1). Each recommendation was also linked to its level of quality of evidence. Key strong recommendations included the use of ultrasonography for ruling-in pleural effusion and assisting its drainage, ascites drainage, ruling-in pneumothorax, central venous cannulation, particularly for internal jugular and femoral sites, and for diagnosis of deep venous thrombosis. Conditional recommendations were given to the use of ultrasound by the intensivist for diagnosis of acalculous cholecystitis, renal failure, and interstitial and parenchymal lung diseases. No recommendations were made regarding static (vs dynamic) ultrasound guidance of vascular access or the use of needle guide devices. CONCLUSIONS: There was strong agreement among a large cohort of international experts regarding several recommendations for the use of ultrasound in the ICU. Evidence-based recommendations regarding the appropriate use of this technology are a step toward improving patient outcomes in relevant patients.

Carolyn F. Waltz, Ora L. Strickland, Elizabeth R. Lenz, et al., Research, Measurement in Nursing Research, 1991, 533, $55 hardcover

The present study was conducted to provide future researchers and dental educators with an overview of stress amongst undergraduate dental students reported in the literature. This overview is needed for the development of a new questionnaire measuring the level of stressors including students, staff and process of dental education. In addition, the review can be used to modify dental curricula to decrease such stress and produce better dentists. Our study consisted of a systematic review of 49 peer-reviewed articles published between 1966 till October 2008 in English, discussing different aspects of stress amongst undergraduate dental students. These aspects are demographic variables of stress, sources of stress, impact of stress, indicators of stress, instruments measuring stress level and management of stress. Major sources of reported stress were related to examinations, clinical requirements and dental supervisors. Studies suggest using signs and symptoms for early detection of stress and proper intervention.

BACKGROUND: The coronavirus disease 2019 pandemic continues to affect millions worldwide. Given the rapidly growing evidence base, we implemented a living guideline model to provide guidance on the management of patients with severe or critical coronavirus disease 2019 in the ICU. METHODS: The Surviving Sepsis Campaign Coronavirus Disease 2019 panel has expanded to include 43 experts from 14 countries; all panel members completed an electronic conflict-of-interest disclosure form. In this update, the panel addressed nine questions relevant to managing severe or critical coronavirus disease 2019 in the ICU. We used the World Health Organization's definition of severe and critical coronavirus disease 2019. The systematic reviews team searched the literature for relevant evidence, aiming to identify systematic reviews and clinical trials. When appropriate, we performed a random-effects meta-analysis to summarize treatment effects. We assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach, then used the evidence-to-decision framework to generate recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. RESULTS: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued nine statements (three new and six updated) related to ICU patients with severe or critical coronavirus disease 2019. For severe or critical coronavirus disease 2019, the panel strongly recommends using systemic corticosteroids and venous thromboprophylaxis but strongly recommends against using hydroxychloroquine. In addition, the panel suggests using dexamethasone (compared with other corticosteroids) and suggests against using convalescent plasma and therapeutic anticoagulation outside clinical trials. The Surviving Sepsis Campaign Coronavirus Diease 2019 panel suggests using remdesivir in nonventilated patients with severe coronavirus disease 2019 and suggests against starting remdesivir in patients with critical coronavirus disease 2019 outside clinical trials. Because of insufficient evidence, the panel did not issue a recommendation on the use of awake prone positioning. CONCLUSION: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued several recommendations to guide healthcare professionals caring for adults with critical or severe coronavirus disease 2019 in the ICU. Based on a living guideline model the recommendations will be updated as new evidence becomes available.

Heat stroke is a life-threatening condition clinically diagnosed as a severe elevation in body temperature with central nervous system dysfunction that often includes combativeness, delirium, seizures, and coma. Classic heat stroke primarily occurs in immunocompromised individuals during annual heat waves. Exertional heat stroke is observed in young fit individuals performing strenuous physical activity in hot or temperature environments. Long-term consequences of heat stroke are thought to be due to a systemic inflammatory response syndrome. This article provides a comprehensive review of recent advances in the identification of risk factors that predispose to heat stroke, the role of endotoxin and cytokines in mediation of multi-organ damage, the incidence of hypothermia and fever during heat stroke recovery, clinical biomarkers of organ damage severity, and protective cooling strategies. Risk factors include environmental factors, medications, drug use, compromised health status, and genetic conditions. The role of endotoxin and cytokines is discussed in the framework of research conducted over 30 years ago that requires reassessment to more clearly identify the role of these factors in the systemic inflammatory response syndrome. We challenge the notion that hypothalamic damage is responsible for thermoregulatory disturbances during heat stroke recovery and highlight recent advances in our understanding of the regulated nature of these responses. The need for more sensitive clinical biomarkers of organ damage is examined. Conventional and emerging cooling methods are discussed with reference to protection against peripheral organ damage and selective brain cooling.

BACKGROUND: Second victims are healthcare workers who experience emotional distress following patient adverse events. Studies indicate the need to develop organisational support programmes for these workers. The RISE (Resilience In Stressful Events) programme was developed at the Johns Hopkins Hospital to provide this support. OBJECTIVE: To describe the development of RISE and evaluate its initial feasibility and subsequent implementation. Programme phases included (1) developing the RISE programme, (2) recruiting and training peer responders, (3) pilot launch in the Department of Paediatrics and (4) hospital-wide implementation. METHODS: Mixed-methods study, including frequency counts of encounters, staff surveys and evaluations by RISE peer responders. Descriptive statistics were used to summarise demographic characteristics and proportions of responses to categorical, Likert and ordinal scales. Qualitative analysis and coding were used to analyse open-ended responses from questionnaires and focus groups. RESULTS: A baseline staff survey found that most staff had experienced an unanticipated adverse event, and most would prefer peer support. A total of 119 calls, involving ∼500 individuals, were received in the first 52 months. The majority of calls were from nurses, and very few were related to medical errors (4%). Peer responders reported that the encounters were successful in 88% of cases and 83.3% reported meeting the caller's needs. Low awareness of the programme was a barrier to hospital-wide expansion. However, over the 4 years, the rate of calls increased from ∼1-4 calls per month. The programme evolved to accommodate requests for group support. CONCLUSIONS: Hospital staff identified the need for a multidisciplinary peer support programme for second victims. Peer responders reported success in responding to calls, the majority of which were for adverse events rather than for medical errors. The low initial volume of calls emphasises the importance of promoting awareness of the value of emotional support and the availability of the programme.

BACKGROUND: There is increasing interest to make primary data from published research publicly available. We aimed to assess the current status of making research data available in highly-cited journals across the scientific literature. METHODS AND RESULTS: We reviewed the first 10 original research papers of 2009 published in the 50 original research journals with the highest impact factor. For each journal we documented the policies related to public availability and sharing of data. Of the 50 journals, 44 (88%) had a statement in their instructions to authors related to public availability and sharing of data. However, there was wide variation in journal requirements, ranging from requiring the sharing of all primary data related to the research to just including a statement in the published manuscript that data can be available on request. Of the 500 assessed papers, 149 (30%) were not subject to any data availability policy. Of the remaining 351 papers that were covered by some data availability policy, 208 papers (59%) did not fully adhere to the data availability instructions of the journals they were published in, most commonly (73%) by not publicly depositing microarray data. The other 143 papers that adhered to the data availability instructions did so by publicly depositing only the specific data type as required, making a statement of willingness to share, or actually sharing all the primary data. Overall, only 47 papers (9%) deposited full primary raw data online. None of the 149 papers not subject to data availability policies made their full primary data publicly available. CONCLUSION: A substantial proportion of original research papers published in high-impact journals are either not subject to any data availability policies, or do not adhere to the data availability instructions in their respective journals. This empiric evaluation highlights opportunities for improvement.