Alfred Health

IMPORTANCE: The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19. OBSERVATIONS: SARS-CoV-2 is spread primarily via respiratory droplets during close face-to-face contact. Infection can be spread by asymptomatic, presymptomatic, and symptomatic carriers. The average time from exposure to symptom onset is 5 days, and 97.5% of people who develop symptoms do so within 11.5 days. The most common symptoms are fever, dry cough, and shortness of breath. Radiographic and laboratory abnormalities, such as lymphopenia and elevated lactate dehydrogenase, are common, but nonspecific. Diagnosis is made by detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing, although false-negative test results may occur in up to 20% to 67% of patients; however, this is dependent on the quality and timing of testing. Manifestations of COVID-19 include asymptomatic carriers and fulminant disease characterized by sepsis and acute respiratory failure. Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. More than 75% of patients hospitalized with COVID-19 require supplemental oxygen. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]) and that remdesivir improves time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. In a randomized trial of 103 patients with COVID-19, convalescent plasma did not shorten time to recovery. Ongoing trials are testing antiviral therapies, immune modulators, and anticoagulants. The case-fatality rate for COVID-19 varies markedly by age, ranging from 0.3 deaths per 1000 cases among patients aged 5 to 17 years to 304.9 deaths per 1000 cases among patients aged 85 years or older in the US. Among patients hospitalized in the intensive care unit, the case fatality is up to 40%. At least 120 SARS-CoV-2 vaccines are under development. Until an effective vaccine is available, the primary methods to reduce spread are face masks, social distancing, and contact tracing. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies. CONCLUSIONS AND RELEVANCE: As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.

BACKGROUND: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. METHODS: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. RESULTS: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. CONCLUSIONS: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

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 ICU admission, we suggest admitting the patients to the ICU within 6 hr. Weak , low quality of evidence INFECTION 11. For adults with suspected sepsis or septic shock but unconfirmed infection, we recommend continuously re-evaluating and searching for alternative diagnoses and discontinuing empiric antimicrobials if an alternative cause of illness is demonstrated or strongly suspected. Best practice statement 12. For adults with possible septic shock or a high likelihood for sepsis, we recommend administering antimicrobials immediately, ideally within 1 hr of recognition. Strong , low quality of evidence (Septic shock) CHANGED from previous: "We recommend that administration of intravenous antimicrobials should be initiated as soon as possible after recognition and within one hour for both a) septic shock and b) sepsis without shock" Strong , very low quality of evidence (Sepsis without shock) strong recommendation , moderate quality of evidence 13. For adults with possible sepsis without shock, we recommend rapid assessment of the likelihood of infectious versus noninfectious causes of acute illness. Best practice statement 14. For adults with possible sepsis without shock, we suggest a time-limited course of rapid investigation and if concern for infection persists, the administration of antimicrobials within 3 hr from the time when sepsis was first recognized. Weak , very low quality of evidence NEW from previous: "We recommend that administration of IV antimicrobials should be initiated as soon as possible after recognition and within 1 hr for both a) septic shock and b) sepsis without shock" strong recommendation , moderate quality of evidence 15. For adults with a low likelihood of infection and without shock, we suggest deferring antimicrobials while continuing to closely monitor the patient. Weak , very low quality of evidence NEW from previous: "We recommend that administration of IV antimicrobials should be initiated as soon as possible after recognition and within 1 hr for both a) septic shock and b) sepsis without shock" strong recommendation , moderate quality of evidence 16. For adults with suspected sepsis or septic shock, we suggest against using procalcitonin plus clinical evaluation to decide when to start antimicrobials, as compared to clinical evaluation alone. Weak , very low quality of evidence 17. For adults with sepsis or septic shock at high risk of MRSA, we recommend using empiric antimicrobials with MRSA coverage over using antimicrobials without MRSA coverage. Best practice statement NEW from previous: "We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage." Strong recommendation , moderate quality of evidence 18. For adults with sepsis or septic shock at low risk of MRSA, we suggest against using empiric antimicrobials with MRSA coverage, as compared with using antimicrobials without MRSA coverage. Weak , low quality of evidence NEW from previous: "We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage." Strong recommendation , moderate quality of evidence 19. For adults with sepsis or septic shock and high risk for multidrug resistant (MDR) organisms, we suggest using two antimicrobials with gram-negative coverage for empiric treatment over one gram-negative agent. Weak , very low quality of evidence 20. For adults with sepsis or septic shock and low risk for multidrug resistant (MDR) organisms, we suggest against using two gram-negative agents for empiric treatment, as compared to one gram-negative agent. Weak , very low quality of evidence 21. For adults with sepsis or septic shock, we suggest against using double gram-negative coverage once the causative pathogen and the susceptibilities are known. Weak , very low quality of evidence 22. For adults with sepsis or septic shock at high risk of fungal infection, we suggest using empiric antifungal therapy over no antifungal therapy. Weak , low quality of evidence NEW from previous: "We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage." Strong recommendation , moderate quality of evidence 23. For adults with sepsis or septic shock at low risk of fungal infection, we suggest against empiric use of antifungal therapy Weak , low quality of evidence NEW from previous: "We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage. " Strong recommendation , moderate quality of evidence 24. We make no recommendation on the use of antiviral agents. No recommendation 25. For adults with sepsis or septic shock, we suggest using prolonged infusion of beta-lactams for maintenance (after an initial bolus) over conventional bolus infusion. Weak , moderate-quality evidence 26. For adults with sepsis or septic shock, we recommend optimising dosing strategies of antimicrobials based on accepted pharmacokinetic/pharmacodynamic (PK/PD) principles and specific drug properties. Best practice statement 27. For adults with sepsis or septic shock, we recommend rapidly identifying or excluding a specific anatomical diagnosis of infection that requires emergent source control and implementing any required source control intervention as soon as medically and logistically practical. Best practice statement 28. For adults with sepsis or septic shock, we recommend prompt removal of intravascular access devices that are a possible source of sepsis or septic shock after other vascular access has been established. Best practice statement 29. For adults with sepsis or septic shock, we suggest daily assessment for de-escalation of antimicrobials over using fixed durations of therapy without daily reassessment for de-escalation. Weak , very low quality of evidence 30. For adults with an initial diagnosis of sepsis or septic shock and adequate source control, we suggest using shorter over longer duration of antimicrobial therapy. Weak , very low quality of evidence 31. For adults with an initial diagnosis of sepsis or septic shock and adequate source control where optimal duration of therapy is unclear, we suggest using procalcitonin AND clinical evaluation to decide when to discontinue antimicrobials over clinical evaluation alone. Weak , low quality of evidence HEMODYNAMIC MANAGEMENT 32. For adults with sepsis or septic shock, we recommend using crystalloids as first-line fluid for resuscitation. Strong , moderate-quality evidence 33. For adults with sepsis or septic shock, we suggest using balanced crystalloids instead of normal saline for resuscitation. Weak , low quality of evidence CHANGED from weak recommendation , low quality of evidence. "We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock" 34. For adults with sepsis or septic shock, we suggest using albumin in patients who received large volumes of crystalloids. Weak , moderate-quality evidence 35. For adults with sepsis or septic shock, we recommend against using starches for resuscitation. Strong , high-quality evidence 36. For adults with sepsis and septic shock, we suggest against using gelatin for resuscitation. Weak , moderate-quality evidence UPGRADE from weak recommendation , low quality of evidence "We suggest using crystalloids over gelatins when resuscitating patients with sepsis or septic shock." 37. For adults with septic shock, we recommend using norepinephrine as the first-line agent over other vasopressors. Strong Dopamine. High-quality evidence Vasopressin. Moderate-quality evidence Epinephrine. Low quality of evidence Selepressin. Low quality of evidence Angiotensin II. Very low-quality evidence 38. For adults with septic shock on norepinephrine with inadequate mean arterial pressure levels, we suggest adding vasopressin instead of escalating the dose of norepinephrine. Weak , moderate quality evidence 39. For adults with septic shock and inadequate mean arterial pressure levels despite norepinephrine and vasopressin, we suggest adding epinephrine. Weak , low quality of evidence 40. For adults with septic shock, we suggest against using terlipressin. Weak , low quality of evidence 41. For adults with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate volume status and arterial blood pressure, we suggest either adding dobutamine to norepinephrine or using epinephrine alone. Weak , low quality of evidence 42. For adults with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate volume status and arterial blood pressure, we suggest against using levosimendan. Weak , low quality of evidence NEW 43. For adults with septic shock, we suggest invasive monitoring of arterial blood pressure over noninvasive monitoring, as soon as practical and if resources are available. Weak , very low quality of evidence 44. 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. Weak , very low quality of evidence NEW 45. There is insufficient evidence to make a recommendation on the use of restrictive versus liberal fluid strategies in the first 24 hr of resuscitation in patients with sepsis and septic shock who still have signs of hypoperfusion and volume depletion after the initial resuscitation. No recommendation NEW "We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock" Weak recommendation , low quality of evidence "We suggest using crystalloids over gelatins when resuscitating patients with sepsis or septic shock." Weak recommendation , low quality of evidence VENTILATION 46.There is insufficient evidence to make a recommendation on the use of conservative oxygen targets in adults with sepsis-induced hypoxemic respiratory failure. No recommendation 47. For adults with sepsis-induced hypoxemic respiratory failure, we suggest the use of high flow nasal oxygen over noninvasive ventilation. Weak , low quality of evidence NEW 48. There is insufficient evidence to make a recommendation on the use of noninvasive ventilation in comparison to invasive ventilation for adults with sepsis-induced hypoxemic respiratory failure. No recommendation 49. For adults with sepsis-induced ARDS, we recommend using a low tidal volume ventilation strategy (6 mL/kg), over a high tidal volume strategy (> 10 mL/kg). Strong , high-quality evidence 50. For adults with sepsis-induced severe ARDS, we recommend using an upper limit goal for plateau pressures of 30 cm H2O, over higher plateau pressures. Strong , moderate-quality evidence 51. For adults with moderate to severe sepsis-induced ARDS, we suggest using higher PEEP over lower PEEP. Weak , moderate-quality evidence 52. For adults with sepsis-induced respiratory failure (without ARDS), we suggest using low tidal volume as compared with high tidal volume ventilation. Weak , low quality of evidence 53. For adults with sepsis-induced moderate-severe ARDS, we suggest using traditional recruitment maneuvers. Weak , moderate-quality evidence 54. When using recruitment maneuvers, we recommend against using incremental PEEP titration/strategy. Strong , moderate-quality evidence 55. For adults with sepsis-induced moderate-severe ARDS, we recommend using prone ventilation for greater than 12 hr daily. Strong , moderate-quality evidence 56. For adults with sepsis induced moderate-severe ARDS, we suggest using intermittent NMBA boluses, over NMBA continuous infusion. Weak , moderate-quality evidence 57. For adults with sepsis-induced severe ARDS, we suggest using Veno-venous (VV) ECMO when conventional mechanical ventilation fails in experienced centers with the infrastructure in place to support its use. Weak , low quality of evidence NEW ADDITIONAL THERAPIES 58. For adults with septic shock and an ongoing requirement for vasopressor therapy we suggest using IV corticosteroids. Weak , moderate-quality evidence UPGRADE from Weak recommendation , low quality of evidence "We suggest against using IV hydrocortisone to treat septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (see goals for Initial Resuscitation). If this is not achievable, we suggest IV hydrocortisone at a dose of 200 mg/day." 59. For adults with sepsis or septic shock we suggest against using polymyxin B hemoperfusion. Weak , low quality of evidence NEW from previous: "We make no recommendation regarding the use of blood purification techniques" 60. There is insufficient evidence to make a recommendation on the use of other blood purification techniques. No recommendation 61. For adults with sepsis or septic shock we recommend using a restrictive (over liberal) transfusion strategy. Strong , moderate-quality evidence 62. For adults with sepsis or septic shock we suggest against using IV immunoglobulins. Weak , low quality of evidence 63. For adults with sepsis or septic shock, and who have risk factors for gastrointestinal (GI) bleeding, we suggest using stress ulcer prophylaxis. Weak , moderate-quality evidence 64. For adults with sepsis or septic shock, we recommend using pharmacologic venous thromboembolism (VTE) prophylaxis unless a contraindication to such therapy exists. Strong , moderate-quality evidence 65. For adults with sepsis or septic shock, we recommend using low molecular weight heparin over unfractionated heparin for VTE prophylaxis Strong , moderate-quality evidence 66. For adults with sepsis or septic shock, we suggest against using mechanical VTE prophylaxis, in addition to pharmacological prophylaxis, over pharmacologic prophylaxis alone. Weak , low quality of evidence 67. In adults with sepsis or septic shock and AKI, we suggest using either continuous or intermittent renal replacement therapy. Weak , low quality of evidence 68. In adults with sepsis or septic shock and AKI, with no definitive indications for renal replacement therapy, we suggest against using renal replacement therapy. Weak , moderate-quality evidence 69. For adults with sepsis or septic shock, we recommend initiating insulin therapy at a glucose level of ≥ 180mg/dL (10 mmol/L). Strong , moderate-quality evidence 70. For adults with sepsis or septic shock we suggest against using IV vitamin C. Weak , low quality of evidence NEW 71. For adults with septic shock and hypoperfusion-induced lactic acidemia, we suggest against using sodium bicarbonate therapy to improve hemodynamics or to reduce vasopressor requirements. Weak , low quality of evidence 72. For adults with septic shock and severe metabolic acidemia (pH ≤ 7.2) and acute kidney injury (AKIN score 2 or 3), we suggest using sodium bicarbonate therapy Weak , low quality of evidence 73. For adult patients with sepsis or septic shock who can be fed enterally, we suggest early (within 72 hr) initiation of enteral nutrition. Weak , very low quality of evidence LONG-TERM OUTCOMES AND GOALS OF CARE 74. For adults with sepsis or septic shock, we recommend discussing goals of care and prognosis with patients and families over no such discussion. Best practice statement 75. For adults with sepsis or septic shock, we suggest addressing goals of care early (within 72 hr) over late (72 hr or later). Weak , low quality of evidence 76. For adults with sepsis or septic shock, there is insufficient evidence to make a recommendation on any specific standardized criterion to trigger goals of care discussion. No recommendation 77. For adults with sepsis or septic shock, we recommend that the principles of palliative care (which may include palliative care consultation based on clinician judgement) be integrated into the treatment plan, when appropriate, to address patient and family symptoms and suffering. Best practice statement 78. For adults with sepsis or septic shock, we suggest against routine formal palliative care consultation for all patients over palliative care consultation based on clinician judgement. Weak , low quality of evidence 79. For adult survivors of sepsis or septic shock and their families, we suggest referral to peer support groups over no such referral. Weak , very low quality of evidence 80. For adults with sepsis or septic shock, we suggest using a handoff process of critically important information at transitions of care over no such handoff process. Weak , very low quality of evidence 81. For adults with sepsis or septic shock, there is insufficient evidence to make a recommendation on the use of any specific structured handoff tool over usual handoff processes. No recommendation 82. For adults with sepsis or septic shock and their families, we recommend screening for economic and social support (including housing, nutritional, financial, and spiritual support), and make referrals where available to meet these needs. Best practice statement 83. For adults with sepsis or septic shock and their families, we suggest offering written and verbal sepsis education (diagnosis, treatment, and post-ICU/post-sepsis syndrome) prior to hospital discharge and in the follow-up setting. Weak , very low quality of evidence 84. For adults with sepsis or septic shock and their families, we recommend the clinical team provide the opportunity to participate in shared decision making in post-ICU and hospital discharge planning to ensure discharge plans are acceptable and feasible. Best practice statement 85. For adults with sepsis and septic shock and their families, we suggest using a critical care transition program, compared with usual care, upon transfer to the floor. Weak , very low quality of evidence 86. For adults with sepsis and septic shock, we recommend reconciling medications at both ICU and hospital discharge. Best practice statement 87. For adult survivors of sepsis and septic shock and their families, we recommend including information about the ICU stay, sepsis and related diagnoses, treatments, and common impairments after sepsis in the written and verbal hospital discharge summary. Best practice statement 88. For adults with sepsis or septic shock who developed new impairments, we recommend hospital discharge plans include follow-up with clinicians able to support and manage new and long-term sequelae. Best practice statement 89. For adults with sepsis or septic shock and their families, there is insufficient evidence to make a recommendation on early post-hospital discharge follow-up compared with routine post-hospital discharge follow-up. No recommendation 90. For adults with sepsis or septic shock, there is insufficient evidence to make a recommendation for or against early cognitive therapy. No recommendation 91. For adult survivors of sepsis or septic shock, we recommend assessment and follow-up for physical, cognitive, and emotional problems after hospital discharge. Best practice statement 92. For adult survivors of sepsis or septic shock, we suggest referral to a post-critical illness follow-up program if available. Weak , very low quality of evidence 93. For adult survivors of sepsis or septic shock receiving mechanical ventilation for > 48hr or an ICU stay of > 72 hr, we suggest referral to a post-hospital rehabilitation program. Weak , very low quality of evidence (References 5–24 are referred to in the Methodology section which can be accessed at Supplemental Digital Content: Methodology.) SCREENING AND EARLY TREATMENT Screening for Patients With Sepsis and Septic Shock - 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 recommendation, moderate quality of evidence for screening. Strong recommendation, very low-quality evidence for standard operating procedures. Rationale Sepsis performance improvement programs generally consist of sepsis screening, education, measurement of sepsis bundle performance, patient outcomes, and actions for identified opportunities (25,26). Despite some inconsistency, a meta-analysis of 50 observational studies on the effect of performance improvement programs showed that these programs were associated with better adherence to sepsis bundles along with a reduction in mortality (OR, 0.66; 95% CI, 0.61–0.72) in patients with sepsis and septic shock (27). The specific components of performance improvement did not appear to be as important as the presence of a program that included sepsis screening and metrics. Sepsis screening tools are designed to promote early identification of sepsis and consist of manual methods or automated use of the electronic health record (EHR). There is wide variation in diagnostic accuracy of these tools with most having poor predictive values, although the use of some was associated with improvements in care processes (28–31). A variety of clinical variables and tools are used for sepsis screening, such as systemic inflammatory response syndrome (SIRS) criteria, vital signs, signs of infection, quick Sequential Organ Failure Score (qSOFA) or Sequential Organ Failure Assessment (SOFA) criteria, National Early Warning Score (NEWS), or Modified Early Warning Score (MEWS) (26,32). Machine learning may improve performance of screening tools, and in a meta-analysis of 42,623 patients from seven studies for predicting hospital acquired sepsis the pooled area under the receiving operating curve (SAUROC) (0.89; 95% CI, 0.86−0.92); sensitivity (81%; 95% CI, 80−81), and specificity (72%; 95% CI, 72−72) was higher for machine learning than the SAUROC for traditional screening tools such as SIRS (0.70), MEWS (0.50), and SOFA (0.78) (32). Screening tools may target patients in various locations, such as in-patient wards, emergency departments, or ICUs (28–30,32). A pooled analysis of three RCTs did not demonstrate a mortality benefit of active screening (RR, 0.90; 95% CI, 0.51−1.58) (33–35). However, while there is wide variation in sensitivity and specificity of sepsis screening tools, they are an important component of identifying sepsis early for timely intervention. Standard operating procedures are a set of practices that specify a preferred response to specific clinical circumstances Sepsis standard operating as Early have to which a standard with components of the sepsis early and A large the between of sepsis and A of sepsis to hospitals in the in a mortality and after of sepsis with a control from other In this time mortality was lower in hospitals with higher with the sepsis bundles may a A meta-analysis of two RCTs in higher mortality (RR, 95% CI, with standard operating procedures compared with usual care, while it was in one observational 95% CI, - Recommendation 2. We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a screening tool for sepsis or septic shock. Strong recommendation, moderate-quality evidence. Rationale The qSOFA three variables to and prolonged ICU stay in patients with or suspected a Score a respiratory ≥ and a blood pressure ≤ mm When any two of these variables are the patient is qSOFA analysis used to support the recommendations of the on the of Sepsis identified qSOFA as a of poor in patients with or suspected infection, but no analysis was to support its use as a screening tool that time studies have the use of the qSOFA as a screening tool for sepsis The have been as to its have that qSOFA is more specific but than having two of SIRS for early identification of infection induced organ dysfunction SIRS qSOFA are screening tools for sepsis and the clinician to the of In the that of patients a qSOFA score 2 or but these patients for of poor have been when against the National Early Score and the Modified Early Score (MEWS) the presence of a qSOFA should the clinician to the of sepsis in all given the poor sensitivity of the the a strong recommendation against its use as a screening -

PURPOSE: The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify patients with MM. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM). PATIENTS AND METHODS: Clinical and laboratory data from 4,445 patients with NDMM enrolled onto 11 international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival. RESULTS: ISS, CA, and LDH data were simultaneously available in 3,060 of 4,445 patients. We defined the following three groups: revised ISS (R-ISS) I (n = 871), including ISS stage I (serum β2-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (less than the upper limit of normal range); R-ISS III (n = 295), including ISS stage III (serum β2-microglobulin level > 5.5 mg/L) and high-risk CA or high LDH level; and R-ISS II (n = 1,894), including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS I, 62% in the R-ISS II, and 40% in the R-ISS III groups; the 5-year PFS rates were 55%, 36%, and 24%, respectively. CONCLUSION: The R-ISS is a simple and powerful prognostic staging system, and we recommend its use in future clinical studies to stratify patients with NDMM effectively with respect to the relative risk to their survival.

OBJECTIVE: To assess the cancer risk in children and adolescents following exposure to low dose ionising radiation from diagnostic computed tomography (CT) scans. DESIGN: Population based, cohort, data linkage study in Australia. COHORT MEMBERS: 10.9 million people identified from Australian Medicare records, aged 0-19 years on 1 January 1985 or born between 1 January 1985 and 31 December 2005; all exposures to CT scans funded by Medicare during 1985-2005 were identified for this cohort. Cancers diagnosed in cohort members up to 31 December 2007 were obtained through linkage to national cancer records. MAIN OUTCOME: Cancer incidence rates in individuals exposed to a CT scan more than one year before any cancer diagnosis, compared with cancer incidence rates in unexposed individuals. RESULTS: 60,674 cancers were recorded, including 3150 in 680,211 people exposed to a CT scan at least one year before any cancer diagnosis. The mean duration of follow-up after exposure was 9.5 years. Overall cancer incidence was 24% greater for exposed than for unexposed people, after accounting for age, sex, and year of birth (incidence rate ratio (IRR) 1.24 (95% confidence interval 1.20 to 1.29); P<0.001). We saw a dose-response relation, and the IRR increased by 0.16 (0.13 to 0.19) for each additional CT scan. The IRR was greater after exposure at younger ages (P<0.001 for trend). At 1-4, 5-9, 10-14, and 15 or more years since first exposure, IRRs were 1.35 (1.25 to 1.45), 1.25 (1.17 to 1.34), 1.14 (1.06 to 1.22), and 1.24 (1.14 to 1.34), respectively. The IRR increased significantly for many types of solid cancer (digestive organs, melanoma, soft tissue, female genital, urinary tract, brain, and thyroid); leukaemia, myelodysplasia, and some other lymphoid cancers. There was an excess of 608 cancers in people exposed to CT scans (147 brain, 356 other solid, 48 leukaemia or myelodysplasia, and 57 other lymphoid). The absolute excess incidence rate for all cancers combined was 9.38 per 100,000 person years at risk, as of 31 December 2007. The average effective radiation dose per scan was estimated as 4.5 mSv. CONCLUSIONS: The increased incidence of cancer after CT scan exposure in this cohort was mostly due to irradiation. Because the cancer excess was still continuing at the end of follow-up, the eventual lifetime risk from CT scans cannot yet be determined. Radiation doses from contemporary CT scans are likely to be lower than those in 1985-2005, but some increase in cancer risk is still likely from current scans. Future CT scans should be limited to situations where there is a definite clinical indication, with every scan optimised to provide a diagnostic CT image at the lowest possible radiation dose.

RATIONALE: This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings. METHODS: In January 2016, the Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. GLIM appointed a core leadership committee and a supporting working group with representatives bringing additional global diversity and expertise. Empirical consensus was reached through a series of face-to-face meetings, telephone conferences, and e-mail communications. RESULTS: A two-step approach for the malnutrition diagnosis was selected, i.e., first screening to identify "at risk" status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among the GLIM core and supporting working group members. The top five ranked criteria included three phenotypic criteria (weight loss, low body mass index, and reduced muscle mass) and two etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least one phenotypic criterion and one etiologic criterion should be present. Phenotypic metrics for grading severity as Stage 1 (moderate) and Stage 2 (severe) malnutrition are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology-related diagnosis categories. CONCLUSION: A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure further collaboration and endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The diagnostic construct should be re-considered every 3-5 years.

BACKGROUND: Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival. RESULTS: A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion. CONCLUSIONS: Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134.).

BACKGROUND: This initiative aims to build a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings. METHODS: The Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. Empirical consensus was reached through a series of face-to-face meetings, telephone conferences, and e-mail communications. RESULTS: A 2-step approach for the malnutrition diagnosis was selected, that is, first screening to identify at risk status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among GLIM participants that selected 3 phenotypic criteria (non-volitional weight loss, low body mass index, and reduced muscle mass) and 2 etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least 1 phenotypic criterion and 1 etiologic criterion should be present. Phenotypic metrics for grading severity are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology-related diagnosis categories. CONCLUSIONS: A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The construct should be re-considered every 3-5 years.

BACKGROUND: Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group). Coprimary end points were progression-free survival and the overall response rate. Final results for the coprimary end points are reported on the basis of a planned interim analysis of progression-free survival. RESULTS: Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the rate of progression-free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio for progression or death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85; P<0.001). The overall response rate in the elotuzumab group was 79%, versus 66% in the control group (P<0.001). Common grade 3 or 4 adverse events in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients. CONCLUSIONS: Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-2 ClinicalTrials.gov number, NCT01239797.).

PURPOSE The oligometastatic paradigm hypothesizes that patients with a limited number of metastases may achieve long-term disease control, or even cure, if all sites of disease can be ablated. However, long-term randomized data that test this paradigm are lacking. METHODS We enrolled patients with a controlled primary malignancy and 1-5 metastatic lesions, with all metastases amenable to stereotactic ablative radiotherapy (SABR). We stratified by the number of metastases (1-3 v 4-5) and randomized in a 1:2 ratio between palliative standard-of-care (SOC) treatments (arm 1) and SOC plus SABR (arm 2). We used a randomized phase II screening design with a primary end point of overall survival (OS), using an α of .20 (wherein P &lt; .20 indicates a positive trial). Secondary end points included progression-free survival (PFS), toxicity, and quality of life (QOL). Herein, we present long-term outcomes from the trial. RESULTS Between 2012 and 2016, 99 patients were randomly assigned at 10 centers internationally. The most common primary tumor types were breast (n = 18), lung (n = 18), colorectal (n = 18), and prostate (n = 16). Median follow-up was 51 months. The 5-year OS rate was 17.7% in arm 1 (95% CI, 6% to 34%) versus 42.3% in arm 2 (95% CI, 28% to 56%; stratified log-rank P = .006). The 5-year PFS rate was not reached in arm 1 (3.2%; 95% CI, 0% to 14% at 4 years with last patient censored) and 17.3% in arm 2 (95% CI, 8% to 30%; P = .001). There were no new grade 2-5 adverse events and no differences in QOL between arms. CONCLUSION With extended follow-up, the impact of SABR on OS was larger in magnitude than in the initial analysis and durable over time. There were no new safety signals, and SABR had no detrimental impact on QOL.

BACKGROUND: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. METHODS: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. RESULTS: A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score ≥4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. CONCLUSIONS: In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.).

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

BACKGROUND: In phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3. METHODS: We conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir for 12 weeks (277 patients) or sofosbuvir-ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Among patients with HCV genotype 2, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 99% (95% confidence interval [CI], 96 to 100), which was superior to the rate of 94% (95% CI, 88 to 97) in the sofosbuvir-ribavirin group (P=0.02). Among patients with HCV genotype 3, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 95% (95% CI, 92 to 98), which was superior to the rate of 80% (95% CI, 75 to 85) in the sofosbuvir-ribavirin group (P<0.001). The most common adverse events in the two studies were fatigue, headache, nausea, and insomnia. CONCLUSIONS: Among patients with HCV genotype 2 or 3 with or without previous treatment, including those with compensated cirrhosis, 12 weeks of treatment with sofosbuvir-velpatasvir resulted in rates of sustained virologic response that were superior to those with standard treatment with sofosbuvir-ribavirin. (Funded by Gilead Sciences; ASTRAL-2 ClinicalTrials.gov number, NCT02220998; and ASTRAL-3, NCT02201953.).

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.

Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver disease that affects approximately one-quarter of the global adult population, causing a substantial burden of ill health with wide-ranging social and economic implications. It is a multisystem disease and is considered the hepatic component of metabolic syndrome. Unlike other highly prevalent conditions, NAFLD has received little attention from the global public health community. Health system and public health responses to NAFLD have been weak and fragmented, and, despite its pervasiveness, NAFLD is largely unknown outside hepatology and gastroenterology. There is only a nascent global public health movement addressing NAFLD, and the disease is absent from nearly all national and international strategies and policies for non-communicable diseases, including obesity. In this global Delphi study, a multidisciplinary group of experts developed consensus statements and recommendations, which a larger group of collaborators reviewed over three rounds until consensus was achieved. The resulting consensus statements and recommendations address a broad range of topics - from epidemiology, awareness, care and treatment to public health policies and leadership - that have general relevance for policy-makers, health-care practitioners, civil society groups, research institutions and affected populations. These recommendations should provide a strong foundation for a comprehensive public health response to NAFLD.

OBJECTIVE: Type 2 diabetes confers a greater excess risk of cardiovascular disease in women than in men. Diabetes is also a risk factor for dementia, but whether the association is similar in women and men remains unknown. We performed a meta-analysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia. RESEARCH DESIGN AND METHODS: A systematic search identified studies published prior to November 2014 that had reported on the prospective association between diabetes and dementia. Study authors contributed unpublished sex-specific relative risks (RRs) and 95% CIs on the association between diabetes and all dementia and its subtypes. Sex-specific RRs and the women-to-men ratio of RRs (RRRs) were pooled using random-effects meta-analyses. RESULTS: Study-level data from 14 studies, 2,310,330 individuals, and 102,174 dementia case patients were included. In multiple-adjusted analyses, diabetes was associated with a 60% increased risk of any dementia in both sexes (women: pooled RR 1.62 [95% CI 1.45-1.80]; men: pooled RR 1.58 [95% CI 1.38-1.81]). The diabetes-associated RRs for vascular dementia were 2.34 (95% CI 1.86-2.94) in women and 1.73 (95% CI 1.61-1.85) in men, and for nonvascular dementia, the RRs were 1.53 (95% CI 1.35-1.73) in women and 1.49 (95% CI 1.31-1.69) in men. Overall, women with diabetes had a 19% greater risk for the development of vascular dementia than men (multiple-adjusted RRR 1.19 [95% CI 1.08-1.30]; P < 0.001). CONCLUSIONS: Individuals with type 2 diabetes are at ∼60% greater risk for the development of dementia compared with those without diabetes. For vascular dementia, but not for nonvascular dementia, the additional risk is greater in women.

Inflammation is an important part of the pathophysiology of traumatic brain injury. Although the central nervous system differs from the other organs because of the almost complete isolation from the blood stream mediated by the blood-brain barrier, the main steps characterizing the immune activation within the brain follow a scenario similar to that in other organs. The key players in these processes are the numerous immune mediators released within minutes of the primary injury. They guide a sequence of events including expression of adhesion molecules, cellular infiltration, and additional secretion of inflammatory molecules and growth factors, resulting in either regeneration or cell death. The question is this: to what extent is inflammation beneficial for the injured brain tissue, and how does it contribute to secondary brain damage and progressive neuronal loss? This review briefly reports recent evidence supporting the dual, the beneficial, or the deleterious role of neuroinflammation after traumatic brain injury.

INTRODUCTION: The aim of this study was to develop consensus recommendations on safety parameters for mobilizing adult, mechanically ventilated, intensive care unit (ICU) patients. METHODS: A systematic literature review was followed by a meeting of 23 multidisciplinary ICU experts to seek consensus regarding the safe mobilization of mechanically ventilated patients. RESULTS: Safety considerations were summarized in four categories: respiratory, cardiovascular, neurological and other. Consensus was achieved on all criteria for safe mobilization, with the exception being levels of vasoactive agents. Intubation via an endotracheal tube was not a contraindication to early mobilization and a fraction of inspired oxygen less than 0.6 with a percutaneous oxygen saturation more than 90% and a respiratory rate less than 30 breaths/minute were considered safe criteria for in- and out-of-bed mobilization if there were no other contraindications. At an international meeting, 94 multidisciplinary ICU clinicians concurred with the proposed recommendations. CONCLUSION: Consensus recommendations regarding safety criteria for mobilization of adult, mechanically ventilated patients in the ICU have the potential to guide ICU rehabilitation whilst minimizing the risk of adverse events.

BACKGROUND: Klebsiella pneumoniae is an opportunistic pathogen and leading cause of hospital-associated infections. Intensive care unit (ICU) patients are particularly at risk. Klebsiella pneumoniae is part of the healthy human microbiome, providing a potential reservoir for infection. However, the frequency of gut colonization and its contribution to infections are not well characterized. METHODS: We conducted a 1-year prospective cohort study in which 498 ICU patients were screened for rectal and throat carriage of K. pneumoniae shortly after admission. Klebsiella pneumoniae isolated from screening swabs and clinical diagnostic samples were characterized using whole genome sequencing and combined with epidemiological data to identify likely transmission events. RESULTS: Klebsiella pneumoniae carriage frequencies were estimated at 6% (95% confidence interval [CI], 3%-8%) among ICU patients admitted direct from the community, and 19% (95% CI, 14%-51%) among those with recent healthcare contact. Gut colonization on admission was significantly associated with subsequent infection (infection risk 16% vs 3%, odds ratio [OR] = 6.9, P < .001), and genome data indicated matching carriage and infection isolates in 80% of isolate pairs. Five likely transmission chains were identified, responsible for 12% of K. pneumoniae infections in ICU. In sum, 49% of K. pneumoniae infections were caused by the patients' own unique strain, and 48% of screened patients with infections were positive for prior colonization. CONCLUSIONS: These data confirm K. pneumoniae colonization is a significant risk factor for infection in ICU, and indicate ~50% of K. pneumoniae infections result from patients' own microbiota. Screening for colonization on admission could limit risk of infection in the colonized patient and others.

Finding, testing and demonstrating efficacy of new treatments for stroke recovery is a multifaceted challenge. We believe that to advance the field, neurorehabilitation trials need a conceptually rigorous starting framework. An essential first step is to agree on definitions of sensorimotor recovery and on measures consistent with these definitions. Such standardization would allow pooling of participant data across studies and institutions aiding meta-analyses of completed trials, more detailed exploration of recovery profiles of our patients and the generation of new hypotheses. Here, we present the results of a consensus meeting about measurement standards and patient characteristics that we suggest should be collected in all future stroke recovery trials. Recommendations are made considering time post stroke and are aligned with the international classification of functioning and disability. A strong case is made for addition of kinematic and kinetic movement quantification. Further work is being undertaken by our group to form consensus on clinical predictors and pre-stroke clinical data that should be collected, as well as recommendations for additional outcome measurement tools. To improve stroke recovery trials, we urge the research community to consider adopting our recommendations in their trial design.