BackgroundEmergency department (ED) crowding is a serious problem worldwide causing decreased quality of care. It is reasonable to assume that the negative effects of crowding are at least partially due to high staff workload, but previous crowding metrics based on high workload have not been generalisable to Swedish EDs and have not been associated with increased mortality, in contrast to, e.g., occupancy rate. We recently derived and validated the modified Skane Emergency Department Assessment of Patient Load model (mSEAL) that measures crowding based on staff workload in Swedish EDs, but its ability to identify situations with increased mortality is unclear. In this study, we aimed to investigate the association between ED crowding measured by mSEAL model, or occupancy rate, and mortality. MethodsAll ED patients from 2017-01-01 to 2017-06-30 from two regional healthcare systems (Skane and ostergotland Counties with a combined population of approximately 1.8 million) in Sweden were included. Exposure was ED- and hour-adjusted mSEAL or occupancy rate. Primary outcome was mortality within 7 days of ED arrival, with one-day and 30-day mortality as secondary outcomes. We used Cox regression hazard ratio (HR) adjusted for age, sex, arrival by ambulance, hospital admission and chief complaint. ResultsWe included a total of 122,893 patients with 168,900 visits to the six participating EDs. Arriving at an hour with a mSEAL score above the 95th percentile for that ED and hour of day was associated with an non-significant HR for death at 7 days of 1.04 (95% CI 0.96-1.13). For one- and 30-day mortality the HR was non-significant at 1.03 (95% CI 0.9-1.18) and 1.03 (95% CI 0.97-1.09). Similarly, occupancy rate above the 95th percentile with a HR of 1.04 (95% CI 0.9-1.19), 1.03 (95%CI 0.95-1.13) and 1.04 (95% CI 0.98-1.11) for one-, 7- and 30-day mortality, respectively. ConclusionIn this multicenter study in Sweden, ED crowding measured by mSEAL or occupancy rate was not associated with a significant increase in short-term mortality.

IntroductionEmergency medicine (EM) is a growing field in Sub-Saharan Africa. Characterising the current capacity of hospitals to provide emergency care is important in identifying gaps and future directions of growth. This study aimed to characterise the ability of emergency units (EU) to provide emergency care in the Kilimanjaro region in Northern Tanzania.MethodsThis was a cross-sectional study conducted at 11 hospitals with emergency care capacity in three districts in the Kilimanjaro region of Northern Tanzania assessed in May 2021. An exhaustive sampling approach was used, whereby all hospitals within the three-district area were surveyed. Hospital representatives were surveyed by two EM physicians using the Hospital Emergency Assessment tool developed by the WHO; data were analysed in Excel and STATA.ResultsAll hospitals provided emergency services 24 hours a day. Nine had a designated area for emergency care, four had a core of fixed providers assigned to the EU, two lacked a protocol for systematic triage. For Airway and Breathing interventions, oxygen administration was adequate in 10 hospitals, yet manual airway manoeuvres were only adequate in six and needle decompression in two. For Circulation interventions, fluid administration was adequate in all facilities, yet intraosseous access and external defibrillation were each only available in two. Only one facility had an ECG readily available in the EU and none was able to administer thrombolytic therapy. For trauma interventions, all facilities could immobilise fractures, yet lacked interventions such as cervical spinal immobilisation and pelvic binding. These deficiencies were primarily due to lack of training and resources.ConclusionMost facilities perform systematic triage of emergency patients, though major gaps were found in the diagnosis and treatment of acute coronary syndrome and initial stabilisation manoeuvres of patients with trauma. Resource limitations were primarily due to equipment and training deficiencies. We recommend the development of future interventions in all levels of facilities to improve the level of training.

Vital signs reflect circulatory function and hence hemodynamics on a macroscopic scale and are often unreliable or late indicators of hemodynamic instability. Previous studies support that alterations in the microcirculation may provide early indicators of deterioration and impending shock. Microcirculation is also restored late in the recovery process. Hence, monitoring microcirculation is important since treatments based on normalizing classical vital signs will not always restore microvascular hemodynamics and the microcirculation may remain in shock although e.g., blood pressure seems normal. The aim of this study was to investigate alterations in skin microcirculation dynamics during lower body negative pressure as a model of shock and central hypovolemia. By using spatial frequency domain imaging (SFDI) and polarized reflectance imaging, we investigated the association between micro- and macrovascular function during these conditions. Furthermore, we evaluated microvascular reactivity using the capillary refill test. A cohort of 9 subjects were subjected to a progressive lower body negative pressure (LBNP) protocol. At baseline and at LBNP = -20mmHg, -30mmHg and -40mmHg, SFDI images were acquired and analyzed for tissue hemoglobin content and oxygenation. Superficial hemoglobin content was estimated by polarized reflectance imaging. We found that microcirculatory reactivity was prolonged during LBNP, but recovered after end of the protocol. These results indicate a correlation between negative pressure and microcirculatory function and that may provide a basis for early detection of shock in emergency care settings.

To establish the impact of COVID-19 on the pre-test probability for VTE in patients with suspected VTE. This was a retrospective, observational, cross-sectional study of patients 18 years and older undergoing diagnostic tests for VTE in an integrated healthcare system covering a population of 465,000 during the calendar year of 2020. We adjusted for risk factors such as age, sex, previous VTE, ongoing anticoagulant treatment, malignancy, Charlson score, ward care, ICU care and wave of COVID-19. In total, 303 of 5041 patients had a positive diagnosis of COVID-19 around the time of investigation. The prevalence of VTE in COVID-positive patients was 10.2% (36/354), 14.7% (473/3219) in COVID-19 negative patients, and 15.6% (399/2589) in patients without a COVID-19 test. A COVID-positive status was not associated with an increased risk for VTE (crude odds ratio 0.64, 95% CI 0.45-0.91, adjusted odds ratio 0.46, 95%CI 0.19-1.16). We found no increased VTE risk in COVID-positive patients. This indicates that COVID-19 status should not influence VTE workup.The study was pre-registered on May 26, 2020 at ClinicalTrials.gov with identifier NCT04400877.

Background: One of the most critical decisions that emergency department (ED) physicians make is the discharge versus admission of patients. We aimed to study the association of the decision in the ED to admit patients with chest pain and/or breathlessness to a ward with risk assessment using the Rapid Emergency Triage and Treatment System (RETTS), the National Early Warning Score (NEWS), and plasma levels of the biomarkers copeptin, midregional proadrenomedulin (MR-proADM), and midregional proatrial natriuretic peptide (MR-proANP). Methods: Patients presenting at the ED with chest pain and/or breathlessness with less than one week onset were enrolled. Patients were triaged according to RETTS. NEWS was calculated from the vital signs retrospectively. Results: Three hundred and thirty-four patients (167 males), mean age 63.8 +/- 16.8 years, were included. Of which, 210 (62.8%) patients complained of chest pain, 65 (19.5%) of breathlessness, and 59 (17.7%) of both. Of these, 176 (52.7%) patients were admitted to a ward, and 158 (47.3%) patients were discharged from the ED. In binary logistic models, age, gender, vital signs (O-2 saturation and heart rate), NEWS class, and copeptin were associated with admission to a ward from the ED. In receiver-operating-characteristics (ROC) analysis, copeptin had an incremental predictive value compared to NEWS alone (P = 0.002). Conclusions: Emergency physicians decisions to admit patients with chest pain and/or breathlessness from the ED to a ward are related to age, O-2 saturation, heart rate, NEWS category, and copeptin. As an independent predictive marker for admission, early analysis of copeptin might be beneficial when improving patient pathways at the ED.

Background With the on-going debate about which specialty should be responsible for intubations in the emergency department in mind, the aim of this study was to describe the prevalence of endotracheal intubation and other airway management procedures in emergency department patients in Sweden. Methods All patients registered in the Swedish Intensive Care Registry with admission date from January 1 2013 until June 7 2018 and reported admission type "from the emergency department" or "emergency department" reported in the SAPS3 scoring were included. All patients missing codes for procedures were excluded. Results A total of 110,072 admissions from an emergency department to an ICU were registered during the study period. Of these, 41,619 admissions (37.8%) were excluded due to lack of codes for medical procedures. The remaining 68,453 admissions (62.2%) were included, and 31,888 emergency airway procedures (within 3 h from admission time to the intensive care unit) were registered. Invasive emergency airway procedures were the most common type of airway procedure (n = 23,446), followed by non-invasive airway procedures (n = 8377) and high-flow nasal cannula (n = 880). In 2017 a total of 4720 invasive emergency airway management procedures were registered. Conclusions The frequency of invasive airway management procedures in Swedish EDs is low. With approximately 1.9 million adult ED visits per year, this gives an estimated incidence of 2.4 invasive airway management procedures per thousand ED visits in 2017.

Background Emergency department (ED) crowding causes increased patient morbidity and mortality. ED occupancy rate (OR; patients by treatment beds) is a common measure of crowding, but the comparability of ORs between EDs is unknown. The objective of this investigation was to investigate differences in ORs between EDs using staff-perceived workload as reference. Methods This was a national cross-sectional study in Sweden. EDs provided data on census, treatment beds, staffing, and workload (1-6) at 5 time points. A baseline patient turnover was calculated as the average daily census by treatment beds, denoted turnover per treatment bed (TTB), for each ED. A census ratio (CR), current by daily census, was calculated to adjust for differences in the number of treatment beds. Results Data were returned from 37 (51%) EDs. TTB varied considerably (mean = 4, standard deviation = 1.6; range, 2.1-9.2), and the OR was higher in EDs with TTB >4 compared with <= 4, 0.86 versus 0.43 (0.43; 95% confidence interval [CI], 0.27-0.59), but not workload, 2.75 versus 2.52 (0.23; 95% CI, -0.19 to 0.64). After adjusting for confounders, both TTB (k = -0.3; 95% CI, -0.49 to -0.14) and OR (k = 3.4; 95% CI, 1.76-5.03) affected workload. Correlation with workload was better for CR than for OR (r = 0.75 vs 0.60, respectively). Conclusion OR is affected by patient-to-treatment bed ratios that differ significantly between EDs and should be accounted for when measuring crowding. CR is not affected by baseline treatment beds and is a better comparable measure of crowding compared with OR in this national comparator study.

Objective The aim of this study was to evaluate the effect of a novel, oral, modified-release formulation of the lipase inhibitor orlistat and the glucosidase/amylase inhibitor acarbose (denoted EMP16) on relative body weight after 26 weeks compared with placebo. Methods The randomized, double-blind, placebo-controlled trial had a 26-week treatment period, with dose escalation up to 6 weeks. Participants, adults between ages 18 and 75 years, with BMI >= 30 kg/m(2) or >= 28 kg/m(2) with risk factors, were randomly assigned to EMP16 120-mg orlistat/40-mg acarbose (EMP16-120/40), EMP16-150/50, or placebo. The primary end point was relative weight loss from baseline to week 26 assessed in participants with at least one post-baseline weight measurement. Results Of 156 randomized participants, 149 constituted the intention-to-treat population. The mean (95% CI) estimated treatment difference to placebo in relative weight loss after 26 weeks in the intention-to-treat population was -4.70% (-6.16% to -3.24%; p < 0.0001) with EMP16-120/40 and -5.42% (-6.60% to -4.24%; p < 0.0001) with EMP16-150/50. Conclusions This trial indicates that orlistat and acarbose can be successfully combined in a modified-release formulation to provide efficacious weight loss with no unexpected safety issues. EMP16 may be a promising candidate among other medications for improved weight management.

Transdermal iontophoresis offers an in vivo alternative to the strain-gauge model for measurement of vascular function but is limited due to lack of technical solutions for outcome assessment. The aims of this study were to, after measurement by polarized reflectance spectroscopy (PRS), use pharmacodynamic dose-response analysis on responses to different concentrations of acetylcholine (ACh); and to examine the effect of three consecutively administered iontophoretic current pulses. The vascular responses in 15 healthy volunteers to iontophorised ACh (5 concentrations, range 0.0001% to 1%, three consecutive pulses of 0.02 mA for 10 min each) were recorded using PRS. Data were fitted to a four-parameter logistic dose response model and compared. Vascular responses were quantifiable by PRS. Similar pharmacodynamic dose response curves could be generated irrespectively of the ACh concentration. Linearly increasing maximum vasodilatory responses were registered with increasing concentration of ACh. A limited linear dose effect of the concentration of ACh was seen between pulses. Polarized reflectance spectroscopy is well suited for measuring vascular responses to iontophoretically administrated ACh. The results of this study support further development of iontophoresis as a method to study vascular function and pharmacological responses in vivo.

Introduction As frailty among the elderly is receiving increasing attention in emergency departments (EDs) around the world, the use of frailty assessment tools is growing. An often used such tool is the Clinical Frailty Scale (CFS), whose inter-rater reliability has been sparingly investigated in ED settings. No inter-rater reliability study regarding CFS has previously been performed within the Scandinavian ED context. The primary aim of this study was to evaluate the inter-rater reliability of the CFS in a Swedish ED setting. Methods This was a prospective observational study conducted at three Swedish EDs. Patients >= 65 years were independently assessed with CFS by their responsible physician, registered nurse, and assistant nurse. Demographic information for each assessor was collected, along with frailty status (frail/not frail) on the basis of clinical judgment. Inter-rater reliability was calculated using intraclass correlation coefficient (ICC), whereas agreement of frailty assessed by CFS (dichotomized between frail/not frail, cutoff at >= 5 points) versus solely by clinical judgment was calculated by using cross-tabulation. Results One-hundred patients were included. We found inter-rater reliability to be moderate to good (ICC 0.78, 95% confidence interval [CI] 0.72-0.84), regardless of whether the care team included an emergency physician (ICC 0.74, 95% CI 0.62-0.83) or an intern/resident from another specialty (ICC 0.83, 95% CI 0.74-0.89). The agreement of clinically judged frailty compared to frailty according to CFS was 84%. In the opposing cases, staff tended to assess patients as frail to a higher extent using clinical judgment than by applying CFS on the same patient. Conclusions The CFS appears to have a moderate to good inter-rater reliability when used in a clinical ED setting. When guiding clinical decisions, we advise that the CFS score should be discussed within the team. Further research needs to be performed on the accuracy of clinical judgment to identify frailty in ED patients.

Background Swedish Emergency Departments (EDs) see 2.6 million visits annually. Sweden has a strong tradition of health care databases, but information on patients pathways to the ED is not documented in any registry. The aim of this study was to provide a national overview of pathways, degree of medical acuteness according to triage, chief complaints, and hospital admission rates for adult patients (>= 18 years) visiting Swedish EDs during 24 h. Methods A national cross-sectional study including all patients at 43 of Swedens 72 EDs during 24 h on April 25th, 2018. Pathway to the ED, medical acuteness at triage, admission and basic demographics were registered by dedicated assessors present at every ED for the duration of the study. Descriptive data are reported. Results A total of 3875 adult patients (median age 59; range 18 to 107; 50% men) were included in the study. Complete data for pathway to the ED was reported for 3693 patients (98%). The most common pathway was self-referred walk-in (n = 1310; 34%), followed by ambulance (n = 920; 24%), referral from a general practitioner (n = 497; 1 3%), and telephone referral by the national medical helpline "1177" (n = 409; 10%). In patients 18 to 64 years, self-referred walk-in was most common, whereas transport by ambulance dominated in patients > 64 years. Of the 3365 patients who received a medical acuteness level at triage, 4% were classified as Red (Immediate), 18% as Orange (very urgent), 47% as Yellow (Urgent), 26% as Green (Standard), and 5% as Blue (Non-Urgent). Abdominal or chest pain were the most common chief complaints representing approximately 1/3 of all presentations. Overall, the admission rate was 27%. Arrival by ambulance was associated with the highest rate of admission (53%), whereas walk-in patients and telephone referrals were less often admitted. Conclusion Self-referred walk-in was the overall most common pathway followed by ambulance. Patients arriving by ambulance were often elderly, critically ill and often admitted to in-patient care, whereas arrival by self-referred walk-in was more common in younger patients.

ObjectivePriority areas for emergency care research are emerging and becoming ever more important. The objectives of this scoping review were to (1) provide a comprehensive overview of published emergency care priority-setting studies by collating and comparing priority-setting methodology and (2) describe the resulting research priorities identified. MethodsThe Joanna Briggs Institute methodological framework was used. Inclusion criteria were peer-review articles available in English, published between January 1, 2008 and March 31, 2019 and used 2 or more search terms. Five databases (Scopus, AustHealth, EMBASE, CINAHL, and Ovid MEDLINE) were searched. REporting guideline for PRIority SEtting of health research (REPRISE) criteria were used to assess the quality of evidence of included articles. ResultsForty-five studies were included. Fourteen themes for emergency care research were considered within 3 overarching research domains: emergency populations (pediatrics, geriatrics), emergency care workforce and processes (nursing, shared decision making, general workforce, and process), and emergency care clinical areas (imaging, falls, pain management, trauma care, substance misuse, infectious diseases, mental health, cardiology, general clinical care). Variation in the reporting of research priority areas was evident. Priority areas to drive the global agenda for emergency care research are limited given the country and professional group-specific context of existing studies. ConclusionThis comprehensive summary of generated research priorities across emergency care provides insight into current and future research agendas. With the nature of emergency care being inherently broad, future priorities may warrant population (eg, children, geriatrics) or subspecialty (eg, trauma, toxicology, mental health) focus and be derived using a rigorous framework and patient engagement.

Monitoring of respiration is a central task in clinical medicine, crucial to patient safety. Despite the uncontroversial role of altered respiratory frequency as an important sign of impending or manifest deterioration, reliable measurement methods are mostly lacking outside of intensive care units and operating theaters. Photoplethysmography targeting the central blood circulation in the sternum could offer accurate and inexpensive monitoring of respiration. Changes in blood flow related to the different parts of the respiratory cycle are used to identify the respiratory pattern. The aim of this observational study was to compare photoplethysmography at the sternum to standard capnography in healthy volunteers. Bland Altman analysis showed good agreement (bias -0.21, SD 1.6, 95% limits of agreement -3.4 to 2.9) in respiratory rate values. Photoplethysmography provided high-quality measurements of respiratory rate comparable to capnographic measurements. This suggests that photoplethysmography may become a precise, cost-effective alternative for respiratory monitoring.

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Background Emergency departments (EDs) see a rising number of patients, but only a small fraction of ED patients need immediate intensive care. The characteristics of these patients are mostly unknown and there is reason to believe that there are large inter-hospital differences in thresholds for intensive care admissions from the ED. The purpose of this study was to give a nationwide overview of ED admissions directly to intensive care units. Methods We used the Swedish Intensive care Registry to identify all patients admitted to intensive care from the ED (January 1, 2013 until June 7, 2018). The primary outcome was discharge diagnosis after intensive care (primary ICU diagnosis code). ICU mortality and" ICU admission due to only observation" were analyzed as secondary outcomes. Results 110,072 ICU admissions were included, representing 94,546 unique patients. Intoxication, trauma and neurological conditions were the most common causes for intensive care, but large variations according to age, sex and hospital type were seen. Intoxication was the most prevalent diagnosis in young adults (46.8% of admissions in 18-29 years old), whereas infectious diseases predominated in the elderly (17.0% in 65-79 years old). Overall, ICU mortality was 7.2%, but varied substantially with age, sex, type of hospital and medical condition. Cardiac conditions had the highest mortality rates, reaching 32.9%. The mortality was higher in academic centers compared to rural hospitals (9.3% vs 5.0%). It was more common to be admitted to ICU for only observation in rural hospitals than in academic centers (20.1% vs 7.8%). Being admitted to ICU only for observation was most common in patients with intoxication (30.6%). Conclusions Overall, intoxication was the most common cause for ICU admission from the ED. However, causes of ED ICU admissions differ substantially according to age, sex and hospital type. Being admitted to the ICU only for observation was most common in intoxicated patients.

Objectives The aim of this study was to identify prehospital and early hospital risk factors associated with 30-day mortality in patients with blood culture-confirmed community-acquired bloodstream infection (CA-BSI) in Sweden.

Methods A retrospective case–control study of 1624 patients with CA-BSI (2015–2016), 195 non-survivors satisfying the inclusion criteria were matched 1:1 with 195 survivors for age, gender and microorganism. All forms of contact with a healthcare provider for symptoms of infection within 7 days prior CA-BSI episode were registered. Logistic regression was used to analyse risk factors for 30-day all-cause mortality.

Results Of the 390 patients, 61% (115 non-survivors and 121 survivors) sought prehospital contact. The median time from first prehospital contact till hospital admission was 13 hours (6–52) for non-survivors and 7 hours (3–24) for survivors (p<0.01). Several risk factors for 30-day all-cause mortality were identified: prehospital delay OR=1.26 (95% CI: 1.07 to 1.47), p<0.01; severity of illness (Sequential Organ Failure Assessment score) OR=1.60 (95% CI: 1.40 to 1.83), p<0.01; comorbidity score (updated Charlson Index) OR=1.13 (95% CI: 1.05 to 1.22), p<0.01 and inadequate empirical antimicrobial therapy OR=3.92 (95% CI: 1.64 to 9.33), p<0.01. In a multivariable model, prehospital delay >24 hours from first contact remained an important risk factor for 30-day all-cause mortality due to CA-BSI OR=6.17 (95% CI: 2.19 to 17.38), p<0.01.

Conclusion Prehospital delay and inappropriate empirical antibiotic therapy were found to be important risk factors for 30-day all-cause mortality associated with CA-BSI. Increased awareness and earlier detection of BSI in prehospital and early hospital care is critical for rapid initiation of adequate management and antibiotic treatment.All data relevant to the study are included in the article or uploaded as supplemental information.

Objective The objective of this study was to investigate the risk and prevalence of venous thromboembolism (VTE) for patients undergoing a diagnostic test for VTE with confirmed COVID-19 infection compared with patients with no COVID-19 infection. Methods This was a retrospective cross-sectional study of patients in an integrated healthcare system in Sweden, covering a population of 465,000, with a diagnostic test for VTE between March 1 and May 31 in the years 2015 to 2020. Risk for VTE with COVID-19 was assessed by logistic regression, adjusting for baseline risk factors. Results A total of 8702 patients were included, and 88 of those patients tested positive on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction test. A positive SARS-CoV-2 test did not increase the odds for VTE (odds ratio, 0.97; 95% confidence interval [CI], 0.55-1.74) and did not change when adjusting for sex, previous VTE, previous malignancy, Charlson score, hospital admission, intensive care, or ongoing treatment with anticoagulation (odds ratio, 0.72; 95% CI, 0.16-3.3). The prevalence of VTE was unchanged in 2020 compared with 2015 to 2019 (16.5% vs 16.1%, respectively), and there was no difference in VTE between the SARS-CoV-2 positive, negative, or untested groups in 2020 (15.9%, 17.6%, and 15.7%, respectively; P = 0.85). Conclusions We found no increased prevalence of VTE in the general population compared with previous years and no increased risk of VTE in patients who were SARS-CoV-2 positive, suggesting that SARS-CoV-2 status should not influence VTE workup in the emergency department. The prevalence of VTE was high in patients with SARS-CoV-2 treated in the intensive care unit (ICU), where the suspicion for VTE should remain high.

Background

Emergency Department crowding is associated with increased morbidity and mortality but no measure of crowding has been validated in Sweden. We have previously derived and internally validated the Skåne Emergency Department Assessment of Patient Load (SEAL) score as a measure of crowding in Emergency Departments (ED) in a large regional healthcare system in Sweden. Due to differences in electronic health records (EHRs) between health care systems in Sweden, all variables in the original SEAL-score could not be measured reliably nationally. We aimed to derive and validate a modified SEAL (mSEAL) model and to compare it with established international measures of crowding.

Methods

This was an observational cross sectional study at four EDs in Sweden. All clinical staff assessed their workload (1–6 where 6 is the highest workload) at 5 timepoints each day. We used linear regression with stepwise backward elimination on the original SEAL dataset to derive and internally validate the mSEAL score against staff workload assessments. We externally validated the mSEAL at four hospitals and compared it with the National Emergency Department Overcrowding Score (NEDOCS), the simplified International Crowding Measure in Emergency Department (sICMED), and Occupancy Rate. Area under the receiver operating curve (AuROC) and coefficient of determination was used to compare crowding models. Crowding was defined as an average workload of 4.5 or higher.

Results

The mSEAL score contains the variables Patient Hours and Time to physician and showed strong correlation with crowding in the derivation (r2 = 0.47), internal validation (r2 = 0.64 and 0.69) and in the external validation (r2 = 0.48 to 0.60). AuROC scores for crowding in the external validation were 0.91, 0.90, 0.97 and 0.80 for mSEAL, Occupancy Rate, NEDOCS and sICMED respectively.

Conclusions

The mSEAL model can measure crowding based on workload in Swedish EDs with good discriminatory capacity and has the potential to systematically evaluate crowding and help policymakers and researchers target its causes and effects. In Swedish EDs, Occupancy Rate and NEDOCS are good alternatives to measure crowding based on workload.

Lipopolysaccharide (LPS) induces fever through cytokines like receptor-activator of nuclear factor kappa B ligand (RANKL), triggering mediators like prostaglandins (PG), endothelin-1 (ET-1), corticotrophin-releasing factor (CRF), substance P (SP) and endogenous opioids. LPS-induced fever is reduced in females compared with males except in ovariectomized (OVX) females which show increased fever mediated by PG. The present study aimed to identify the mediators involved in fever in intact and OVX female rats. Fever was induced with LPS (50 mu g/kg) intraperitoneally or CRF (2.5 mu g), ET-1 (1 pg), morphine (10 mu g) and SP (500 ng) intracerebroventricularly in sham-operated and OVX rats. The role of RANKL was evaluated with osteoprotegerin (OPG, 1 mu g, intracerebroventricularly). Expression of RANK, CRFI/II, ETB, mu-opioid (MOR) and NK1 receptors was evaluated by confocal microscopy. Besides LPS, only morphine induced fever in OVX rats while all mediators induced fever in sham-operated animals. OPG abolished LPS-induced fever in OVX but not sham-operated animals. Overall, fever involves similar central mediators in cycling females and males but only morphine induced fever in OVX females. Importantly, RANK/RANKL participates in LPS-induced fever in OVX females, as in males but not in cycling females.

Background The ED Stressor Scale outlines 15 stressors that are of importance for ED staff. Limited research has identified how commonly such stressors occur, or whether such factors are perceived with similar importance across different hospitals. This study sought to examine the frequency or perceived severity of these 15 stressors using a multicentre cohort of emergency clinicians (nurses and physicians) in EDs in two countries (Australia and Sweden). Method This was a cross-sectional survey of staff working in eight hospitals in Australia and Sweden. Data were collected between July 2016 and June 2017 (depending on local site approvals) via a printed survey incorporating the 15-item ED stressor scale. The median stress score for each item and the frequency of experiencing each event was reported. Results Events causing most distress include heavy workload, death or sexual abuse of a child, inability to provide optimum care and workplace violence. Stressors reported most frequently include dealing with high acuity patients, heavy workload and crowding. Violence, workload, inability to provide optimal care, poor professional relations, poor professional development and dealing with high-acuity patients were reported more commonly by Australian staff. Swedish respondents reported more frequent exposure to mass casualty incidents, crisis management and administrative concerns. Conclusions Workload, inability to provide optimal care, workplace violence and death or sexual abuse of a child were consistently reported as the most distressing events across sites. The frequency with which these occurred differed in Australia and Sweden, likely due to differences in the healthcare systems.

Background Emergency Department (ED) crowding occurs when demand for care exceeds the available resources. Crowding has been associated with decreased quality of care and increased mortality, but the prevalence on a national level is unknown in most countries. Method We performed a national, cross-sectional study on staffing levels, staff workload, occupancy rate and patients waiting for an in-hospital bed (boarding) at five time points during 24 h in Swedish EDs. Results Complete data were collected from 37 (51% of all) EDs in Sweden. High occupancy rate indicated crowding at 12 hospitals (37.5%) at 31 out of 170 (18.2%) time points. Mean workload (measured on a scale from 1, no workload to 6, very high workload) was moderate at 2.65 (+/- 1.25). Boarding was more prevalent in academic EDs than rural EDs (median 3 vs 0). There were an average of 2.6, 4.6 and 3.2 patients per registered nurse, enrolled nurse and physician, respectively. Conclusion ED crowding based on occupancy rate was prevalent on a national level in Sweden and comparable with international data. Staff workload, boarding and patient to staff ratios were generally lower than previously described.

Hot flushes are common and troublesome symptoms of menopause. The neuropeptide calcitonin gene-related peptide (CGRP) is increased in plasma during hot flushes but it has not been clear if CGRP is causally involved in the mechanism underpinning the flushes. Here, we examined the effect of interventions with CGRP in a mouse model of hot flushes based on flush-like temperature increases triggered by forced physical activity in ovariectomized mice. Compared to normal mice, ovariectomized mice reacted with an exaggerated, flush-like, temperature increase after physical exercise. This increase was completely blocked by the non-peptide CGRP-antagonist MK-8825 (-0.41 degrees Celsius, 95% CI: -0,83 to 0,012, p amp;lt; 0.0001) at a dose that had no obvious effects on locomotor activity (50 mg/kg). Further, the flush-like temperature increases were strongly attenuated in ovariectomized mice lacking alpha CGRP due to a genetic modification. Collectively, our findings suggest that CGRP is an important mediator of experimentally induced hot flushes and they identify CGRP antagonists as promising treatment candidates for women and possibly also men with hot flushes.

Objectives The aim of this study was to develop and validate a scale to measure the coping strategies used by emergency staff in response to workplace stress. To achieve this aim, we developed a refined Jalowiec Coping Scale (JCS), termed the Jalowiec Coping Scale-Emergency Department (JCS-ED) and validated this scale on a sample of emergency clinicians. Design A cross-sectional survey incorporating the JCS, the working environment scale-10 and a measure of workplace stressors was administered between July 2016 and June 2017. The JCS-ED was developed in three stages: 1) item reduction through content matter experts, 2) exploratory factor analysis for further item reduction and to identify the factor structure of the revised scale and 3) confirmatory factor analyses to confirm the factors identified within the exploratory factor analysis. Setting Six Emergency Departments (EDs) in Australia and four in Sweden. There were three tertiary hospitals, five large urban hospitals and two small urban hospitals. Participants Participants were eligible for inclusion if they worked full-time or part-time as medical or nursing staff in the study EDs. The median age of participants was 35 years (IQR: 28-45 years) and they had been working in the ED for a median of 5 years (IQR: 2-10 years). 79% were females and 76% were nurses. Results A total of 875 ED staff completed the survey (response rate 51%). The content matter experts reduced the 60-item scale to 32 items. Exploratory factor analyses then further reduced the scale to 18 items assessing three categories of coping: problem-focussed coping, positive emotion-focussed coping and negative emotion-focussed coping. Confirmatory factor analysis supported this three-factor structure. Negative coping strategies were associated with poor perceptions of the work environment and higher ratings of stress. Conclusions The JCS-ED assesses maladaptive coping strategies along with problem-focussed and emotion-focussed coping styles. It is a short instrument that is likely to be useful in measuring the types of coping strategies employed by staff.

Background: Emergency Departments (EDs) today rely heavily on Electronic Health Records (EHRs) and associated support systems. EHR updates are known to be associated with adverse events, but reports on the consequences of breakdowns in EDs are lacking.

Objectives: To describe the effects on workload, occupancy, patient Length Of Stay (LOS), and admissions at three EDs (a regional trauma center, a community hospital and a rural community hospital) during a 96 h period of EHR downtime, of which 48 h represented an unexpected breakdown.

Methods: Assessments of workload, on a scale from 1 (no workload) to 6 (very high workload), were obtained from all staff before, during and after the downtime period. Occupancy, LOS and hospital admissions were extracted from data recorded in the fallback system at each ED during the downtime, and compared with the period before and after (uptime).

Results: Workload increased considerably at two EDs during the downtime whereas the third ED lacked resources to assess workload due to the breakdown. The proportion of assessments ≥4 were 28.5% during uptime compared to 38.4% during downtime at the regional trauma center ED (difference 9.9%, p = 0.006, 95% CI 2.7–17%), and 22.9% compared to 41% at the rural community ED (difference 18.1%, p = 0.0002, 95%CI 7.9–28.3%). Median LOS increased by 19 min (3:56 vs. 4:15, p < 0.004) at the regional trauma center ED, by 76 min (3:34 vs. 4:50, p < 0.001) at the community ED and was unaltered at the rural community ED (2:47 vs. 2:51, p = 0.3) during downtime. Occupancy increased significantly at the community ED (1.59 vs. 0.71, p < 0.0001). Admissions rates remained unchanged during the breakdown. Fallback systems and initiatives to manage the effects of the breakdown differed between the EDs.

Conclusions: EHR downtime or unexpected breakdowns increased staff workload, and had variable effects on ED crowding as measured by LOS and occupancy. Additional staff and digital fallback systems may reduce the effects on ED crowding, but this descriptive study cannot determine causality.

Sepsis is a major health concern with global estimates of 31.5 million cases per year. Case fatality rates are still unacceptably high, and early detection and treatment is vital since it significantly reduces mortality rates for this condition. Appropriately designed automated detection tools have the potential to reduce the morbidity and mortality of sepsis by providing early and accurate identification of patients who are at risk of developing sepsis. In this paper, we present "LiSep LSTM"; a Long Short-Term Memory neural network designed for early identification of septic shock. LSTM networks are typically well-suited for detecting long-term dependencies in time series data. LiSep LSTM was developed using the machine learning framework Keras with a Google TensorFlow back end. The model was trained with data from the Medical Information Mart for Intensive Care database which contains vital signs, laboratory data, and journal entries from approximately 59,000 ICU patients. We show that LiSep LSTM can outperform a less complex model, using the same features and targets, with an AUROC 0.8306 (95% confidence interval: 0.8236, 0.8376) and median offsets between prediction and septic shock onset up to 40 hours (interquartile range, 20 to 135 hours). Moreover, we discuss how our classifier performs at specific offsets before septic shock onset, and compare it with five state-of-the-art machine learning algorithms for early detection of sepsis.

Sepsis is a major health concern with global estimates of 31.5 million cases per year. Case fatality rates are still unacceptably high, and early detection and treatment is vital since it significantly reduces mortality rates for this condition. Appropriately designed automated detection tools have the potential to reduce the morbidity and mortality of sepsis by providing early and accurate identification of patients who are at risk of developing sepsis. In this paper, we present "LiSep LSTM"; a Long Short-Term Memory neural network designed for early identification of septic shock. LSTM networks are typically well-suited for detecting long-term dependencies in time series data. LiSep LSTM was developed using the machine learning framework Keras with a Google TensorFlow back end. The model was trained with data from the Medical Information Mart for Intensive Care database which contains vital signs, laboratory data, and journal entries from approximately 59,000 ICU patients. We show that LiSep LSTM can outperform a less complex model, using the same features and targets, with an AUROC 0.8306 (95% confidence interval: 0.8236, 0.8376) and median offsets between prediction and septic shock onset up to 40 hours (interquartile range, 20 to 135 hours). Moreover, we discuss how our classifier performs at specific offsets before septic shock onset, and compare it with five state-of-the-art machine learning algorithms for early detection of sepsis.

Background Capillary refill (CR) time is traditionally assessed by naked-eye inspection of the return to original colour of a tissue after blanching pressure. Few studies have addressed intra-observer reliability or used objective quantification techniques to assess time to original colour. This study compares naked-eye assessment with quantified CR (qCR) time using polarisation spectroscopy and examines intra-observer and interobserver agreements in using the naked eye. Method A film of 18 CR tests (shown in a random fixed order) performed in healthy adults was assessed by a convenience sample of 14 doctors, 15 nurses and 19 secretaries (Department of Emergency Medicine, Linkoping University, September to November 2017), who were asked to estimate the time to return to colour and characterise it as fast, normal or slow. The qCR times and corresponding naked-eye time assessments were compared using the Kruskal-Wallis test. Three videos were shown twice without observers knowledge to measure intra-observer repeatability. Intra-observer categorical assessments were compared using Cohens Kappa analysis. Interobserver repeatability was measured and depicted with multiple-observer Bland-Altman plotting. Differences in naked-eye estimation between professions were analysed using ANOVA. Results Naked-eye assessed CR time and qCR time differ substantially, and agreement for the categorical assessments (naked-eye assessment vs qCR classification) was poor (Cohens kappa 0.27). Bland-Altman intra-observer repeatability ranged from 6% to 60%. Interobserver agreement was low as shown by the Bland-Altman plotting with a 95% limit of agreement with the mean of +/- 1.98 s for doctors, +/- 1.6 s for nurses and +/- 1.75 s for secretaries. The difference in CR time estimation (in seconds) between professions was not significant. Conclusions Our study suggests that naked-eye-assessed CR time shows poor reproducibility, even by the same observers, and differs from an objective measure of CR time.

Vital sign assessment is a common task in emergency medicine, but resources for continuous monitoring are restricted, data is often recorded manually, and entangled wires cause frustration. Therefore, we designed a small, wireless photoplethysmographic device capable of continuously assessing pulse, respiratory frequency and oxygen saturation on the sternum and tested the performance and feasibility in an emergency department setting. Fifty (56.3 20.2 years), consenting emergency patients (29 male) were recruited. Heart rate, respiratory rate and oxygen saturation were recorded simultaneously using the device and standard monitoring equipment. Data was compared using Bland-Altman plotting (heart rate, respiratory rate) and mean difference (oxygen saturation). The bias for heart- and respiratory rate was 0.4 (limits of agreements -11.3, 12.2 and -6.1, 7.0). Mean difference for oxygen saturation was -0.21 +/- 2.35%. This may be the first wireless device to use photoplethysmography on the sternum for vital sign assessment. We noted good agreement with standard monitors, but lack of standardization in data processing between monitoring systems may limit the generalizability of these findings. Although further improvements are needed, the feasibility of this approach provides proof of concept for a new paradigm of large scale, wireless patient monitoring.

Objective

To describe the effect of low ambient temperature on skin temperature and capillary refill (CR) time in forehead, sternum and finger pulp.

Methods

An observational, nonrandomized experimental study on 15 healthy subjects (6 females) in a cold room (8°C). Outcome measures were skin temperature and quantified CR test after application of a standardized blanching pressure (9 N/cm2) using digital photographic polarization spectroscopy to generate CR times.

Results

The finger pulp showed marked temperature fall and prolonged CR times (>10 seconds). The CR registrations of the forehead and sternum were more comparable to curves observed in a control material at room temperature, and skin temperature falls were less marked. CR times were not prolonged in forehead measurements. At the sternum, some individuals showed CR times beyond guideline recommendations despite only a marginal reduction in skin temperature.

Conclusions

Low ambient temperature is a strong independent factor for CR time at peripheral sites. Reservation about sternum as a site of measurement is warranted since cold provocation produced prolonged CR times in some individuals. We found that the forehead is the most thermostable of the 3 sites and thus the preferred site to avoid ambient temperature artifact in measuring CR time.

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The neurotransmitter acetylcholine has been implicated in reward learning and drug addiction. However, the roles of the various cholinergic receptor subtypes on different neuron populations remain elusive. Here we study the function of muscarinic M4 receptors (M4Rs) in dopamine D1 receptor (D1R) expressing neurons and cholinergic neurons (expressing choline acetyltransferase; ChAT), during various reward-enforced behaviors and in a "waiting"-impulsivity test. We applied cell-type-specific gene deletions targeting M4Rs in D1RCre or ChATCre mice. Mice lacking M4Rs in D1R-neurons displayed greater cocaine seeking and drug-primed reinstatement than their littermate controls in a Pavlovian conditioned place preference (CPP) paradigm. Furthermore, the M4R-D1RCre mice initiated significantly more premature responses (PRs) in the 5-choice-serial-reaction-time-task (5CSRTT) than their littermate controls, indicating impaired waiting impulse control. In contrast, mice lacking M4Rs in cholinergic neurons did not acquire cocaine Pavlovian conditioning. The M4R-ChATCre mice were also unable to learn positive reinforcement to either natural reward or cocaine in an operant runway paradigm. Immediate early gene (IEG) expression (cFos and FosB) induced by repeated cocaine injections was significantly increased in the forebrain of M4R-D1RCre mice, whereas it remained normal in the M4R-ChATCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality. Furthermore, we found that neurons expressing both M4Rs and D1Rs are important for signaling impulse control.

To use Bioengineering methodology is used to achieve, at five anatomical sites, a detailed, quantitative assessment of the return of blood content to the blanched area, during the Capillary Refill (CR) test. An observational, non-randomized, experimental study on 23 healthy subjects (14 females) was performed in our climate controlled skin physiology laboratory. Our main outcome measures were based on the chronological assessment and quantification of red blood cell concentration (RBC) after the release of blanching pressure in the CR test, using Tissue Viability Imaging (TiVi), a digital photographic technique based on polarisation spectroscopy. TiVi enabled collection of detailed data on skin RBC concentration during the CR test. The results were shown as curves with skin blood concentration (TiVi-value) on the y-axis and the time on the x-axis. Quantitative CR responses showed site and temperature variability. We also suggest possible objective endpoint values from the capillary refill curve. Detailed data on skin RBC concentration during the CR test is easily obtained and allows objective determination of end points not possible to achieve by naked eye assessment. These findings have the potential to place the utility of the CR test in a clinical setting in a new light. Picture: Regular photograph and TiVi Image showing CR test and corresponding graph for the CR response. [GRAPHICS] .

The capillary refill test was introduced in 1947 to help estimate circulatory status in critically ill patients. Guidelines commonly state that refill should occur within 2 s after releasing 5 s of firm pressure (e.g., by the physicians finger) in the normal healthy supine patient. A slower refill time indicates poor skin perfusion, which can be caused by conditions including sepsis, blood loss, hypoperfusion, and hypothermia. Since its introduction, the clinical usefulness of the test has been debated. Advocates point out its feasibility and simplicity and claim that it can indicate changes in vascular status earlier than changes in vital signs such as heart rate. Critics, on the other hand, stress that the lack of standardization in how the test is performed and the highly subjective nature of the naked eye assessment, as well as the tests susceptibility to ambient factors, markedly lowers the clinical value. The aim of the present work is to describe in detail the course of the refill event and to suggest potentially more objective and exact endpoint values for the capillary refill test using diffuse polarization spectroscopy.

Systemic inflammation evokes an array of brain-mediated responses including fever, anorexia and taste aversion. Both fever and anorexia are prostaglandin dependent but it has been unclear if the cell-type that synthesizes the critical prostaglandins is the same. Here we show that pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not of COX-1, attenuates inflammation-induced anorexia. Mice with deletions of COX-2 selectively in brain endothelial cells displayed attenuated fever, as demonstrated previously, but intact anorexia in response to peripherally injected lipopolysaccharide (10μg/kg). Whereas intracerebroventricular injection of a cyclooxygenase inhibitor markedly reduced anorexia, deletion of COX-2 selectively in neural cells, in myeloid cells or in both brain endothelial and neural cells had no effect on LPS-induced anorexia. In addition, COX-2 in myeloid and neural cells was dispensable for the fever response. Inflammation-induced conditioned taste aversion did not involve prostaglandin signaling at all. These findings collectively show that anorexia, fever and taste aversion are triggered by distinct routes of immune-to-brain signaling.

Cyclooxygenase-2 (COX-2) is the main source of inducible prostaglandin E-2 production and mediates inflammatory symptoms including fever, loss of appetite and hyperalgesia. COX-1 is dispensable for fever, anorexia and hyperalgesia but is important for several other functions both under basal conditions and during inflammation. The differential functionality of the COX isoforms could be due to differences in the regulatory regions of the genes, leading to different expression patterns, or to differences in the coding sequence, resulting in distinct functional properties of the proteins. To study the molecular underpinnings of the functional differences between the two isoforms in the context of inflammatory symptoms, we used mice in which the coding sequence of COX-2 was replaced by the corresponding sequence of COX-1. In these mice, COX-1 mRNA was induced by inflammation but COX-1 protein expression did not fully mimic inflammation-induced COX-2 expression. Just like mice globally lacking COX-2, these mice showed a complete lack of fever and inflammation-induced anorexia as well as an impaired response to inflammatory pain. However, as previously reported, they displayed close to normal survival rates, which contrasts to the high fetal mortality in COX-2 knockout mice. This shows that the COX activity generated from the hybrid gene was strong enough to allow survival but not strong enough to mediate the inflammatory symptoms studied, making the line an interesting alternative to COX-2 knockouts for the study of inflammation. Our results also show that the functional differences between COX-1 and COX-2 in the context of inflammatory symptoms are not only dependent on the features of the promoter regions. Instead they indicate that there are fundamental differences between the isoforms at translational or posttranslational levels.

There are differences in the immune response, and particularly fever, between males and females. In the present study, we investigated how the febrile responses induced by lipopolysaccharide (LPS) and different endogenous pyrogens were affected by female gonadal hormones. The febrile response to i.p. injection of LPS (50g/kg) was 40% lower in female rats compared to male or ovariectomised (OVX) female rats. Accordingly, oestrogen replacement in OVX animals reduced LPS-induced fever. Treatment with the prostaglandin synthesis inhibitor indomethacin (2mg/kg, i.p. 30min before) reduced the febrile response induced by LPS in both OVX (88%) and sham-operated (71%) rats. In line with the enhanced fever in OVX rats, there was increased expression of cyclooxygenase-2 (COX-2) in the hypothalamus and elevated levels of prostaglandin E-2 (PGE(2)). In addition, OVX rats were hyper-responsive to PGE(2) injected i.c.v. By contrast to the enhanced fever in response to LPS and PGE(2), the febrile response induced by i.c.v. injection of interleukin (IL)-1 was unaffected by ovariectomy, whereas the responses induced by tumour necrosis factor (TNF)- and macrophage inflammatory protein (MIP)-1 were completely abrogated. These results suggest that the mediators involved in the febrile response in females are similar to males, although the reduction of female hormones may decrease the responsiveness of some mediators such as TNF- and MIP-1. Compensatory mechanisms may be activated in females after ovariectomy such as an augmented synthesis of COX-2 and PGE(2).

Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type-specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E-2 (PGE(2)) synthesis. Further, we showed that inflammation-induced PGE(2) targeted EP1 receptors on striatal dopamine D1 receptor-expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE(2)-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.

Cyclooxygenase‐2 (COX‐2) is the main source of inducible prostaglandin E2 production and mediates inflammatory symptoms including fever, loss of appetite and hyperalgesia. In contrast, COX‐1 is dispensable for most inflammatory symptoms. Global deletion of COX‐2 leads to a blockade of inflammation‐induced fever and appetite loss but also to high rates of fetal mortality. The latter is unfortunate since mice without COX‐2 are powerful tools in the study of inflammation and cardiovascular medicine. The differential functionality of the COX isoforms could be due to differences in regulatory regions of the genes, leading to different expression patterns, or to differences in the coding sequence, leading to distinct functional properties of the proteins. To study this in the context of inflammatory symptoms, we used mice in which the coding sequence of COX‐2 was replaced by the corresponding sequence of COX‐1. In these mice, COX‐1 mRNA was induced by inflammation but COX‐1 protein expression did not fully mimic inflammation‐induced COX‐2 expression. Just like mice globally lacking COX‐2, these mice showed a complete lack of fever and inflammation‐induced anorexia. However, as previously reported, they displayed close to normal survival rates. This shows that the COX activity generated from the hybrid gene was strong enough to allow survival but not strong enough to mediate inflammatory symptoms, making the line an interesting alternative to COX‐2 knockouts for the study of inflammation. Our results also show that the functional differences between COX‐1 and COX‐2 in the context of inflammatory symptoms is not only dependent on the features of the promoter regions. Instead they indicate that there are fundamental differences between the isoforms at translational or posttranslational levels, which make hybrid genes less functional.

Fever is a hallmark of inflammatory and infectious diseases. The febrile response is triggered by prostaglandin E-2 synthesis mediated by induced expression of the enzymes cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1). The cellular source for pyrogenic PGE(2) remains a subject of debate; several hypotheses have been forwarded, including immune cells in the periphery and in the brain, as well as the brain endothelium. Here we generated mice with selective deletion of COX-2 and mPGES1 in brain endothelial cells. These mice displayed strongly attenuated febrile responses to peripheral immune challenge. In contrast, inflammation-induced hypoactivity was unaffected, demonstrating the physiological selectivity of the response to the targeted gene deletions. These findings demonstrate that PGE(2) synthesis in brain endothelial cells is critical for inflammation-induced fever.

Fever and loss of appetite are two of the most fundamental manifestations of disease. These disease symptoms, which lead to deviations from normal body temperature and food intake patterns, are seen in a vast array of infectious and inflammatory conditions. It is known that peripheral signals from the immune system are essential triggers for these responses, which are orchestrated by neuronal circuits in the brain. Due to the blood‐brain barrier, peripheral inflammatory signals require a specific mode of transmission into the brain. Such mechanisms have been proposed, but interventional studies of these mechanisms have never rendered conclusive results. In this thesis, we present the first functional evidence of cyclooxygenase 2 (COX‐2) and microsomal prostaglandin E synthase type 1 (mPGES‐1) mediated prostaglandin E2 synthesis in the blood‐brain barrier endothelial cells as a signaling mechanism in the initiation of inflammatory fever. We also show that one of the world’s most widely used antipyretics, paracetamol, acts by inhibition of COX‐2. Combined with the finding that COX‐2 and mPGES‐1 in brain endothelial cells play a key role in inflammatory fever, this finding suggests that paracetamol inhibits fever by specifically blocking prostaglandin E2 synthesis in blood‐brain barrier endothelium. In another symptom of inflammation, anorexia, the cellular origin of peripheral signals triggering acute anorexia are largely unknown. We show that the expression of myeloid differentiation primary response gene 88 (Myd88) in myeloid cells is important for the initiation of acute inflammatory anorexia and the maintenance of cancer anorexia‐cachexia.

Taken together, these findings provide a significant advancement of our understanding of the mechanisms triggering acute inflammatory fever and anorexia and also explain the antipyretic effect of paracetamol.

Acetaminophen is one of the world's most commonly used drugs to treat fever and pain, yet its mechanism of action has remained unclear. Here we tested the hypothesis that acetaminophen blocks fever through inhibition of cyclooxygenase-2 (Cox-2), by monitoring lipopolysaccharide induced fever in mice with genetic manipulations of enzymes in the prostaglandin cascade. We exploited the fact that lowered levels of a specific enzyme make the system more sensitive to any further inhibition of the same enzyme. Mice were immune challenged by an intraperitoneal injection of bacterial wall lipopolysaccharide and their body temperature recorded by telemetry. We found that mice heterozygous for Cox-2, but not for microsomal prostaglandin E synthase-1 (mPGES-1), displayed attenuated fever, indicating a rate limiting role of Cox-2. We then titrated a dose of acetaminophen that did not inhibit the lipopolysaccharide-induced fever in wild-type mice. However, when the same dose of acetaminophen was given to Cox-2 heterozygous mice, the febrile response to lipopolysaccharide was strongly attenuated, resulting in an almost normalized temperature curve, whereas no difference was seen between wild-type and heterozygous mPGES-1 mice. Furthermore, the fever to intracerebrally injected prostaglandin E₂ was unaffected by acetaminophen treatment. These findings reveal that acetaminophen, similar to aspirin and other non-steroidal anti-inflammatory drugs, is antipyretic by inhibiting cyclooxygenase-2, and not by inhibiting mPGES-1 or signaling cascades downstream of prostaglandin E₂.

Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

Loss of appetite concomitant with reduced food intake is a hallmark of both acute and chronic inflammatory diseases. Yet, despite extensive investigations, the underlying mechanisms remain undefined. Here we addressed this issue using mice lacking MyD88, critical for Tolllike and IL-1 receptor family signaling, generally or in specific cell types. Ubiquitous null deletions conferred complete resistance to bacterial lipopolysaccharide (LPS) induced anorexia, but this resistance was lost when knock-out mice subjected to whole-body irradiation to delete hematopoietic cells were transplanted with wild-type bone-marrow. In line with this observation, mice lacking MyD88 in hematopoietic cells were largely protected against LPS-induced anorexia, whereas mice with abrogated MyD88 signaling in neural cells, being leaner and smaller, developed anorexia of similar magnitude as wild-type littermates. The effect of hematopoietic MyD88-deletion on feeding seemed however partially dissociated from the effect on body weight, since LPS triggered weight loss, although attenuated, in these mutants. Furthermore, MyD88 deficiency in the cerebrovascular endothelium affected neither LPS-induced anorexia nor weight loss. In a model for the cancer anorexia-cachexia syndrome, inactivation of MyD88 in hematopoietic cells strongly impaired the anorexia development and protected against body weight loss. These findings identify hematopoietic cells as a critical nexus for acute inflammatory driven anorexia as well as for chronic anorexia associated with malignant disease.