Cholinesterase activities and sepsis-associated encephalopathy in viral versus nonviral sepsis.

PURPOSE: There is evidence that cholinergic imbalance secondary to neuroinflammation plays a role in the pathophysiology of sepsis-associated encephalopathy (SAE). Blood acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities have been proposed as surrogate parameters for the cholinergic function of the central nervous system. Viral sepsis is associated with systemic inflammation and BChE has been reported to be of prognostic value in a small cohort of COVID-19 patients. Nevertheless, the prognostic value of AChE in patients with viral sepsis remains unclear. METHODS: We investigated the role of AChE and BChE activities as prognostic biomarkers of SAE and mortality in patients with viral vs nonviral sepsis enrolled in two prospective cohort studies. We quantified the AChE and BChE activities in whole blood of patients at two time points in the acute phase of viral sepsis (N = 108) and compared them with the activities in patients with nonviral sepsis (N = 117) and healthy volunteers (N = 81). Patients were observed until discharge from the intensive care unit (ICU). RESULTS: Three days after sepsis onset, the median [interquartile range] levels of AChE and BChE were reduced in both patients with viral sepsis (AChE, 5,105 [4,010-6,250] U·L-1; BChE, 1,943 [1,393-2,468] U·L-1) and nonviral sepsis (AChE, 4,424 [3,630-5,055] U·L-1; BChE, 1,095 [834-1,526] U·L-1) compared with healthy volunteers (AChE, 6,693 [5,401-8,020] U·L-1; BChE, 2,645 [2,198-3,478] U·L-1). Patients with viral sepsis with SAE during their ICU stay had lower AChE activity three days after sepsis onset than patients without SAE (4,249 [3,798-5,351] U·L-1 vs 5,544 [4,124-6,461] U·L-1). Butyrylcholinesterase activity seven days after sepsis onset was lower in patients with viral sepsis who died in the ICU than in surviving patients (1,427 [865-2,181] U·L-1 vs 2,122 [1,571-2,787] U·L-1). CONCLUSION: Cholinesterase activities may be relevant prognostic markers for the occurrence of SAE and mortality in the ICU in patients with viral sepsis. STUDY REGISTRATION: This study constitutes an analysis of data from the ongoing studies ICROS (NCT03620409, first submitted 15 May 2018) and ICROVID (DRKS00024162, first submitted 9 February 2021).

RéSUMé: OBJECTIF: Certaines données probantes soutiennent que le déséquilibre cholinergique secondaire à la neuroinflammation joue un rôle dans la physiopathologie de l'encéphalopathie associée au sepsis (EAS). Les activités de l'acétylcholinestérase (AChE) et de la butyrylcholinestérase (BChE) sanguines ont été proposées comme paramètres de substitution de la fonction cholinergique du système nerveux central. Le sepsis viral est associé à une inflammation systémique et il a été rapporté que la BChE possédait une valeur pronostique dans une petite cohorte atteinte de COVID-19. Néanmoins, la valeur pronostique de l'AChE chez les patient·es atteint·es de sepsis viral reste incertaine. MéTHODE: Nous avons étudié le rôle des activités de l'AChE et de la BChE en tant que biomarqueurs pronostiques de l'EAS et de la mortalité chez les patient·es atteint·es de sepsis viral vs non viral recruté·es dans deux études de cohorte prospectives. Nous avons quantifié les activités de l'AChE et de la BChE dans le sang total de patient·es à deux moments de la phase aiguë du sepsis viral (N = 108) et les avons comparées aux activités chez les patient·es atteint·es de sepsis non viral (N = 117) et chez des volontaires sain·es (N = 81). Les patient·es ont été observé·es jusqu'à leur sortie de l'unité de soins intensifs (USI). RéSULTATS: Trois jours après l'apparition du sepsis, les taux médians [écart interquartile] d'AChE et BChE étaient réduits tant chez la patientèle atteinte de sepsis viral (AChE, 5105 [4010­6250] U·L−1; BChE, 1943 [1393­2468] U·L−1) et de sepsis non viral (AChE, 4424 [3630­5055] U·L−1; BChE, 1095 [834­1526] U·L−1) par rapport aux volontaires sain·es (AChE, 6693 [5401­8020] U·L−1; BChE, 2645 [2198­3478] U·L−1). Les patient·es atteint·es de sepsis viral avec EAS pendant leur séjour aux soins intensifs avaient une activité AChE plus faible trois jours après l'apparition du sepsis que les personnes sans EAS (4249 [3798­5351] U·L−1 vs 5544 [4124­6461] U·L−1). L'activité de la butyrylcholinestérase sept jours après l'apparition du sepsis était plus faible chez les patient·es atteint·es de sepsis viral décédé·es à l'USI que chez les personnes ayant survécu (1427 [865­2181] U·L-1 vs 2122 [1571­2787] U·L-1). CONCLUSION: Les activités des cholinestérases pourraient constituer des marqueurs pronostiques pertinents pour la survenue d'EAS et la mortalité en soins intensifs chez la patientèle atteinte de sepsis viral. ENREGISTREMENT DE L'éTUDE: Cette étude constitue une analyse des données des études en cours ICROS (NCT03620409, première soumission le 15 mai 2018) et ICROVID (DRKS00024162, première soumission le 9 février 2021).

Trajectories of pain and opioid use up to one year after surgery: analysis of a European registry.

BACKGROUND: Long-term opioid use after surgery is a crucial healthcare problem in North America. Data from European hospitals are scarce and differentiation of chronic pain has rarely been considered. METHODS: In a mixed surgical cohort of the PAIN OUT registry, opioid use and chronic pain were evaluated before surgery, and 6 and 12 months after surgery (M6/M12). Subgroups with or without opioid medication and pre-existing chronic pain were analysed. M12-chronic pain was categorised as chronic postsurgical pain (CPSP) meeting the ICD-11 definition, chronic pain related to surgery not meeting the ICD-11 definition, and chronic pain unrelated to surgery. Primary endpoint was the rate of M12 opioid users. Variables associated with M12 opioid use and patient-reported outcomes were evaluated. RESULTS: Of 2326 patients, 5.5% were preoperative opioid users; 4.4% and 3.5% took opioids at M6 and M12 (P<0.001). Chronic pain before operation and at M6/M12 was reported by 41.2%, 41.8%, and 34.7% of patients, respectively (P<0.001). The rate of M12 opioid users was highest in group unrelated (22.3%; related 8.3%, CPSP 1.5%; P<0.001). New opioid users were 1.1% (unrelated 7.1%, related 2.3%, CPSP 0.7%; P<0.001). M12 opioid users reported more pain, pain-related physical and affective interference, and needed more opioids than non-users. The predominant variable associated with M12 opioids was preoperative opioid use (estimated odds ratio [95% confidence interval]: 28.3 [14.1-56.7], P<0.001). CONCLUSIONS: Opioid use was low in patients with CPSP, and more problematic in patients with chronic pain unrelated to surgery. A detailed assessment of chronic pain unrelated or related to surgery or CPSP is necessary. CLINICAL TRIAL REGISTRATION: NCT02083835.

Pain After Outpatient Surgical Procedures.

BACKGROUND: Approximately 8.1 million outpatient surgical procedures were performed in Germany in 2021. Little is known about the quality of postoperative pain treatment in the outpatient sector. METHODS: The AQS1 project comprises a combined survey of patients and staff in the framework of quality control for ambulatory surgery. The primary endpoint of this study was the prevalence of relevant incisional pain (≥ 4/10 on the numerical rating scale) up to postoperative day 3. Secondary endpoints included prognostic variables for pain and pain-associated outcomes, based on the AQS1 patient questionnaire. Moreover, mixed regression models were used to analyze potential prognostic variables and associations of pain with other outcomes (study registration number DRKS00028052). RESULTS: Data from 330 008 patients were evaluated (from 1 July 2001 to 31 December 2021). The overall prevalence of relevant incisional pain up to postoperative day 3 was 22.5%, with major differences between different types of procedure (3.2%-51.2%). Pain was most common after hemorrhoid surgery (51.2%) and the laparoscopic lysis of large and small bowel adhesions (45.4%). The main associations of relevant pain were with younger age (odds ratio [OR] 1.87, 95% confidence interval [1.82; 1.91]), early postoperative pain (1.34, [1.30; 1.39]), inadequate provision of analgesics (2.90, [2.71; 3.09]), and surgical wound infections (2.60, [2.43; 2.78]). Patients with pain reported lower overall satisfaction with the procedure and a longer inability to work. CONCLUSION: These data have not been tested for representativeness. They can serve as a point of departure for the optimization of individualized perioperative pain therapy and for the planning of prospective studies.

Cost-effectiveness of the Perioperative Pain Management Bundle a registry-based study.

Introduction: The Perioperative Pain Management Bundle was introduced in 10 Serbian PAIN OUT network hospitals to improve the quality of postoperative pain management. The Bundle consists of 4 elements: informing patients about postoperative pain treatment options; administering a full daily dose of 1-2 non-opioid analgesics; administering regional blocks and/or surgical wound infiltration; and assessing pain after surgery. In this study, we aimed to assess the cost-effectiveness of the Bundle during the initial 24 h after surgery. Materials and methods: The assessment of cost-effectiveness was carried out by comparing patients before and after Bundle implementation and by comparing patients who received all Bundle elements to those with no Bundle element. Costs of postoperative pain management included costs of the analgesic medications, costs of labor for administering these medications, and related disposable materials. A multidimensional Pain Composite Score (PCS), the effectiveness measurement, was obtained by averaging variables from the International Pain Outcomes questionnaire evaluating pain intensity, interference of pain with activities and emotions, and side effects of analgesic medications. The incremental cost-effectiveness ratio (ICER) was calculated as the incremental change in costs divided by the incremental change in PCS and plotted on the cost-effectiveness plane along with the economic preference analysis. Results: The ICER value calculated when comparing patients before and after Bundle implementation was 181.89 RSD (1.55 EUR) with plotted ICERs located in the northeast and southeast quadrants of the cost-effectiveness plane. However, when comparing patients with no Bundle elements and those with all four Bundle elements, the calculated ICER was -800.63 RSD (-6.82 EUR) with plotted ICERs located in the southeast quadrant of the cost-effectiveness plane. ICER values differ across surgical disciplines. Conclusion: The proposed perioperative pain management Bundle is cost-effective. The cost-effectiveness varies depending on the number of implemented Bundle elements and fluctuates across surgical disciplines.

The Perioperative Pain Management Bundle is Feasible: Findings From the PAIN OUT Registry.

OBJECTIVES: The quality of postoperative pain management is often poor. A "bundle," a small set of evidence-based interventions, is associated with improved outcomes in different settings. We assessed whether staff caring for surgical patients could implement a "Perioperative Pain Management Bundle" and whether this would be associated with improved multidimensional pain-related patient-reported outcomes (PROs). METHODS: "PAIN OUT," a perioperative pain registry, offers tools for auditing pain-related PROs and obtaining information about perioperative pain management during the first 24 hours after surgery. Staff from 10 hospitals in Serbia used this methodology to collect data at baseline. They then implemented the "Perioperative Pain Management Bundle" into the clinical routine and collected another round of data. The bundle consists of 4 treatment elements: (1) a full daily dose of 1 to 2 nonopioid analgesics (eg, paracetamol and/or nonsteroidal anti-inflammatory drugs), (2) at least 1 type of local/regional anesthesia, (3) pain assessment by staff, and (4) offering patients information about pain management. The primary endpoint was a multidimensional pain composite score (PCS), evaluating pain intensity, interference, and side effects that was compared between patients who received the full bundle versus not. RESULTS: Implementation of the complete bundle was associated with a significant reduction in the PCS ( P < 0.001, small-medium effect size [ES]). When each treatment element was evaluated independently, nonopioid analgesics were associated with a higher PCS (ie, poorer outcome, and negligible ES), and the other elements were associated with a lower PCS (all negligible small ES). Individual PROs were consistently better in patients receiving the full bundle compared with 0 to 3 elements. The PCS was not associated with the surgical discipline. DISCUSSION: We report findings from using a bundle approach for perioperative pain management in patients undergoing mixed surgical procedures. Future work will seek strategies to improve the effect.

Variations and Predictors of Post-COVID Syndrome Severity in Patients Attending a Post-COVID Outpatient Clinic.

A relevant proportion of patients suffer from long-lasting impairments following an acute SARS-CoV-2 infection. The proposed post-COVID syndrome (PCS) score may improve comparison in the course and classification of affected patients. A prospective cohort of 952 patients presenting to the post-COVID outpatient clinic at Jena University Hospital, Germany, was enrolled. Patients received a structured examination. PCS score was calculated per visit. A total of 378 (39.7%) and 129 (13.6%) patients of the entire population visited the outpatient clinic two or three times, respectively (female: 66.4%; age: 49.5 (SD = 13) years). The initial presentation took place, on average, 290 (SD = 138) days after acute infection. The most frequently reported symptoms were fatigue (80.4%) and neurological impairments (76.1%). The mean PCS scores of patients with three visits were 24.6 points (SD = 10.9), 23.0 points (SD = 10.9) and 23.5 points (SD = 11.5) (p = 0.407), indicating moderate PCS. Female sex (p < 0.001), preexisting coagulation disorder (p = 0.021) and coronary artery disease (p = 0.032) were associated with higher PCS scores. PCS is associated with a multitude of long-lasting problems. The PCS score has proven its capability to objectify and quantify PCS symptoms in an outpatient setting. The influence of therapeutic measures on various PCS aspects should be the subject of further analyses.

Following Evidence-Based Recommendations for Perioperative Pain Management after Cesarean Section Is Associated with Better Pain-Related Outcomes: Analysis of Registry Data.

Women who have had a Cesarean Section (CS) frequently report severe pain and pain-related interference. One reason for insufficient pain treatment might be inconsistent implementation of evidence-based guidelines. We assessed the association between implementing three elements of care recommended by guidelines for postoperative pain management and pain-related patient-reported outcomes (PROs) in women after CS. The analysis relied on an anonymized dataset of women undergoing CS, retrieved from PAIN OUT. PAIN OUT, an international perioperative pain registry, provides clinicians with treatment assessment methodology and tools for patients to assess multi-dimensional pain-related PROs on the first postoperative day. We examined whether the care included [i] regional anesthesia with a neuraxial opioid OR general anesthesia with wound infiltration or a Transvesus Abdominis Plane block; [ii] at least one non-opioid analgesic at the full daily dose; and [iii] pain assessment and recording. Credit for care was given only if all three elements were administered (= "full"); otherwise, it was "incomplete". A "Pain Composite Score-total" (PCStotal), evaluating outcomes of pain intensity, pain-related interference with function, and side-effects, was the primary endpoint in the total cohort (women receiving GA and/or RA) or a sub-group of women with RA only. Data from 5182 women was analyzed. "Full" care was administered to 20% of women in the total cohort and to 21% in the RA sub-group. In both groups, the PCStotal was significantly lower compared to "incomplete" care (p < 0.001); this was a small-to-moderate effect size. Administering all three elements of care was associated with better pain-related outcomes after CS. These should be straightforward and inexpensive for integration into routine care after CS. However, even in this group, a high proportion of women reported poor outcomes, indicating that additional work needs to be carried out to close the evidence-practice gap so that women who have undergone CS can be comfortable when caring for themselves and their newborn.

Infliximab in the treatment of patients with severe COVID-19 (INFLIXCOVID): protocol for a randomised, controlled, multicentre, open-label phase II clinical study.

BACKGROUND: Despite the intense global research endeavour to improve the treatment of patients with COVID-19, the current therapy remains insufficient, resulting in persisting high mortality. Severe cases are characterised by a systemic inflammatory reaction driven by the release of pro-inflammatory cytokines such as IL-6 and tumour-necrosis-factor alpha (TNF-α). TNF-α-blocking therapies have proved beneficial in patients with chronic inflammatory diseases and could therefore pose a new treatment option in COVID-19. Hitherto, no results from randomised controlled trials assessing the effectiveness and safety of infliximab-a monoclonal antibody targeting TNF-α-in the treatment of COVID-19 have been published. METHODS: In this phase-2 clinical trial, patients with COVID-19 and clinical and laboratory signs of hyperinflammation will be randomised to receive either one dose of infliximab (5 mg/kg body weight) in addition to the standard of care or the standard of care alone. The primary endpoint is the difference in 28-day mortality. Further assessments concern the safety of infliximab therapy in COVID-19 and the influence of infliximab on morbidity and the course of the disease. For the supplementary scientific programme, blood and urine samples are collected to assess concomitant molecular changes. The Ethics Committee of the Friedrich Schiller University Jena (2021-2236-AMG-ff) and the Paul-Ehrlich-Institute (4513/01) approved the study. DISCUSSION: The results of this study could influence the therapy of patients with COVID-19 and affect the course of the disease worldwide, as infliximab is globally available and approved by several international drug agencies. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov ( NCT04922827 , 11 June 2021) and at EudraCT ( 2021-002098-25 , 19 May 2021).

Body composition, mitochondrial oxygen metabolism and metabolome of patients with obesity before and after bariatric surgery (COMMITMENT): protocol for a monocentric prospective cohort study.

INTRODUCTION: Obesity, defined as a body mass index ≥30 kg/m2, is one of the most prevalent health conditions worldwide. It is part of the metabolic syndrome, which encompasses arterial hypertension, dyslipoproteinaemia and diabetes. Obesity is viewed as a systemic disease with pathophysiological mechanisms on the molecular level. Dysfunction of the mitochondrion and systemic low-grade inflammation are among the proposed causes for the metabolic changes. In severe cases of obesity, laparoscopic sleeve gastrectomy, a bariatric operation, can achieve the desired weight loss and has been associated with clinical outcome improvement. Hitherto, the influence of patients' body composition on mitochondrial function and concomitant metabolic changes has not been fully understood. This study aims to quantify the patient's body composition before and after laparoscopic sleeve gastrectomy and to correlate these findings with changes in mitochondrial oxygen metabolism, metabolome and immune status. METHODS AND ANALYSIS: In this prospective monocentric cohort study, patients undergoing laparoscopic sleeve gastrectomy (n=30) at Jena University Hospital (Germany) will be assessed before surgery and at four time points during a 1-year follow-up. Body composition will be measured by bioimpedance analysis. Non-invasive assessment of mitochondrial oxygen metabolism using protoporphyrin IX-triplet state lifetime technique (PPIX-TSLT) and blood sampling for, among other, metabolomic and immunological analysis, will be performed. The primary outcome is the difference in relative fat mass between the preoperative time point and 6 months postoperatively. Further outcomes comprise longitudinal changes of PPIX-TSLT and metabolic and immunological variables. Outcomes will be assessed using paired t-tests, Wilcoxon signed-rank tests and regression analyses. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of Friedrich Schiller University Jena (2018-1192-BO). Written informed consent will be obtained from all patients prior to enrolment in the study. The results will be published in peer-reviewed journals and presented at appropriate conferences. TRIAL REGISTRATION NUMBER: DRKS00015891.

Identification of cardiovascular and molecular prognostic factors for the morbidity and mortality in COVID-19-sepsis (ICROVID): Protocol for a prospective multi-centre cohort study.

INTRODUCTION: Severe COVID-19 constitutes a form of viral sepsis. Part of the specific pathophysiological pattern of this condition is the occurrence of cardiovascular events. These include pulmonary embolism, arrhythmias and cardiomyopathy as manifestations of extra-pulmonary organ dysfunction. Hitherto, the prognostic impact of these cardiovascular events and their predisposing risk factors remains unclear. This study aims to explore this question in two cohorts of viral sepsis-COVID-19 and influenza-in order to identify new theragnostic strategies to improve the short- and long-term outcome of these two diseases. METHODS AND ANALYSIS: In this prospective multi-centre cohort study, clinical assessment will take place during the acute and post-acute phase of sepsis and be complemented by molecular laboratory analyses. Specifically, echocardiography and cardiovascular risk factor documentation will be performed during the first two weeks after sepsis onset. Aside from routine haematological and biochemical laboratory tests, molecular phenotyping will comprise analyses of the metabolome, lipidome and immune status. The primary endpoint of this study is the difference in 3-month mortality of patients with and without septic cardiomyopathy in COVID-19 sepsis. Patients will be followed up until 6 months after onset of sepsis via telephone interviews and questionnaires. The results will be compared with a cohort of patients with influenza sepsis as well as previous cohorts of patients with bacterial sepsis and healthy controls. ETHICS AND DISSEMINATION: Approval was obtained from the Ethics Committee of the Friedrich Schiller University Jena (2020-2052-BO). The results will be published in peer-reviewed journals and presented at appropriate conferences. TRIAL REGISTRATION: DRKS00024162.

Functional connectivity and neurotransmitter impairments of the salience brain network in chronic low back pain patients: a combined resting-state functional magnetic resonance imaging and 1 H-MRS study.

ABSTRACT: Functional reorganisation of the salience network (SN) has been proposed as one of the key pathomechanisms associated with central nociceptive processing in the chronic pain state. Being associated with an altered functional connectivity within the SN, these processes have been hypothesized to result from a loss of inhibitory function leading to node hyperexcitability and spontaneous pain. Combined resting-state BOLD functional magnetic resonance imaging (MRI) and 1 H-MR spectroscopy was applied to chronic back pain patients and healthy subjects to assess deviations from functional integrity (weighted closeness centrality [wCC], derived from resting-state functional MRI), oscillatory BOLD characteristics (spectral power), and neurotransmitter levels (GABA + , glutamate+glutamine) in 2 key SN nodes, anterior insular (aIns R ) and anterior mid-cingulate cortices. In addition, examinations were repeated in chronic back pain patients after a 4-week interdisciplinary multimodal pain treatment and in healthy subjects after 4 weeks to explore longitudinal, treatment-mediated changes in target variables. The aIns R and, to a lesser extent, the anterior mid-cingulate of patients exhibited significantly reduced wCC accompanied by a spectral power shift from a lower to a higher frequency band, indicating a desynchronization of their neuronal activity within the SN, possibly because of increased spontaneous activations. Without revealing neurotransmitter differences, patients alone showed significant positive associations between local GABA + levels and wCC in aIns R , suggesting a stronger dependence of node synchronization on the inhibitory tone in the chronic pain state. However, this needs to be explored in the future using magnetic resonance spectroscopy techniques that are more sensitive to detecting subtle neurotransmitter changes and also allow multifocal characterization of neurotransmitter tone.

Overnight Immune Regulation and Subjective Measures of Sleep: A Three Night Observational Study in Adolescent Track and Field Athletes.

To ensure health maintenance of young athletes, immunological stress due to physical exercise has to be balanced for performance development and health maintenance. Sleep is an important influencing factor for immune regulation because of its regenerating effect. In an attempt to assess overnight immune regulation, this observational study aimed to examine associations between changes in capillary immunological blood markers and measures of sleep in adolescent athletes. Over a period of three nights, 12 male (n = 6) and female (n = 6) adolescent track and field athletes aged 16.4 ± 1.1 years were monitored for their sleep behavior (e.g., sleep duration, sleep depth) and immune regulation by using subjective (e.g., sleep) and objective (capillary blood markers) measurement tools. Over the 4 day (three nights), athletes followed their daily routines (school, homework, free time activities, and training). Training was performed for different disciplines (sprint, hurdles, and long-jump) following their daily training routines. Training included dynamic core stability training, coordination training, speed training, resistance training, and endurance training. Capillary blood samples were taken 30-45 min after the last training session (10:00-12:00 a.m. or 5:00-6:00 p.m.) and every morning between 7:00 and 10:00 a.m. Changes in capillary blood markers from post-training to the next morning and morning-to-morning fluctuations in capillary blood markers were analyzed over a three-night period using a generalized estimating equations (GEE) statistical approach. Associations of overnight changes with measures of sleep were analyzed using GEE. We found significant decreases in white blood cell count (WBC), granulocytes (GRAN), granulocytes% (GRAN%), monocytes (MID), and granulocyte-lymphocyte-ratio. In contrast, lymphocytes% (LYM%) increased significantly and systemic inflammation index showed no difference from post-training to the next morning. Furthermore, there was a significant decrease in WBC and GRAN between morning 1 and morning 3. At morning 4, values returned to baseline (morning 1), irrespective if athletes performed a training session or rested on day 3. Furthermore, sleep duration was significantly and negatively associated with changes in WBC (ßz = -0.491) and lymphocytes (ßz = -0.451). Our results indicate that overnight sleep duration is an important parameter of immunological overnight regulation for adolescent athletes.

The Right Hemisphere Is Responsible for the Greatest Differences in Human Brain Response to High-Arousing Emotional versus Neutral Stimuli: A MEG Study.

Studies investigating human brain response to emotional stimuli-particularly high-arousing versus neutral stimuli-have obtained inconsistent results. The present study was the first to combine magnetoencephalography (MEG) with the bootstrapping method to examine the whole brain and identify the cortical regions involved in this differential response. Seventeen healthy participants (11 females, aged 19 to 33 years; mean age, 26.9 years) were presented with high-arousing emotional (pleasant and unpleasant) and neutral pictures, and their brain responses were measured using MEG. When random resampling bootstrapping was performed for each participant, the greatest differences between high-arousing emotional and neutral stimuli during M300 (270-320 ms) were found to occur in the right temporo-parietal region. This finding was observed in response to both pleasant and unpleasant stimuli. The results, which may be more robust than previous studies because of bootstrapping and examination of the whole brain, reinforce the essential role of the right hemisphere in emotion processing.

Automated emotion classification in the early stages of cortical processing: An MEG study.

PURPOSE: Here we aimed to automatically classify human emotion earlier than is typically attempted. There is increasing evidence that the human brain differentiates emotional categories within 100-300 ms after stimulus onset. Therefore, here we evaluate the possibility of automatically classifying human emotions within the first 300 ms after the stimulus and identify the time-interval of the highest classification performance. METHODS: To address this issue, MEG signals of 17 healthy volunteers were recorded in response to three different picture stimuli (pleasant, unpleasant, and neutral pictures). Six Linear Discriminant Analysis (LDA) classifiers were used based on two binary comparisons (pleasant versus neutral and unpleasant versus neutral) and three different time-intervals (100-150 ms, 150-200 ms, and 200-300 ms post-stimulus). The selection of the feature subsets was performed by Genetic Algorithm and LDA. RESULTS: We demonstrated significant classification performances in both comparisons. The best classification performance was achieved with a median AUC of 0.83 (95 %- CI [0.71; 0.87]) classifying brain responses evoked by unpleasant and neutral stimuli within 100-150 ms, which is at least 850 ms earlier than attempted by other studies. CONCLUSION: Our results indicate that using the proposed algorithm, brain emotional responses can be significantly classified at very early stages of cortical processing (within 300 ms). Moreover, our results suggest that emotional processing in the human brain occurs within the first 100-150 ms.

Towards Better Perioperative Pain Management in Mexico: A Study in a Network of Hospitals Using Quality Improvement Methods from PAIN OUT.

OBJECTIVE: This was a pre-post study in a network of hospitals in Mexico-City, Mexico. Participants developed and implemented Quality Improvement (QI) interventions addressing perioperative pain management. METHODS: PAIN OUT, an international QI and research network, provided tools for web-based auditing and feedback of pain management and patient-reported outcomes (PROs) in the clinical routine. Ward- and patient-level factors were evaluated with multi-level models. Change in proportion of patients reporting worst pain ≥6/10 between project phases was the primary outcome. RESULTS: Participants created locally adapted resources for teaching and pain management, available to providers in the form of a website and a special issue of a national anesthesia journal. They offered teaching to anesthesiologists, surgeons, including residents, and nurses. Information was offered to patients and families. A total of 2658 patients were audited in 9 hospitals, between July 2016 and December 2018. Participants reported that the project made them aware of the importance of: training in pain management; auditing one's own patients to learn about PROs and that QI requires collaboration between multi-disciplinary teams. Participants reported being unaware that their patients experienced severe pain and lacked information about pain treatment options. Worst pain decreased significantly between the two project phases, as did PROs related to pain interfering with movement, taking a deep breath/coughing or sleep. The opportunity of patients receiving information about their pain treatment options increased from 44% to 77%. CONCLUSIONS: Patients benefited from improved care and pain-related PROs. Clinicians appreciated gaining increased expertise in perioperative pain management and methods of QI.

Desire to Receive More Pain Treatment - A Relevant Patient-Reported Outcome Measure to Assess Quality of Post-Operative Pain Management? Results From 79,996 Patients Enrolled in the Pain Registry QUIPS from 2016 to 2019.

Acute postoperative pain is frequently evaluated by pain intensity scores. However, interpretation of the results is difficult and thresholds requiring treatment are not well defined. Additional patient-reported outcome measures (PROMs) might be helpful to better understand individual pain experience and quality of pain management after surgery. We used data from the QUIPS pain registry for a cross-sectional study in order to investigate associations between the desire to receive more pain treatment (D2RMPT) with pain intensity ratings and other PROMs. Responses from 79,996 patients were analyzed, of whom 10.7% reported D2RMPT. A generalized estimating equation Poisson model showed that women had a lower risk ratio (RR) to answer this question with "yes" (RR: .92, P < .001). Factors that increased the risk most were "maximal pain intensity ≥ 6/10 on a numerical rating scale" (RR: 2.48, P < .001) and "any pain interference" (RR: 2.48, P < .001). The largest reduction in risk was observed if patients were "allowed to participate in pain treatment decisions" (RR: .41, P < .001) and if they felt that they "received sufficient treatment information" (RR: .58, P < .001). Our results indicate that the (easily assessed) question D2RMPT gives additional information to other PROMs like pain intensity. The small proportion of patients with D2RMPT (even for high pain scores) opens the discussion about clinicians' understanding of over- und under-treatment and questions the exclusive use of pain intensity as quality indicator. Future studies need to investigate whether asking about D2RMPT in clinical routine can improve postoperative pain outcome. PERSPECTIVE: This article presents characteristics of the patient-reported outcome measure "Desire to receive more pain treatment." This measure could be used to apply pain treatment in a more individualized way and lead to improved treatment strategies and quality.

The Temporal and Spatial Dynamics of Cortical Emotion Processing in Different Brain Frequencies as Assessed Using the Cluster-Based Permutation Test: An MEG Study.

The processing of emotions in the human brain is an extremely complex process that extends across a large number of brain areas and various temporal processing steps. In the case of magnetoencephalography (MEG) data, various frequency bands also contribute differently. Therefore, in most studies, the analysis of emotional processing has to be limited to specific sub-aspects. Here, we demonstrated that these problems can be overcome by using a nonparametric statistical test called the cluster-based permutation test (CBPT). To the best of our knowledge, our study is the first to apply the CBPT to MEG data of brain responses to emotional stimuli. For this purpose, different emotionally impacting (pleasant and unpleasant) and neutral pictures were presented to 17 healthy subjects. The CBPT was applied to the power spectra of five brain frequencies, comparing responses to emotional versus neutral stimuli over entire MEG channels and time intervals within 1500 ms post-stimulus. Our results showed significant clusters in different frequency bands, and agreed well with many previous emotion studies. However, the use of the CBPT allowed us to easily include large numbers of MEG channels, wide frequency, and long time-ranges in one study, which is a more reliable alternative to other studies that consider only specific sub-aspects.

Identification of cardiovascular and molecular prognostic factors for the medium-term and long-term outcomes of sepsis (ICROS): protocol for a prospective monocentric cohort study.

INTRODUCTION: Sepsis is one of the most prevalent life-threatening conditions in the intensive care unit. Patients suffer from impaired organ function, reduced physical functional capacity and decreased quality of life even after surviving sepsis. The identification of prognostic factors for the medium-term and long-term outcomes of this condition is necessary to develop personalised theragnostic approaches. Sepsis can cause cardiac impairment. The impact of this septic cardiomyopathy on patient's long-term outcome remains unclear. This study aims to evaluate cardiovascular risk factors, particularly the occurrence of septic cardiomyopathy, regarding their suitability as prognostic factors for the short-term and long-term outcomes of septic patients. Additionally, the study seeks to validate preclinical pathophysiological findings of septic cardiomyopathy in the clinical setting. METHODS AND ANALYSIS: In this prospective monocentric cohort study, patients will be clinically assessed during the acute and postacute phase of sepsis and two follow-ups after 6 and 12 months. To determine the effect of septic cardiomyopathy and concomitant cellular and molecular changes on patient mortality and morbidity, a comprehensive cardiovascular and molecular deep phenotyping of patients will be performed. This includes an echocardiographic and electrocardiographic assessment, and the evaluation of heart rate variability, body composition, mitochondrial oxygen metabolism, macrocirculation and microcirculation, and endothelial barrier function. These analyses are complemented by routine immunological, haematological and biochemical laboratory tests and analyses of the serum metabolome and lipidome, microbiome and epigenetic modifications of immune cells. The reversibility of patients' organ dysfunction, their quality of life and physical functional capacity will be investigated in the follow-ups. Patients with cardiomyopathy without infection and healthy subjects will serve as control groups. ETHICS AND DISSEMINATION: Approval was obtained from the Ethics Committee of the Friedrich Schiller University Jena (5276-09/17). The results will be published in peer-reviewed journals and presented at appropriate conferences. TRIAL REGISTRATION NUMBERS: DRKS00013347; NCT03620409.

Non-invasive Assessment of Mitochondrial Oxygen Metabolism in the Critically Ill Patient Using the Protoporphyrin IX-Triplet State Lifetime Technique-A Feasibility Study.

The imbalance of oxygen delivery and oxygen consumption resulting in insufficient tissue oxygenation is pathognomonic for all forms of shock. Mitochondrial function plays an important role in the cellular oxygen metabolism and has been shown to impact a variety of diseases in the intensive care setting, specifically sepsis. Clinical assessment of tissue oxygenation and mitochondrial function remains elusive. The in vivo protoporphyrin IX-triplet state lifetime technique (PpIX-TSLT) allows the direct, non-invasive measurement of mitochondrial oxygen tension (mitoPO2) in the human skin. Our recently established measurement protocol for the Cellular Oxygen Metabolism (COMET) Monitor, a novel device employing the PpIX-TSLT, additionally allows the evaluation of oxygen consumption (mitoVO2) and delivery (mitoDO2). In the intensive care setting, these variables might provide new insight into mitochondrial oxygen metabolism and especially mitoDO2 might be a surrogate parameter of microcirculatory function. However, the feasibility of the PpIX-TSLT in critically ill patients has not been analyzed systematically. In this interim study analysis, we evaluated PpIX-TSLT measurements of 40 patients during the acute phase of sepsis. We assessed (a) potential adverse side effects of the method, (b) the rate of analyzable measurements, (c) the stability of mitoPO2, mitoVO2, and mitoDO2, and (d) potential covariates. Due to excessive edema in patients with sepsis, we specifically analyzed the association of patients' hydration status, assessed by bioimpedance analysis (BIA), with the aforementioned variables. We observed no side effects and acquired analyzable measurements sessions in 92.5% of patients (n = 37/40). Different measures of stability indicated moderate to good repeatability of the PpIX-TSLT variables within one session of multiple measurements. The determined limits of agreement and minimum detectable differences may be helpful in identifying outlier measurements. In conjunction with signal quality they mark a first step in developing a previously unavailable standardized measurement quality protocol. Notably, higher levels of hydration were associated with lower mitochondrial oxygen tension. We conclude that COMET measurements are viable in patients with sepsis. To validate the clinical and diagnostic relevance of the PpIX-TSLT using the COMET in the intensive care setting, future studies in critically ill patients and healthy controls are needed.