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Processed electroencephalography (pEEG) may help clinicians optimize depth of general anesthesia. Avoiding excessive depth of anesthesia may reduce intraoperative hypotension and the need for vasopressors. We tested the hypothesis that pEEG-guided – compared to non-pEEG-guided – general anesthesia reduces the amount of norepinephrine needed to keep intraoperative mean arterial pressure above 65 mmHg in patients having vascular surgery. Randomized controlled clinical trial. University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 110 patients having vascular surgery. pEEG-guided general anesthesia. Our primary endpoint was the average norepinephrine infusion rate from the beginning of induction of anesthesia until the end of surgery. 96 patients were analyzed. The mean ± standard deviation average norepinephrine infusion rate was 0.08 ± 0.04 μg kg−1 min−1 in patients assigned to pEEG-guided and 0.12 ± 0.09 μg kg−1 min−1 in patients assigned to non-pEEG-guided general anesthesia (mean difference 0.04 μg kg−1 min−1, 95% confidence interval 0.01 to 0.07 μg kg−1 min−1, p = 0.004). Patients assigned to pEEG-guided versus non-pEEG-guided general anesthesia, had a median time-weighted minimum alveolar concentration of 0.7 (0.6, 0.8) versus 0.8 (0.7, 0.8) (p = 0.006) and a median percentage of time Patient State Index was <25 of 12 (1, 41) % versus 23 (3, 49) % (p = 0.279). pEEG-guided – compared to non-pEEG-guided – general anesthesia reduced the amount of norepinephrine needed to keep mean arterial pressure above 65 mmHg by about a third in patients having vascular surgery. Whether reduced intraoperative norepinephrine requirements resulting from pEEG-guided general anesthesia translate into improved patient-centered outcomes remains to be determined in larger trials. •To prevent and treat intraoperative hypotension, vasopressors are commonly used.•Avoiding excessive depth of anesthesia may reduce the need for vasopressors.•Processed electroencephalography helps avoid excessive anesthetic depth.•Processed electroencephalography reduces norepinephrine requirements

Background Intraoperative hypotension is common in patients having non-cardiac surgery and is associated with serious complications and death. However, optimal intraoperative blood pressures for individual patients remain unknown. We therefore aim to test the hypothesis that personalized perioperative blood pressure management—based on preoperative automated blood pressure monitoring—reduces the incidence of a composite outcome of acute kidney injury, acute myocardial injury, non-fatal cardiac arrest, and death within 7 days after surgery compared to routine blood pressure management in high-risk patients having major abdominal surgery. Methods IMPROVE-multi is a multicenter randomized trial in 1272 high-risk patients having elective major abdominal surgery that we plan to conduct at 16 German university medical centers. Preoperative automated blood pressure monitoring using upper arm cuff oscillometry will be performed in all patients for one night to obtain the mean of the nighttime mean arterial pressures. Patients will then be randomized either to personalized blood pressure management or to routine blood pressure management. In patients assigned to personalized management, intraoperative mean arterial pressure will be maintained at least at the mean of the nighttime mean arterial pressures. In patients assigned to routine management, intraoperative blood pressure will be managed per routine. The primary outcome will be a composite of acute kidney injury, acute myocardial injury, non-fatal cardiac arrest, and death within 7 days after surgery. Discussion Our trial will determine whether personalized perioperative blood pressure management reduces the incidence of major postoperative complications and death within 7 days after surgery compared to routine blood pressure management in high-risk patients having major abdominal surgery. Trial registration ClinicalTrials.gov NCT05416944. Registered on June 14, 2022.

IntroductionMultimorbidity is prevalent and associated with complex treatment requirements. In order to assist general practitioners (GPs) addressing these requirements, the web application gp-multitool.de has been designed, which facilitates implementation of the German clinical practice guideline for multimorbidity. We will conduct a cluster-randomised clinical trial evaluating an intervention based on this tool. This protocol summarises methods and discusses ethics and dissemination of this study.Methods and analysisParticipating patients are recruited by cooperating GP practices. Inclusion criteria are an age of 65 years or older, enrolment in any disease management programme and multimorbidity operationalised by two additional chronic conditions. To avoid postrandomisation selection bias, practices are randomised as clusters after baseline assessment of all participating patients from the respective practice. In our intervention, patients receive access to different assessments including patient preferences by email, fill out the electronic assessment forms on any device with access to the internet, receive a medication review and discuss the assessment results with their GPs. GPs in the control group do not have access to the digital tool and provide care as usual. The primary outcome is staying at least once for at least one night in hospital during the 12-month observation period. Secondary outcomes are contacts with GPs and outpatient specialists, self-reported health, health-related quality of life, patient satisfaction and GP-reported and patient-reported quality of care. A sample size of 660 patients from 66 GP practices is needed. Data are analysed by mixed effects regression models.Ethics and disseminationEthics approval was obtained by the ethics committee of the Medical Association of Hamburg (2022–1 00 786-BO-ff). Study results will be presented on scientific conferences and published in journal articles. In addition, healthcare professionals, patient representatives and the interested public will be informed about study results at a symposium.Trial registration numberThe study was registered in clinicaltrials.gov (NCT06831994).

Background Intraoperative hemodynamic management is intended to ensure adequate tissue perfusion and oxygen delivery and eventually help avoid organ injury. However, the optimal strategy for intraoperative hemodynamic management in patients having non-cardiac surgery remains unclear. We here report the protocol of a trial designed to test the hypothesis that personalized intraoperative hemodynamic management targeting preoperative baseline cardiac index reduces the incidence of a composite outcome of major postoperative complications and death within 7 days after surgery compared to routine hemodynamic management in high-risk patients having elective major abdominal surgery. Methods The PELICAN trial is an international multicenter randomized trial in 1,128 high-risk patients having elective major abdominal surgery. The individual preoperative baseline cardiac index is determined with the patient being awake and resting in the supine position using noninvasive bioreactance. Patients are randomized to personalized hemodynamic management (intervention) or to routine hemodynamic management (control) during surgery. In patients assigned to personalized hemodynamic management, intraoperative cardiac index is maintained at least at the preoperative baseline cardiac index. In patients assigned to routine hemodynamic management, it is performed as per anesthesiologist preference (with blinded cardiac index monitoring). The primary outcome is the incidence of a composite outcome (“any event versus none”) of acute kidney injury, acute myocardial injury (including myocardial infarction), non-fatal cardiac arrest, severe infectious complications, and death within 7 days after surgery. Discussion Our trial will determine whether personalized intraoperative hemodynamic management targeting preoperative baseline cardiac index reduces the incidence of major postoperative complications and death within 7 days in high-risk patients having elective major abdominal surgery compared to routine hemodynamic management. Trial registration ClinicalTrials.gov Identifier NCT05648279. Registered on 5 December 2022.

Breakdown of synthesis, excretion and detoxification defines liver failure. Post-hepatectomy liver failure (PHLF) is specific for liver resection and a rightfully feared complication due to high lethality and limited therapeutic success. Individual cytokine and growth factor profiles may represent potent predictive markers for recovery of liver function. We aimed to investigate these profiles in post-hepatectomy regeneration. This study combined a time-dependent cytokine and growth factor profiling dataset of a training (30 patients) and a validation (14 patients) cohorts undergoing major liver resection with statistical and predictive models identifying individual pathway signatures. 2319 associations were tested. Primary hepatocytes isolated from patient tissue samples were stimulated and their proliferation was analysed through DNA content assay. Common expression trajectories of cytokines and growth factors with strong correlation to PHLF, morbidity and mortality were identified despite highly individual perioperative dynamics. Especially, dynamics of EGF, HGF, and PLGF were associated with mortality. PLGF was additionally associated with PHLF and complications. A global association-network was calculated and validated to investigate interdependence of cytokines and growth factors with clinical attributes. Preoperative cytokine and growth factor signatures were identified allowing prediction of mortality following major liver resection by regression modelling. Proliferation analysis of corresponding primary human hepatocytes showed associations of individual regenerative potential with clinical outcome. Prediction of PHLF was possible on as early as first postoperative day (POD1) with AUC above 0.75. Prediction of PHLF and mortality is possible on POD1 with liquid-biopsy based risk profiling. Further utilization of these models would allow tailoring of interventional strategies according to individual profiles.

Background Proton-pump inhibitors (PPI) are liberally prescribed in patients with liver cirrhosis. Observational studies link PPI therapy in cirrhotic patients with an increased risk for infectious complications, hepatic encephalopathy and an increased risk for hospitalization and mortality. However, patients with liver cirrhosis are also considered to be at risk for peptic ulcer bleeding. The STOPPIT trial evaluates if discontinuation of a pre-existing PPI treatment delays a composite endpoint of re-hospitalization and/or death in patients (recently) hospitalized with liver cirrhosis compared to patients on continued PPI medication. Methods The STOPPIT-trial is a prospective, multicentre, randomized, double-blinded, placebo-controlled, parallel-group trial. In total, 476 patients with complicated liver cirrhosis who already receive long-term PPI therapy without evidence-based indication are 1:1 randomized to receive either esomeprazole 20 mg (control group) or placebo (intervention group) for 360 days. Patients with an indication for PPI therapy (such as a recent diagnosis of peptic ulcers, severe reflux esophagitis, severe hemorrhagic gastritis, recent endoscopic therapy for oesophageal varices) are excluded. The primary composite endpoint is the time-to re-hospitalization and/or death. Secondary endpoints include rates of re-hospitalization, mortality, occurrence of infections, hepatic decompensation and acute-on-chronic liver failure. The safety endpoint is defined as manifestation of an evidence-based indication for PPI re-therapy. The impact of PPI continuation or discontinuation on the intestinal microbiota will be studied. The recruitment will take place at 18 study sites throughout Germany. Recruitment has started in April 2021. Discussion The STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis. If the hypothesis that PPI withdrawal improves clinical outcomes of cirrhosis patients is confirmed, this would argue for a strong restriction of the currently liberal prescription practice of PPIs in this population. If, on the other hand, the trial demonstrates an increased risk of gastrointestinal bleeding events in patients after PPI withdrawal, this could create a rationale for a more liberal, prophylactic PPI treatment in patients with liver cirrhosis. Trial registration EU clinical trials register EudraCT 2019-005008-16 (registered December 27, 2019). ClinicalTrials.gov NCT04448028 (registered June 25, 2020). German Clinical Trials Register DRKS00021290 (registered March 10, 2021).

Background: The COVID-19 pandemic exposes individuals to multiple stressors, such as quarantine, physical distancing, job loss, risk of infection, and loss of loved ones. Such a complex array of stressors potentially lead to symptoms of adjustment disorder. Objective: This cross-sectional exploratory study examined relationships between risk and protective factors, stressors, and symptoms of adjustment disorder during the first year of the COVID-19 pandemic. Methods: Data from the first wave of the European Society of Traumatic Stress Studies (ESTSS) longitudinal ADJUST Study were used. N = 15,563 participants aged 18 years and above were recruited in eleven countries (Austria, Croatia, Georgia, Germany, Greece, Italy, Lithuania, the Netherlands, Poland, Portugal, and Sweden) from June to November 2020. Associations between risk and protective factors (e.g. gender, diagnosis of a mental health disorder), stressors (e.g. fear of infection, restricted face-to-face contact), and symptoms of adjustment disorder (ADNM-8) were examined using multivariate linear regression. Results: The prevalence of self-reported probable adjustment disorder was 18.2%. Risk factors associated with higher levels of symptoms of adjustment disorder were female gender, older age, being at risk for severe COVID-19 illness, poorer general health status, current or previous trauma exposure, a current or previous mental health disorder, and longer exposure to COVID-19 news. Protective factors related to lower levels of symptoms of adjustment disorder were higher income, being retired, and having more face-to-face contact with loved ones or friends. Pandemic-related stressors associated with higher levels of symptoms of adjustment disorder included fear of infection, governmental crisis management, restricted social contact, work-related problems, restricted activity, and difficult housing conditions. Conclusions: We identified stressors, risk, and protective factors that may help identify individuals at higher risk for adjustment disorder. We examined symptoms of adjustment disorder in 15,563 adults during the COVID-19 pandemic. The prevalence of probable adjustment disorder was 18.2%. We identified stressors, risk, and protective factors that may help identify individuals at higher risk for adjustment disorder.

Background The immunological composition of the tumor microenvironment has a decisive influence on the biological course of cancer and is therefore of profound clinical relevance. In this study, we analyzed the cooperative effects of integrin β4 (ITGB4) on tumor cells and E-/P-selectin on endothelial cells within the tumor stroma for regulating tumor growth by shaping the local and systemic immune environment. Methods We used several preclinical mouse models for different solid human cancer types (xenograft and syngeneic) to explore the role of ITGB4 (shRNA-mediated knockdown in tumor cells) and E-/P-selectins (knockout in mice) for tumor growth; effects on apoptosis, proliferation and intratumoral signaling pathways were determined by histological and biochemical methods and 3D in vitro experiments; changes in the intratumoral and systemic immune cell composition were determined by flow cytometry and immunohistochemistry; chemokine levels and their attracting potential were measured by ELISA and 3D invasion assays. Results We observed a very robust synergism between ITGB4 and E-/P-selectin for the regulation of tumor growth, accompanied by an increased recruitment of CD11b + Gr-1 Hi cells with low granularity (i.e., myeloid-derived suppressor cells, MDSCs) specifically into ITGB4-depleted tumors. ITGB4-depleted tumors undergo apoptosis and actively attract MDSCs, well-known to promote tumor growth in several cancers, via increased secretion of different chemokines. MDSC trafficking into tumors crucially depends on E-/P-selectin expression. Analyses of clinical samples confirmed an inverse relationship between ITGB4 expression in tumors and number of tumor-infiltrating leukocytes. Conclusions These findings suggest a distinct vulnerability of ITGB4 Lo tumors for MDSC-directed immunotherapies. Graphical Abstract

Hematogenous metastasis limits the survival of colorectal cancer (CRC) patients. Here, we illuminated the roles of CD44 isoforms in this process. Isoforms 3 and 4 were predominantly expressed in CRC patients. CD44 isoform 4 indicated poor outcome and correlated with epithelial–mesenchymal transition (EMT) and decreased oxidative phosphorylation (OxPhos) in patients; opposite associations were found for isoform 3. Pan‐CD44 knockdown (kd) independently impaired primary tumor formation and abrogated distant metastasis in CRC xenografts. The xenograft tumors mainly expressed the clinically relevant CD44 isoforms 3 and 4. Both isoforms were enhanced in the paranecrotic, hypoxic tumor regions but were generally absent in lung metastases. Upon CD44 kd, tumor angiogenesis was increased in the paranecrotic areas, accompanied by reduced hypoxia‐inducible factor‐1α and CEACAM5 but increased E‐cadherin expression. Mitochondrial genes and proteins were induced upon pan‐CD44 kd, as were OxPhos genes. Hypoxia increased VEGF release from tumor spheres, particularly upon CD44 kd. Genes affected upon CD44 kd in xenografts specifically overlapped concordantly with genes correlating with CD44 isoform 4 (but not isoform 3) in patients, validating the clinical relevance of the used model and highlighting the metastasis‐promoting role of CD44 isoform 4. Pan‐CD44 knockdown decreases spontaneous metastasis in human colorectal cancer xenograft models. Concurrent intratumoral gene expression alterations significantly correlate with genes differentially regulated among CD44 isoform 4 (but not isoform 3) high vs. low patients (TCGA). The corresponding gene sets and pathways include epithelial–mesenchymal transition, angiogenesis, and OxPhos. CD44 isoform 4 (but not isoform 3) correlates with poor patient outcomes.

Background The rational use of antibiotics is of great importance in health care. In primary care, acute respiratory infections are the most common cause of inappropriate antibiotic prescribing. Since existing studies aiming to optimize antibiotic use are usually based on the voluntary participation of physicians, general practitioners (GPs) with inappropriate prescribing behavior are underrepresented. For the first time in Germany, the ElektRA study will assess and compare the effects of three interventions on antibiotic prescribing rates for respiratory and urinary tract infections among high prescribers in primary care. Method ElektRA is a 4-arm cluster-randomized controlled trial among German GPs in nine regional Associations of Statutory Health Insurance Physicians. On their behalf, the Central Research Institute of Ambulatory Health Care in Germany (Zi) analyses all outpatient claims and prescription data. Based on this database, high antibiotic prescribing GPs are identified and randomized into four groups: a control group ( N =2000) and three intervention arms. We test social norm feedback on antibiotic prescribing ( N =2000), social norm feedback plus online training on rational prescribing practice and communication strategies ( N =2000), and social norm feedback plus online peer-moderated training on rational antibiotic prescribing, communication strategies, and sustainable behavior change ( N =1250). The primary outcome is the overall rate of antibiotic prescriptions. Outcomes are measured before intervention (T0, October 2020–September 2022) and over a period of 15 months (T1, October 2022 to December 2023) after randomization. Discussion The aim of the study is to implement individualized, low-threshold interventions to reduce antibiotic prescribing among high prescribers in primary care. If successful, a change in behavior among otherwise difficult-to-reach high prescribers will directly improve patient care. The increase in quality of care will ideally be achieved both in terms of the quantity of antibiotics used as well as the kind of substances prescribed. Also, if effective strategies for high prescribers are identified through this study, they can be applied not only to the antibiotics addressed in this study, but also to other areas of prescription management. Trial registration Current Controlled Trials ISRCTN95468513.