Quorum Regulation via Nested Antagonistic Feedback Circuits Mediated by the Receptors CD28 and CTLA-4 Confers Robustness to T Cell Population Dynamics.

T cell responses upon infection display a remarkably reproducible pattern of expansion, contraction, and memory formation. If the robustness of this pattern builds entirely on signals derived from other cell types or if activated T cells themselves contribute to the orchestration of these population dynamics-akin to bacterial quorum regulation-is unclear. Here, we examined this question using time-lapse microscopy, genetic perturbation, bioinformatic predictions, and mathematical modeling. We found that ICAM-1-mediated cell clustering enabled CD8+ T cells to collectively regulate the balance between proliferation and apoptosis. Mechanistically, T cell expressed CD80 and CD86 interacted with the receptors CD28 and CTLA-4 on neighboring T cells; these interactions fed two nested antagonistic feedback circuits that regulated interleukin 2 production in a manner dependent on T cell density as confirmed by in vivo modulation of this network. Thus, CD8+ T cell-population-intrinsic mechanisms regulate cellular behavior, thereby promoting robustness of population dynamics.

Swiss chiropractic cohort (Swiss ChiCo) pilot study: feasibility for a musculoskeletal cohort study conducted within a nationwide practice-based research network.

PURPOSE: Practice-based research networks are collaborations between clinicians and researchers to advance primary care research. This study aims to assess the feasibility for longitudinal data collection within a newly established chiropractic PBRN in Switzerland. METHODS: A prospective observational cohort feasibility study was performed. PBRN participating chiropractors were asked to recruit patients seeking new conservative health care for musculoskeletal pain from March 28, 2022, to September 28, 2022. Participants completed clinically oriented survey questions and patient-reported outcome measures before the initial chiropractic assessment as well as 1 h, 2 weeks, 6 weeks, and 12 weeks thereafter. Feasibility was assessed through a variety of process, resource, and management metrics. Patient clinical outcomes were also assessed. RESULTS: A total of 76 clinicians from 35 unique primary care chiropractic clinics across Switzerland participated. A total of 1431 patients were invited to participate, of which 573 (mean age 47 years, 51% female) were enrolled. Patient survey response proportions were 76%, 64%, 61%, and 56%, at the 1-h, 2-, 6-, and 12-week survey follow-ups, respectively. Evidence of an association was found between increased patient age (OR = 1.03, 95%CI 1.01-1.04), patient from a German-speaking region (OR = 1.81, 95%CI 1.17-2.86), non-smokers (OR = 1.89, 95%CI 1.13-3.17), and increased pain impact score at baseline (OR = 1.18, 95%CI 1.01-1.38) and response to all surveys. CONCLUSION: The Swiss ChiCo pilot study exceeded its prespecified feasibility objectives. Nationwide longitudinal data capture was highly feasible. Similar to other practice-based cohorts, participant retention remains a challenge. Trial registration Swiss chiropractic cohort (Swiss ChiCo) pilot study (ClinicalTrials.gov identifier: NCT05116020).

Effect of a physical activity intervention on lower body bone health in childhood cancer survivors: A randomized controlled trial (SURfit).

It remains controversial whether physical activity promotes bone health in childhood cancer survivors (CCS). We aimed to assess the effect of a one-year general exercise intervention on lower body bone parameters of CCS. CCS ≥16 years at enrollment, <16 years at diagnosis and ≥5 years in remission were identified from the national Childhood Cancer Registry. Participants randomized to the intervention group were asked to perform an additional ≥2.5 hours of intense physical activity/week, controls continued exercise as usual. Bone health was assessed as a secondary trial endpoint at baseline and after 12-months. We measured tibia bone mineral density (BMD) and morphology by peripheral quantitative computed tomography and lumbar spine, hip and femoral neck BMD by dual-energy x-ray absorptiometry. We performed intention-to-treat, per protocol, and an explorative subgroup analyses looking at low BMD using multiple linear regressions. One hundred fifty-one survivors (44% females, 7.5 ± 4.9 years at diagnosis, 30.4 ± 8.6 years at baseline) were included. Intention-to-treat analysis revealed no differences in changes between the intervention and control group. Per protocol analyses showed evidence for an improvement in femoral neck and trabecular BMD between 1.5% and 1.8% more in participants being compliant with the exercise program. Trabecular BMD increased 2.8% more in survivors of the intervention group with BMD z-score ≤-1 compared to those starting at z-score >-1. A nonstandardized personalized exercise programs might not be specific enough to promote bone health in CCS, although those compliant and those most in need may benefit. Future trials should include bone stimulating exercise programs targeting risk groups with reduced bone health and motivational features to maximize compliance.

Alcohol consumption: context and association with mortality in Switzerland.

PURPOSE: Non-communicable diseases generate the largest number of avoidable deaths often caused by risk factors such as alcohol, smoking, and unhealthy diets. Our study investigates the association between amount and context of alcohol consumption and mortality from major non-communicable diseases in Switzerland. METHODS: Generalized linear regression models were fitted on data of the cross-sectional population-based National Nutrition Survey menuCH (2014-2015, n = 2057). Mortality rates based on the Swiss mortality data (2015-2018) were modeled by the alcohol consumption group considering the amount and context (i.e., during or outside mealtime) of alcohol consumption and potential confounders. The models were checked for spatial autocorrelation using Moran's I statistic. Integrated nested Laplace approximation (INLA) models were fitted when evidence for missing spatial information was found. RESULTS: Higher mortality rates were detected among drinkers compared to non-drinkers for all-cancer (rate ratio (RR) ranging from 1.01 to 1.07) and upper aero-digestive tract cancer (RR ranging from 1.15 to 1.20) mortality. Global Moran's I statistic revealed spatial autocorrelation at the Swiss district level for all-cancer mortality. An INLA model led to the identification of three districts with a significant decrease and four districts with a significant increase in all-cancer mortality. CONCLUSION: Significant associations of alcohol consumption with all-cancer and upper aero-digestive tract cancer mortality were detected. Our study results indicate the need for further studies to improve the next alcohol-prevention scheme and to lower the number of avoidable deaths in Switzerland.

Achieving a preoperative haemoglobin above 130 g L-1 may be more important in female than in male patients before cardiac surgery.

Sex-specific preoperative haemoglobin levels and the need for perioperative red cell transfusion in men and women are still debated. Cavalli and colleagues examined the appropriateness of World Health Organization (WHO) anaemia thresholds (haemoglobin <130 g L-1 for males and <120 g L-1 for females) in a retrospective cohort analysis of >6000 adult patients undergoing cardiac surgery with cardiopulmonary bypass. The authors concluded that the WHO anaemia threshold disproportionately disadvantages female cardiac surgery patients, and a preoperative haemoglobin level of at least 130 g L-1 should be targeted in all cardiac surgical patients regardless of sex.

Coagulation Management of Critically Bleeding Patients With Viscoelastic Testing Presented as a 3D-Animated Blood Clot (The Visual Clot): Randomized Controlled High-Fidelity Simulation Study.

BACKGROUND: Guidelines recommend using viscoelastic coagulation tests to guide coagulation management, but interpreting the results remains challenging. Visual Clot, a 3D animated blood clot, facilitates interpretation through a user-centered and situation awareness-oriented design. OBJECTIVE: This study aims to compare the effects of Visual Clot versus conventional viscoelastic test results (rotational thrombelastometry [ROTEM] temograms) on the coagulation management performance of anesthesia teams in critical bleeding situations. METHODS: We conducted a prospective, randomized, high-fidelity simulation study in which anesthesia teams (consisting of a senior anesthesiologist, a resident anesthesiologist, and an anesthesia nurse) managed perioperative bleeding scenarios. Teams had either Visual Clot or ROTEM temograms available to perform targeted coagulation management. We analyzed the 15-minute simulations with post hoc video analysis. The primary outcome was correct targeted coagulation therapy. Secondary outcomes were time to targeted coagulation therapy, confidence, and workload. In addition, we have conducted a qualitative survey on user acceptance of Visual Clot. We used Poisson regression, Cox regression, and mixed logistic regression models, adjusted for various potential confounders, to analyze the data. RESULTS: We analyzed 59 simulations. Teams using Visual Clot were more likely to deliver the overall targeted coagulation therapy correctly (rate ratio 1.56, 95% CI 1.00-2.47; P=.05) and administer the first targeted coagulation product faster (hazard ratio 2.58, 95% CI 1.37-4.85; P=.003). In addition, participants showed higher decision confidence with Visual Clot (odds ratio 3.60, 95% CI 1.49-8.71; P=.005). We found no difference in workload (coefficient -0.03, 95% CI -3.08 to 2.88; P=.99). CONCLUSIONS: Using Visual Clot led to a more accurate and faster-targeted coagulation therapy than using ROTEM temograms. We suggest that relevant viscoelastic test manufacturers consider augmenting their complex result presentation with intuitive, easy-to-understand visualization to ease users' burden from unnecessary cognitive load and enhance patient care.

Does diet map with mortality? Ecological association of dietary patterns with chronic disease mortality and its spatial dependence in Switzerland.

We investigated the associations between dietary patterns and chronic disease mortality in Switzerland using an ecological design and explored their spatial dependence, i.e. the tendency of near locations to present more similar and distant locations to present more different values than randomly expected. Data of the National Nutrition Survey menuCH (n 2057) were used to compute hypothesis- (Alternate Healthy Eating Index (AHEI)) and data-driven dietary patterns. District-level standardised mortality ratios (SMR) were calculated using the Swiss Federal Statistical Office mortality data and linked to dietary data geographically. Quasipoisson regression models were fitted to investigate the associations between dietary patterns and chronic disease mortality; Moran's I statistics were used to explore spatial dependence. Compared with the first, the fifth AHEI quintile (highest diet quality) was associated with district-level SMR of 0·95 (95 % CI 0·93, 0·97) for CVD, 0·91 (95 % CI 0·88, 0·95) for ischaemic heart disease (IHD), 0·97 (95 % CI 0·95, 0·99) for stroke, 0·99 (95 % CI 0·98, 1·00) for all-cancer, 0·98 (95 % CI 0·96, 0·99) for colorectal cancer and 0·93 (95 % CI 0·89, 0·96) for diabetes. The Swiss traditional and Western-like patterns were associated with significantly higher district-level SMR for CVD, IHD, stroke and diabetes (ranging from 1·02 to 1·08) compared with the Prudent pattern. Significant global and local spatial dependence was identified, with similar results across hypothesis- and data-driven dietary patterns. Our study suggests that dietary patterns partly contribute to the explanation of geographic disparities in chronic disease mortality in Switzerland. Further analyses including spatial components in regression models would allow identifying regions where nutritional interventions are particularly needed.

A mobile application to facilitate implementation of programmatic assessment in anaesthesia training.

BACKGROUND: Programmatic assessment is a concept to support learning through continuously providing information about learner progress to trainees and supervisors. Central to the concept are multiple low-stakes workplace-based assessments and meaningful feedback opportunities. Mobile technology may facilitate frequent and concise workplace-based assessments and trigger meaningful feedback. We designed a mobile application (app) for real-time use at the workplace utilising the concept of entrustable professional activities. As the primary outcome, we analysed completion times and as the secondary outcome the quality of documented learning goals. METHODS: The prEPAred app requests trainees and supervisors to rate level of supervision of a professional activity directly after completion. Subsequently, ratings are compared, and supervisors may provide feedback via the app. We tested the app in five anaesthesiology departments at major teaching hospitals, analysing completion times, agreement on ratings, and quality of documented learning goals. RESULTS: We recorded 1518 assessments from 159 trainees and 89 supervisors. Median time for level of supervision rating was 56 (inter-quartile range: 39-85) s for trainees and 17 (11-30) s for supervisors. Learning goals via the app were documented in 767 cases (50.5%). Median feedback time was 2 min, 31 s (confidence interval [CI]: 1 min, 20 s to 5 min, 20 s). In 443 (29%) cases, a specific learning goal was documented. A post hoc analysis revealed that the odds of documenting learning goals increased if trainees rated the level of supervision higher than their supervisors (odds ratio 1.39; CI: 1.03-1.87). CONCLUSIONS: The prEPAred mobile app enabled frequent and concise documentation of workplace-based assessments. Disagreement in level of supervision rating stimulated documentation of specific learning goals indicating more meaningful feedback. Thus, the tool could advance workplace-based assessments towards programmatic assessment.

Interleukin-6 Is an Early Plasma Marker of Severe Postoperative Complications in Thoracic Surgery: Exploratory Results From a Substudy of a Randomized Controlled Multicenter Trial.

BACKGROUND: Postoperative complications in surgery are a significant burden, not only for the patients but also economically. While several predicting factors have already been identified, it is still not well known if increased levels of inflammatory markers in the immediate perioperative phase correlate with a higher incidence of postoperative complications. This study aimed to evaluate which patient characteristics and intraoperative parameters correlate with increased plasma values of monocyte chemoattractant protein 1 (MCP-1) and interleukin 6 (IL-6) of thoracic surgery patients. A second goal was to explore whether MCP-1 and IL-6 are associated with the incidence of postoperative complications. We hypothesized that there is a positive association between inflammatory markers and the occurrence of complications within 6 months after surgery. METHODS: This is a substudy of a recent randomized controlled trial, which defined the effect of desflurane versus propofol anesthesia on morbidity and mortality in patients undergoing thoracic surgery. MCP-1 and IL-6 were determined in plasma obtained before and 30 minutes after 1-lung ventilation, 6 hours after surgery, and on postoperative days 1 and 2. Complications were recorded for 6 months. Mixed linear models were used to examine factors associated with MCP-1 and IL-6 levels. Logistic regression models and receiver operating characteristic curves were used to determine the association between MCP-1 and IL-6 and postoperative complications. RESULTS: In the original study, 460 patients were included, MCP-1 and IL-6 levels were determined in 428 patients. MCP-1 was positively associated with the duration of surgery (P = .016), whereas IL-6 levels increased with both the length (P < .001) and invasiveness of lung surgery (thoracoscopic wedge resection or lobectomy versus open lobectomy, P = .005; thoracoscopic wedge resection or lobectomy versus pneumonectomy, P = .021). In an exploratory approach, elevated IL-6 plasma peaks were associated with the occurrence of severe complications defined as Clavien-Dindo score grade ≥IVa during the postoperative phase up to 6 months after thoracic surgery (P = .006). CONCLUSIONS: In summary, this substudy reveals factors, which correlate with high MCP-1 and IL-6 values. Moreover, higher IL-6 seems to be associated with postoperative severe complications. Perioperative IL-6 monitoring might be helpful for risk estimation in the perioperative setting of patients after lung surgery.

Anesthesia personnel's visual attention regarding patient monitoring in simulated non-critical and critical situations, an eye-tracking study.

BACKGROUND: Cognitive ergonomics design of patient monitoring may reduce human factor errors in high-stress environments. Eye-tracking is a suitable tool to gain insight into the distribution of visual attention of healthcare professionals with patient monitors, which may facilitate their further development. METHODS: This prospective, exploratory, high-fidelity simulation study compared anesthesia personnel's visual attention (fixation count and dwell-time) to 15 areas of interest on the patient monitor during non-critical and critical anesthesia situations. Furthermore, we examined the extent to which participants' experience influenced visual attention and which vital signs displayed on the patient monitor received the most visual attention. We used mixed zero-inflated Poisson regression and mixed linear models to analyze the data. RESULTS: Analyzing 23 ten-minute scenarios, we found significantly more fixations to the areas of interest on the patient monitor during critical than non-critical situations (rate ratio of 1.45; 95% CI 1.33 to 1.59; p < 0.001). However, the dwell-time on the areas of interest did not significantly differ between the non-critical and critical situations (coefficient of - 1.667; 95% CI - 4.549 to 1.229; p = 0.27). The professional experience did not significantly influence the visual attention (fixation: rate ratio of 0.88; 95% CI 0.54 to 1.43; p = 0.61 and dwell-time: coefficient of 0.889; 95% CI - 1.465 to 3.229; p = 0.27). Over all situations, anesthesia personnel paid the most attention to the vital signs blood pressure (fixation: mean [SD] of 108 [74.83]; dwell-time: mean [SD] of 27 [15.90] seconds), end-expiratory carbon dioxide (fixation: mean [SD] of 59 [47.39]; dwell-time: mean [SD] of 30 [21.51] seconds), and the electrocardiogram (fixation: mean [SD] of 58 [64.70]; dwell-time: mean [SD] of 15 [14.95] seconds). CONCLUSIONS: Critical anesthesia situations increased anesthesia personnel's visual interaction with the patient monitor. Furthermore, we found that their visual attention focused mainly on a few vital signs. To assist clinicians in critical situations, manufacturers should optimize monitors to convey necessary information as easily and quickly as possible and optimize the visibility of less frequently observed but equally critical vital signs, especially when they are in an abnormal range.

Voice alerting as a medical alarm modality for next-generation patient monitoring: a randomised international multicentre trial.

BACKGROUND: Acoustic alarms in medical devices are vital for patient safety. State-of-the-art patient monitoring alarms are indistinguishable and contribute to alarm fatigue. There are two promising new sound modalities for vital sign alarms. Auditory icons convey alarms as brief metaphorical sounds, and voice alerts transmit information using a clear-spoken language. We compared how reliably healthcare professionals identified alarms using these two modalities. METHODS: This investigator-initiated computer-based multicentre simulation study included 28 anaesthesia providers who were asked to identify vital sign alarms in randomised order, once with voice alerts and once with auditory icons. We further assessed time to decision, diagnostic confidence, and perceived helpfulness. We analysed the results using mixed models, adjusted for possible confounders. RESULTS: We assessed 14 alarms for each modality, resulting in 392 comparisons across all participants. Compared with auditory icons, healthcare providers had 58 times higher odds of correctly identifying alarms using voice alerts (odds ratio 58.0; 95% confidence interval [CI]: 25.1-133.6; P<0.001), made their decisions about 14 s faster (coefficient -13.9; 95% CI: -15.8 to -12.1 s; P<0.001), perceived higher diagnostic confidence (100% [392 of 392] vs 43% [169 of 392; P<0.001]), and rated voice alerts as more helpful (odds ratio 138.2; 95% CI: 64.9-294.1; P<0.001). The participants were able to identify significantly higher proportions of alarms with voice alerts (98.5%; P<0.001) and auditory icons (54.1%; P<0.001) compared with state-of-the-art alarms (17.9%). CONCLUSIONS: Voice alerts were superior to auditory icons, and both were superior to current state-of-the-art auditory alarms. These findings demonstrate the potential that voice alerts hold for patient monitoring.

Avatar-based patient monitoring in critical anaesthesia events: a randomised high-fidelity simulation study.

BACKGROUND: Failures in situation awareness cause two-thirds of anaesthesia complications. Avatar-based patient monitoring may promote situation awareness in critical situations. METHODS: We conducted a prospective, randomised, high-fidelity simulation study powered for non-inferiority. We used video analysis to grade anaesthesia teams managing three 10 min emergency scenarios using three randomly assigned monitoring modalities: only conventional, only avatar, and split-screen showing both modalities side by side. The primary outcome was time to performance of critical tasks. Secondary outcomes were time to verbalisation of vital sign deviations and the correct cause of the emergency, perceived workload, and usability. We used mixed Cox and linear regression models adjusted for various potential confounders. The non-inferiority margin was 10%, or hazard ratio (HR) 0.9. RESULTS: We analysed 52 teams performing 154 simulations. For performance of critical tasks during a scenario, split-screen was non-inferior to conventional (HR=1.13; 95% confidence interval [CI], 0.96-1.33; not significant in test for superiority); the result for avatar was inconclusive (HR=0.98; 95% CI, 0.83-1.15). Avatar was associated with a higher probability for verbalisation of the cause of the emergency (HR=1.78; 95% CI, 1.13-2.81; P=0.012). We found no evidence for a monitor effect on perceived workload. Perceived usability was lower for avatar (coefficient=-23.0; 95% CI, -27.2 to -18.8; P<0.0001) and split-screen (-6.7; 95% CI, -10.9 to -2.4; P=0.002) compared with conventional. CONCLUSIONS: This study showed non-inferiority of split-screen compared with conventional monitoring for performance of critical tasks during anaesthesia crisis situations. The patient avatar improved verbalisation of the correct cause of the emergency. These results should be interpreted considering participants' minimal avatar but extensive conventional monitoring experience.

Physicians' perceptions regarding acute bleeding management: an international mixed qualitative quantitative study.

BACKGROUND: Acute bleeding is an omnipresent challenge for all physicians. Uncontrolled hemorrhage is the most common preventable cause of death after trauma worldwide. In different surgical disciplines, hemorrhage represents an independent risk factor for increased postoperative morbimortality, directly affecting patients' outcomes. This study asked anesthesiologists about their personal perceived challenges when treating bleeding patients. METHODS: This investigator-initiated, prospective, international, dual-center, mixed qualitative and quantitative study interrogated anesthesiologists about what they found easy and what difficult in treating acutely bleeding patients. Following the template approach for qualitative research, we identified major and minor topics through free inductive coding and word count. In a second step, we derived ten statements from the participants' answers. Using a field survey, we then asked the participants to rate their level of agreement with the derived statements. We analyzed the answers using one sample Wilcoxon test and the Mann-Whitney test. RESULTS: We included a total of 84 physicians in the qualitative interrogations and a different group of 42 anesthesiologists in the quantitative part. We identified 11 major topics and 19 associated subtopics. The main topics and the degree of agreement (here as agree or strongly agree) were as follows: "Complexity of the topic" (52.4% agreed to find the topic complex), "Cognitive aids" (92.9% agreed to find them helpful), "Time management" (64.3% agreed to feeling time pressure), "Human factors" (95.2% agreed that human factors are essential), "Resources" (95.2% agreed that resources are essential), "Experience" and "Low frequency of cases" (57.1% agreed to lack practice), "Diagnostic methods" (31.0% agreed that the interpretation of test results is difficult), "Anticoagulation" (85.7% agreed to it being difficult), "Treatment" (81.0% agreed to knowing the first therapeutic steps), and "Nothing". CONCLUSIONS: Anesthesiologists in two large tertiary care facilities in different parts of the world found coagulation management, especially in anticoagulated patients, complex. We identified the delayed diagnostic test results and their interpretation as challenges. Resources, treatment protocols and human factors such as team communication were perceived to facilitate management. Future studies should explore the challenges in smaller hospitals and other parts of the world and test new technologies addressing the identified difficulties.

Effects of an Animated Blood Clot Technology (Visual Clot) on the Decision-Making of Users Inexperienced in Viscoelastic Testing: Multicenter Trial.

BACKGROUND: Viscoelastic test-guided coagulation management has become increasingly important in assessing hemostasis. We developed Visual Clot, an animated, 3D blood clot that illustrates raw rotational thromboelastometry (ROTEM) parameters in a user-centered and situation awareness-oriented method. OBJECTIVE: This study aimed to evaluate the applicability of Visual Clot by examining its effects on users that are novices in viscoelastic-guided resuscitation. METHODS: We conducted an investigator-initiated, international, multicenter study between September 16, 2020, and October 6, 2020, in 5 tertiary care hospitals in central Europe. We randomly recruited medical students and inexperienced resident physicians without significant prior exposure to viscoelastic testing. The 7 participants per center managed 9 different ROTEM outputs twice, once as standard ROTEM tracings and once as the corresponding Visual Clot. We randomly presented the 18 viscoelastic cases and asked the participants for their therapeutic decisions. We assessed the performance, diagnostic confidence, and perceived workload in managing the tasks using mixed statistical models and adjusted for possible confounding factors. RESULTS: Analyzing a total of 630 results, we found that the participants solved more cases correctly (odds ratio [OR] 33.66, 95% CI 21.13-53.64; P<.001), exhibited more diagnostic confidence (OR 206.2, 95% CI 93.5-454.75; P<.001), and perceived less workload (coefficient -41.63; 95% CI -43.91 to -39.36; P<.001) using Visual Clot compared to using standard ROTEM tracings. CONCLUSIONS: This study emphasizes the practical benefit of presenting viscoelastic test results in a user-centered way. Visual Clot may allow inexperienced users to be involved in the decision-making process to treat bleeding-associated coagulopathy. The increased diagnostic confidence, diagnostic certainty, reduced workload, and positive user feedback associated with this visualization may promote the further adoption of viscoelastic methods in diverse health care settings.

Effects of the antifungal agent ciclopirox in HPV-positive cancer cells: Repression of viral E6/E7 oncogene expression and induction of senescence and apoptosis.

The malignant growth of human papillomavirus (HPV)-positive cancer cells is dependent on the continuous expression of the viral E6/E7 oncogenes. Here, we examined the effects of iron deprivation on the phenotype of HPV-positive cervical cancer cells. We found that iron chelators, such as the topical antifungal agent ciclopirox (CPX), strongly repress HPV E6/E7 oncogene expression, both at the transcript and protein level. CPX efficiently blocks the proliferation of HPV-positive cancer cells by inducing cellular senescence. Although active mTOR signaling is considered to be critical for the cellular senescence response towards a variety of prosenescent agents, CPX-induced senescence occurs under conditions of severely impaired mTOR signaling. Prolonged CPX treatment leads to p53-independent Caspase-3/7 activation and induction of apoptosis. CPX also eliminates HPV-positive cancer cells under hypoxic conditions through induction of apoptosis. Taken together, these results show that iron deprivation exerts profound antiviral and antiproliferative effects in HPV-positive cancer cells and suggest that iron chelators, such as CPX, possess therapeutic potential as HPV-inhibitory, prosenescent and proapoptotic agents in both normoxic and hypoxic environments.

Choices of Therapeutic Strategies for Colorectal Liver Metastases Among Expert Liver Surgeons: A Throw of the Dice?

OBJECTIVE: To test the degree of agreement in selecting therapeutic options for patients suffering from colorectal liver metastasis (CRLM) among surgical experts around the globe. SUMMARY/BACKGROUND: Only few areas in medicine have seen so many novel therapeutic options over the past decades as for liver tumors. Significant variations may therefore exist regarding the choices of treatment, even among experts, which may confuse both the medical community and patients. METHODS: Ten cases of CRLM with different levels of complexity were presented to 43 expert liver surgeons from 23 countries and 4 continents. Experts were defined as experienced surgeons with academic contributions to the field of liver tumors. Experts provided information on their medical education and current practice in liver surgery and transplantation. Using an online platform, they chose their strategy in treating each case from defined multiple choices with added comments. Inter-rater agreement among experts and cases was calculated using free-marginal multirater kappa methodology. A similar, but adjusted survey was presented to 60 general surgeons from Asia, Europe, and North America to test their attitude in treating or referring complex patients to expert centers. RESULTS: Thirty-eight (88%) experts completed the evaluation. Most of them are in leading positions (92%) with a median clinical experience of 25 years. Agreement on therapeutic strategies among them was none to minimal in more than half of the cases with kappa varying from 0.00 to 0.39. Many general surgeons may not refer the complex cases to expert centers, including in Europe, where they also engage in complex liver surgeries. CONCLUSIONS: Considerable inconsistencies of decision-making exist among expert surgeons when choosing a therapeutic strategy for CRLM. This might confuse both patients and referring physicians and indicate that an international high-level consensus statements and widely accepted guidelines are needed.

Impact of rivaroxaban plasma concentration on perioperative red blood cell loss.

BACKGROUND: This study investigates the impact of preoperative calculated rivaroxaban (RXA) plasma concentration on perioperative red blood cell (RBC) loss. STUDY DESIGN AND METHODS: In this retrospective single-center study, we identified patients with RXA intake according to a preoperative determination of RXA levels within 96 hours before surgery. RXA plasma concentration at the beginning of surgery was then calculated from the last RXA intake using a single-compartment pharmacokinetic model with four categories of RXA concentration (≤20, 21-50, 51-100, and >100 µg/L). Patients were classified into surgery with high (≥500 mL) or low (<500 mL) expected blood loss. Perioperative bleeding was determined by calculating RBC loss. RESULTS: We analyzed 308 surgical interventions in 298 patients during the period from January 2012 to July 2018. Among patients undergoing surgery with low expected blood loss, RBC loss varied from 164 mL (standard deviation [SD], 189) to 302 mL (SD, 397) (p = 0.66), and no association of calculated RXA concentration with RBC loss was observed. In patients undergoing surgery with high expected blood loss, we found a significant correlation of calculated RXA concentration with RBC loss (Pearson's correlation coefficient, 0.29; p = 0.002). RBC loss increased with rising RXA concentration from 575 mL (SD, 365) at RXA concentration of 20 µg/L or less up to 1400 mL (SD, 1300) at RXA concentration greater than 100 µg/L. RXA concentration greater than 100 µg/L was associated with a significant increase of in RBC loss of 840 mL (95% confidence interval, 360-1300; p < 0.001). Transfusion of RBC and fresh frozen plasma units tended to increase in patients with RXA concentrations greater than 100 µg/L. The proportion of patients treated with prothrombin complex concentrate and coagulation factor XIII concentrate increased significantly with higher RXA concentrations. CONCLUSION: Only in surgery with high expected blood loss, a calculated RXA concentration of greater than 100 µg/L was associated with a significant increase of perioperative RBC loss.

Anesthesia and Circulating Tumor Cells in Primary Breast Cancer Patients: A Randomized Controlled Trial.

BACKGROUND: The effect of anesthetic drugs on cancer outcomes remains unclear. This trial aimed to assess postoperative circulating tumor cell counts-an independent prognostic factor for breast cancer-to determine how anesthesia may indirectly affect prognosis. It was hypothesized that patients receiving sevoflurane would have higher postoperative tumor cell counts. METHODS: The parallel, randomized controlled trial was conducted in two centers in Switzerland. Patients aged 18 to 85 yr without metastases and scheduled for primary breast cancer surgery were eligible. The patients were randomly assigned to either sevoflurane or propofol anesthesia. The patients and outcome assessors were blinded. The primary outcome was circulating tumor cell counts over time, assessed at three time points postoperatively (0, 48, and 72 h) by the CellSearch assay. Secondary outcomes included maximal circulating tumor cells value, positivity (cutoff: at least 1 and at least 5 tumor cells/7.5 ml blood), and the association between natural killer cell activity and tumor cell counts. This trial was registered with ClinicalTrials.gov (NCT02005770). RESULTS: Between March 2014 and April 2018, 210 participants were enrolled, assigned to sevoflurane (n = 107) or propofol (n = 103) anesthesia, and eventually included in the analysis. Anesthesia type did not affect circulating tumor cell counts over time (median circulating tumor cell count [interquartile range]; for propofol: 1 [0 to 4] at 0 h, 1 [0 to 2] at 48 h, and 0 [0 to 1] at 72 h; and for sevoflurane: 1 [0 to 4] at 0 h, 0 [0 to 2] at 48 h, and 1 [0 to 2] at 72 h; rate ratio, 1.27 [95% CI, 0.95 to 1.71]; P = 0.103) or positivity. In one secondary analysis, administrating sevoflurane led to a significant increase in maximal tumor cell counts postoperatively. There was no association between natural killer cell activity and circulating tumor cell counts. CONCLUSIONS: In this randomized controlled trial investigating the effect of anesthesia on an independent prognostic factor for breast cancer, there was no difference between sevoflurane and propofol with respect to circulating tumor cell counts over time.

Agreement between trainees and supervisors on first-year entrustable professional activities for anaesthesia training.

BACKGROUND: Entrustable professional activities (EPAs) are commonly developed by senior clinicians and education experts. However, if postgraduate training is conceptualised as an educational alliance, the perspective of trainees should be included. This raises the question as to whether the views of trainees and supervisors on entrustability of specific EPAs differ, which we aimed to explore. METHODS: A working group, including all stakeholders, selected and drafted 16 EPAs with the potential for unsupervised practice within the first year of training. For each EPA, first-year trainees, advanced trainees, and supervisors decided whether it should be possible to attain trust for unsupervised practice by the end of the first year of anaesthesiology training (i.e. whether the respective EPA qualified as a 'first-year EPA'). RESULTS: We surveyed 23 first-year trainees, 47 advanced trainees, and 51 supervisors (overall response rate: 68%). All groups fully agreed upon seven EPAs as 'first-year EPAs' and on four EPAs that should not be entrusted within the first year. For all five remaining EPAs, a significantly higher proportion of first-year trainees thought these should be entrusted as first-year EPAs compared with advanced trainees and supervisors. We found no differences between advanced trainees and supervisors. CONCLUSIONS: The views of first-year trainees, advanced trainees, and supervisors showed high agreement. Differing views of young trainees disappeared after the first year. This finding provides a fruitful basis to involve trainees in negotiations of autonomy.

Clinical practice of pre-hospital analgesia: An observational study of 20,978 missions in Switzerland.

BACKGROUND: Pain is a frequent problem faced by emergency medical services (EMS) in pre-hospital settings. This large observational study aims to assess the prevalence of sufficiently provided analgesia and to analyze the efficacy of different analgesics. Moreover, we evaluated if quality of analgesia changed with an emergency physician on scene or depended on paramedics' gender. METHODS: This is a retrospective analysis of all pre-hospital medical charts from adults and adolescents treated by the municipal EMS Schutz & Rettung Zürich over a period of 4 years from 2013 to 2016. Inclusion criteria were age ≥16 years, initial GCS > 13, NACA score ≥I and ≤V, an initial numeric rating scale (NRS) ≥ I and a documented NRS at hospital admission. 20,978 out of 142,484 missions fulfilled the inclusion criteria and therefore underwent further investigation. Descriptive, univariate and multivariate analyses were applied. RESULTS: Initial NRS on scene was on average 5.2 ± 3.0. Mean NRS reduction after treatment was 2.2 ± 2.5 leading to a NRS at hospital admission of 3.0 ± 1.9. This resulted in sufficient analgesia for 77% of included patients. Among analgesics, the highest odds ratio for sufficient analgesia was observed for ketamine (OR 4.7, 95%CI 2.2-10.4, p < 0.001) followed by fentanyl (OR 1.4, 95%CI 1.1-1.7, p = 0.004). Female paramedics provided better analgesia (OR 1.2, 95%CI 1.1-1.2; p < 0.001). Patient's sex had no influence on analgesia. In patients with a NACA score > 2, the presence of an emergency physician on scene improved the quality of analgesia significantly. CONCLUSIONS: Pre-hospital analgesia is mostly adequate, especially when done with ketamine or fentanyl. Female paramedics provided better analgesia and in selected patients, an emergency physician on scene improved quality of analgesia in critical patients.