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Kcv channels from plant viruses represent the autonomous pore module of potassium channels, devoid of any regulatory domains. These small proteins show very reproducible single-channel behavior in planar lipid bilayers. Thus, they are an optimum system for the study of the biophysics of ion transport and gating. Structural models based on homology modeling have been used successfully, but experimental structural data are currently not available. Here we determine the size of the cytosolic pore entrance by studying the blocker kinetics. Blocker binding and dissociation rate constants ranging from 0.01 to 1000 ms -1 were determined for different quaternary ammonium ions. We found that the cytosolic pore entrance of Kcv NTS must be at least 11 Å wide. The results further indicate that the residues controlling a cytosolic gate in one of the Kcv isoforms influence blocker binding/dissociation as well as a second gate even when the cytosolic gate is in the open state. The voltage dependence of the rate constant of blocker release is used to test, which blockers bind to the same binding site.

Cave Automatic Virtual Environment (CAVE) is a virtual reality (VR) environment that has not been fully studied due to its high cost and complexity in system integration. Previous CAVE-related studies mainly focused on comparing its effectiveness with other learning media, such as textbooks, desktop VR, or head-mounted display (HMD) VR. In this study, through the utilization of CAVE in a meteorology class, we concentrated on CAVE itself, measured how CAVE impacted learners' learning outcomes before and after using CAVE in an actual ongoing undergraduate-level class, and investigated how learners perceived their learning experiences. Quantitative data were collected to examine the students' knowledge acquisition and learning experience. We also triangulated the quantitative results with qualitative data from the interviews regarding learners' perceptions of the CAVE-enabled class and their knowledge mastery. The results indicated that their learning outcomes increased through learning with CAVE and that their perceptions of immersion, presence, and engagement significantly correlated with each other. The interview results showed a great fondness of and satisfaction with the learning experience, group collaboration, and effectiveness of the CAVE-enabled class from the learners. We also learned that the learners' learning experiences in CAVE could be further improved if we provided them with more learner-environment interaction, offered them a better sense of immersion, and reduced cybersickness. Implications of these findings are discussed.

Background: Approximately one in three survivors of critical illness suffers from intensive-care-unit-acquired weakness, which increases mortality and impairs quality of life. By counteracting immobilization, a known risk factor, active mobilization may mitigate its negative effects on patients. In this single-center trial, the effect of robotic-assisted early mobilization in the intensive care unit (ICU) on patients' outcomes was investigated., Methods: We enrolled 16 adults scheduled for lung transplantation to receive 20 min of robotic-assisted mobilization and verticalization twice daily during their first week in the ICU (intervention group: IG). A control group (CG) of 13 conventionally mobilized patients after lung transplantation was recruited retrospectively. Outcome measures included the duration of mechanical ventilation, length of ICU stay, muscle parameters evaluated by ultrasound, and quality of life after three months., Results: During the first week in the ICU, the intervention group received a median of 6 (interquartile range 3-8) robotic-assisted sessions of early mobilization and verticalization. There were no statistically significant differences in the duration of mechanical ventilation (IG: median 126 vs. CG: 78 h), length of ICU stay, muscle parameters evaluated by ultrasound, and quality of life after three months between the IG and CG., Conclusion: In this study, robotic-assisted mobilization was successfully implemented in the ICU setting. No significant differences in patients' outcomes were observed between conventional and robotic-assisted mobilization. However, randomized and larger studies are necessary to validate the adequacy of robotic mobilization in other cohorts., Trial Registration: This single-center interventional trial was registered in clinicaltrials.gov as NCT05071248 on 27/08/2021., (© 2024. The Author(s).)

Background: Early mobilization is only carried out to a limited extent in the intensive care unit. To address this issue, the robotic assistance system VEMOTION® was developed to facilitate (early) mobilization measures more easily. This paper describes the first integration of robotic assistance systems in acute clinical intensive care units., Objective: Feasibility test of robotic assistance in early mobilization of intensive care patients in routine clinical practice., Setting: Two intensive care units guided by anesthesiology at a German university hospital., Participants: Patients who underwent elective surgery with postoperative treatment in the intensive care unit and had an estimated ventilation time over 48 h., Methods: Participants underwent robot-assisted mobilization, scheduled for twenty-minute sessions twice a day, ten times or one week, conducted by nursing staff under actual operational conditions on the units. No randomization or blinding took place. We assessed data regarding feasible cutoff points (in brackets): the possibility of enrollment (x ≥ 50 %), duration (pre- and post-setup (x ≤ 25 min), therapy duration (x = 20 min), and intervention-related parameters (number of mobilizing professionals (x ≤ 2), intensity of training, events that led to adverse events, errors or discontinuation). Mobilizing professionals rated each mobilization regarding their physical stress (x ≤ 3) and feasibility (x ≥ 4) on a 7 Point Likert Scale. An estimated sample size of at least twenty patients was calculated. We analyzed the data descriptively., Results: Within 6 months, we screened thirty-two patients for enrollment. 23 patients were included in the study and 16 underwent mobilization using robotic assistance, 7 dropped out (enrollment eligibility = 69 %). On average, 1.9 nurses were involved per therapy unit. Participants received 5.6 robot-assisted mobilizations in mean. Pre- and post-setup had a mean duration of 18 min, therapy a mean of 21 min. The robot-assisted mobilization was started after a median of 18 h after admission to the intensive care unit. We documented two adverse events (pain), twelve errors in handling, and seven unexpected events that led to interruptions or discontinuation. No serious adverse events occurred. The mobilizing nurses rated their physical stress as low (mean 2.0 ± 1.3) and the intervention as feasible (mean 5.3 ± 1.6)., Conclusions: Robot-assisted mobilization was feasible, but specific safety measures should be implemented to prevent errors. Robotic-assisted mobilization requires process adjustments and consideration of unit staffing levels, as the intervention does not save staff resources or time., Registration: clinicaltrials.org TRN: NCT05071248; Date: 2021/10/08; URL https://clinicaltrials.gov/ct2/show/NCT05071248., Tweetable Abstract: Robot-assisted early mobilization in intensive care patients is feasible and no adverse event occurred., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests. The company that manufactures the VEMOTION® system is part of the overall study consortium. However, it was not part of the clinical study or the analysis team., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Providing optimal care for critically ill patients is an extremely important but also highly demanding task, both emotionally and physically. The "ICU Support" team meeting concept aims to support intensive care unit (ICU) teams by promoting interprofessional communication, peer support, and patient safety by providing a structure for daily team meetings. This protocol describes a study to explore the effectiveness of "ICU Support" for patient- and staff-centered outcomes., Methods: ICU Support will be implemented at nine university hospitals located in Germany, following a two-arm randomized parallel group design with an intervention and a control condition and three data collection periods. In the intervention arm, leading ICU personnel (physicians and nurses) will be trained in ICU Support and implement the ICU Support elements into the daily work routine of their units upon completion of data collection period T0 (baseline). In the control arm, ICU Support will not be implemented until the completion of the data collection period T1 (1 month after study start). Until then, the regular daily schedule of the ICU teams will be maintained. The final data collection period (T2) will take place 4 months after the start of the study. Primary outcomes include the number of intensive care complications per patient during their ICU stay during T1 and the sick-related absence of ICU staff during T1. Secondary outcomes include, among others, the average severity of intensive care complications per patient and employee self-reported data regarding their teamwork and patient safety behaviors., Discussion: The need for healthy and well-trained ICU staff is omnipresent; thus, structured and evidence-based interventions aimed at supporting ICU teams and facilitating patient safety are required. This multicenter study aims to explore the effectiveness of ICU Support for patient- and staff-centered outcomes. The insights derived from this study have the potential to significantly improve ICU patient safety, staff communication, and connectedness and decrease sickness-related expenses and social costs associated with high work demands among ICU staff., Trial Registration: German Clinical Trials Register DRKS00028642 . Registered on 4 April 2022., (© 2023. The Author(s).)

Background: Early mobilization can help reduce severe side effects such as muscle atrophy that occur during hospitalization. However, due to time and staff shortages in intensive and critical care as well as safety risks for patients, it is often difficult to adhere to the recommended therapy time of twenty minutes twice a day. New robotic technologies might be one approach to achieve early mobilization effectively for patients and also relieve users from physical effort. Nevertheless, currently there is a lack of knowledge regarding the factors that are important for integrating of these technologies into complex treatment settings like intensive care units or rehabilitation units., Methods: European experts from science, technical development and end-users of robotic systems (n = 13) were interviewed using a semi-structured interview guideline to identify barriers and facilitating factors for the integration of robotic systems into daily clinical practice. They were asked about structural, personnel and environmental factors that had an impact on integration and how they had solved challenges. A latent content analysis was performed regarding the COREQ criteria., Results: We found relevant factors regarding the development, introduction, and routine of the robotic system. In this context, costs, process adjustments, a lack of exemptions, and a lack of support from the manufacturers/developers were identified as challenges. Easy handling, joint decision making between the end-users and the decision makers in the hospital, an accurate process design and the joint development of the robotic system of end-users and technical experts were found to be facilitating factors., Conclusion: The integration and preparation for the integration of robotic assistance systems into the inpatient setting is a complex intervention that involves many parties. This study provides evidence for hospitals or manufacturers to simplify the planning of integrations for permanent use., Trial Registration: DRKS-ID: DRKS00023848; registered 10/12/2020., (© 2023. The Author(s).)

Background: Early mobilization positively influences the outcome of critically ill patients, yet in clinical practice, the implementation is sometimes challenging. In this study, an adaptive robotic assistance system will be used for early mobilization in intensive care units. The study aims to evaluate the experience of the mobilizing professionals and the general feasibility of implementing robotic assistance for mobilization in intensive care as well as the effects on patient outcomes as a secondary outcome., Methods: The study is single-centric, prospective, and interventional and follows a longitudinal study design. To evaluate the feasibility of robotic-assisted early mobilization, the number of patients included, the number of performed VEM (very early mobilization) sessions, and the number and type of adverse events will be collected. The behavior and experience of mobilizing professionals will be evaluated using standardized observations (n > 90) and episodic interviews (n > 36) before implementation, shortly after, and in routine. Patient outcomes such as duration of mechanical ventilation, loss of muscle mass, and physical activity will be measured and compared with a historical patient population. Approximately 30 patients will be included., Discussion: The study will provide information about patient outcomes, feasibility, and the experience of mobilizing professionals. It will show whether robotic systems can increase the early mobilization frequency of critically ill patients. Within ICU structures, early mobilization as therapy could become more of a focus. Effects on the mobilizing professionals such as increased motivation, physical relief, or stress will be evaluated. In addition, this study will focus on whether current structures allow following the recommendation of mobilizing patients twice a day for at least 20 min., Trial Registration: ClinicalTrials.gov, NCT05071248 . Date: 2021/10/21., (© 2022. The Author(s).)

Background: Intensive care unit (ICU) acquired weakness is associated with reduced physical function, increased mortality and reduced quality of life, and affects about 43% of survivors of critical illness. Lacking therapeutic options, the prevention of known risk factors and implementation of early mobilization is essential. Robotic assistance devices are increasingly being studied in mobilization., Objective: This qualitative review synthesizes the evidence of early mobilization in the ICU and focuses on the advantages of robotic assistance devices., Results: Active mobilization should begin early during critical care. Interventions commencing 72 h after admission to the ICU are considered early. Mobilization interventions during critical care have been shown to be safe and reduce the time on mechanical ventilation in the ICU and the length of delirious episodes. Protocolized early mobilization interventions led to more active mobilization and increased functional independence and mobility at hospital discharge. In rehabilitation after stroke, robot-assisted training increases the chance of regaining independent walking ability, especially in more severely impaired patients, seems to be safe and increases muscle strength and quality of life in small trials., Conclusion: Early mobilization improves the outcome of the critically ill. Robotic devices support the gait training after stroke and are the subject of ongoing studies on early mobilization and verticalization in the intensive care setting., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Rationale: The concentration-time profile of linezolid varies considerably in critically ill patients. Question of interest is, if the site of infection influences linezolid serum concentrations., Methods: 68 critically ill patients, treated with linezolid, were included. The concentration-time-profile for linezolid was determined using maximum a-posteriori predictions. A trough concentration (C min ) between 2 and 10 mg/L was defined as the target. A generalized linear model (GLM) was established to evaluate potential covariates., Results: The indications for linezolid therapy were in descending order: peritonitis (38.2%), pneumonia (25.0%), infectious acute respiratory distress syndrome (ARDS) (19.1%), and other non-pulmonary infection (17.7%). 27.2 and 7.9% of C min were subtherapeutic and toxic, respectively. In the GLM, ARDS (mean: -2.1 mg/L, CI: -3.0 to -1.2 mg/L) and pneumonia (mean: -2.2 mg/L, CI: -2.8 to -1.6 mg/L) were significant (p < 0.001) determinants of C min . Patients with ARDS (mean: 2.3 mg/L, 51.2% subtherapeutic, 0.0% toxic) and pneumonia (mean: 3.5 mg/L, 41.5% subtherapeutic, 7.7% toxic) had significantly (p < 0.001) lower C min than those with peritonitis (mean: 5.5 mg/L, 14.4% subtherapeutic, 9.3% toxic) and other non-pulmonary infection (mean: 5.2 mg/L, 3.3% subtherapeutic, 16.5% toxic)., Conclusion: Linezolid serum concentrations are reduced in patients with pulmonary infections. Future studies should investigate if other linezolid thresholds are needed in those patients due to linezolid pooling in patients´ lung., Competing Interests: Declaration of Competing Interest Upon manuscript submission, all authors declare they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To advance a transition towards an indication-based chest radiograph (CXR) ordering in intensive care units (ICUs) without compromising patient safety., Materials and Methods: Single-center prospective cohort study with a retrospective reference group including 857 ICU patients. The routine group (n = 415) received CXRs at the discretion of the ICU physician, the restrictive group (n = 442) if specified by an indication catalogue. Documented data include number of CXRs per day and CXR radiation dose as primary outcomes, re-intubation and re-admission rates, hours of mechanical ventilation and ICU length of stay., Results: CXR numbers were reduced in the restrictive group (964 CXRs in 2479 days vs. 1281 CXRs in 2318 days) and median radiation attributed to CXR per patient was significantly lowered in the restrictive group (0.068 vs. 0.076 Gy x cm 2 , P = 0.003). For patients staying ≥24 h, median number of CXRs per day was significantly reduced in the restrictive group (0.41 (IQR 0.21-0.61) vs. 0.55 (IQR 0.34-0.83), P < 0.001). Survival analysis proved non-inferiority. Secondary outcome parameters were not significantly different between the groups. CXR reduction was significant even for patients in most critical conditions., Conclusions: A substantial reduction of the number of CXRs on ICUs was feasible and safe using an indication catalogue thereby improving resource management., Trial Registration: DRKS00015621, German Clinical Trials Register., Competing Interests: Declaration of Competing Interest All contributing authors declare that no conflict of interest exists., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Hemadsorption of cytokines is used in critically ill patients with sepsis or septic shock. Concerns have been raised that the cytokine adsorber CytoSorb ® unintentionally adsorbs vancomycin. This study aimed to quantify vancomycin elimination by CytoSorb ® ., Methods: Critically ill patients with sepsis or septic shock receiving continuous renal replacement therapy and CytoSorb ® treatment during a prospective observational study were included in the analysis. Vancomycin pharmacokinetics was characterized using population pharmacokinetic modeling. Adsorption of vancomycin by the CytoSorb ® was investigated as linear or saturable process. The final model was used to derive dosing recommendations based on stochastic simulations., Results: 20 CytoSorb ® treatments in 7 patients (160 serum samples/24 during CytoSorb ® -treatment, all continuous infusion) were included in the study. A classical one-compartment model, including effluent flow rate of the continuous hemodialysis as linear covariate on clearance, best described the measured concentrations (without CytoSorb ® ). Significant adsorption with a linear decrease during CytoSorb ® treatment was identified (p < 0.0001) and revealed a maximum increase in vancomycin clearance of 291% (initially after CytoSorb ® installation) and a maximum adsorption capacity of 572 mg. For a representative patient of our cohort a reduction of the area under the curve (AUC) by 93 mg/L*24 h during CytoSorb ® treatment was observed. The additional administration of 500 mg vancomycin over 2 h during CytoSorb ® attenuated the effect and revealed a negligible reduction of the AUC by 4 mg/L*24 h., Conclusion: We recommend the infusion of 500 mg vancomycin over 2 h during CytoSorb ® treatment to avoid subtherapeutic concentrations. Trial registration NCT03985605. Registered 14 June 2019, https://clinicaltrials.gov/ct2/show/NCT03985605., (© 2022. The Author(s).)

Most potassium channels have two main gate locations, hosting an inner gate at the cytosolic entrance and a filter gate in the selectivity filter; the function of these gates is in many channels coupled. To obtain exclusive insights into the molecular mechanisms that determine opening and closing of the filter gate, we use a combination of single-channel recordings and gating analysis in the minimal viral channel Kcv NTS . This channel has no inner gate, and its fast closing at negative voltages can therefore be entirely assigned to the filter gate. We find that mutations of S42 in the pore helix severely slow down closing of this filter gate, an effect which is not correlated with hydrogen bond formation by the amino acid at this position. Hence, different from KcsA, which contains the critical E71 in the equivalent position forming a salt bridge, the coupling between selectivity filter and surrounding structures for filter gating must in Kcv NTS rely on different modes of interaction. Quantitative analysis of concatemers carrying different numbers of S42T mutations reveals that each subunit contributes the same amount of ∼ 0.4 kcal/mol to the energy barrier for filter closure indicating a concerted action of the subunits. Since the mutations have neither an influence on the unitary current nor on the voltage dependency of the gate, the data stress that the high subunit cooperativity is mediated through conformational changes rather than through changes in the ion occupation in the selectivity filter., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This study examined the correlation between preoperative transcutaneous oxygen perfusion (TcPO 2 ) measurement and the success of wound healing after major lower extremity amputation. There is no validated consensus on how to accurately determine appropriate amputation levels. A TcPO 2 greater than 30 to 40 mm Hg is widely cited as a positive predictor of postoperative wound healing, but its validity has not been well defined. A retrospective chart review was performed for patients who underwent above-knee amputation (AKA), through-knee amputation, or below-knee amputation (BKA) at a single institution from 2012 to 2018 with preoperative TcPO 2 values and a minimum 30-day postoperative clinical follow-up. This review yielded 141 total amputations: 93 BKAs, 6 through-knee amputations, and 42 AKAs. Fifty-five amputations were unsuccessful, defined by postoperative wound dehiscence or infection. Of these, 37 were BKAs, 4 were through-knee amputations, and 14 were AKAs. There was a significant difference in preoperative TcPO 2 between the successful and unsuccessful amputations, at 46.2 and 38.3 mm Hg, respectively ( P =.02). A TcPO 2 of 30 to 40 mm Hg showed a 68.8% success rate, and a TcPO 2 of less than 20 mm Hg showed an 18.2% success rate. A receiver operating characteristic curve for TcPO 2 predicting amputation success had an area under the curve of 0.53 for AKAs and 0.61 for BKAs; the diagnostic ability is far from prognostic. There is no linear association between TcPO 2 and success rate. A TcPO 2 of less than 20 mm Hg has a high positive predictive value for failure, but higher levels are not 100% predictive of wound healing success after amputation, as previously reported. [ Orthopedics . 2022;45(3):174-180.].

The controversy surrounding ventilation in coronavirus disease 2019 (COVID-19) continues. Early in the pandemic it was postulated that the high intensive care unit (ICU) mortality may have been due to too early intubation. As the pandemic progressed recommendations changed and the use of noninvasive respiratory support (NIRS) increased; however, this did not result in a clear reduction in ICU mortality. Furthermore, large studies on optimal ventilation in COVID-19 are lacking. This review article summarizes the pathophysiological basis, the current state of the science and the impact of different treatment modalities on the outcome. Potential factors that could undermine the benefits of noninvasive respiratory support are discussed. The authors attempt to provide guidance in answering the difficult question of when is the right time to intubate?, (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) and veno-arterial extracorporeal membrane oxygenation (VA-ECMO), also known as extracorporeal life support (ECLS), can both be used to treat patients with acute pulmonary or cardiovascular failure., Methods: This review is based on publications retrieved by a selective search in PubMed on the topics of cardiogenic shock and acute pulmonary failure, also known as the acute respiratory distress syndrome (ARDS), as well as on ECMO. Attention was given chiefly to randomized, controlled trials and guidelines., Results: Initial findings from prospective, randomized trials of VV-ECMO are now available. Trials of ECLS therapy are now in progress or planned. A meta-analysis of two randomized, controlled trials of VV-ECMO for ARDS revealed more frequent survival 90 days after randomization among patients treated with VV-ECMO, compared to the control groups (36% vs. 48%; RR = 0.75 [95% confidence interval 0.6; 0.94]). For selected patients, after evaluation of the benefit-risk profile, VV-ECMO is a good treatment method for severe pulmonary failure, and ECLS for cardiogenic shock and resuscitation. The goal is to secure the circulation so that native heart function can be stabilized in the patient's further course or a permanent left-heart support system can be implanted, or else to support lung function until recovery., Conclusion: ECMO is a valid option in selected patients when conservative treatment has failed.

Objectives: To compare transfusion rates in patients on direct oral anticoagulants (DOACs) with nonanticoagulated patients undergoing hip fracture surgery and, secondarily, to determine whether time to surgery or complications differ between these groups., Design: Multicenter retrospective cohort., Setting: Three tertiary care, academic, Level I trauma centers., Patients: Acute, operatively treated, low-energy hip fracture patients 55 years of age and older were included. Anticoagulated patients were matched in a 1:2 ratio to "control" nonanticoagulated hip fracture patients using propensity score matching., Main Outcome Measurements: The primary outcome was incidence of perioperative transfusion. The secondary outcomes included time to surgery, length of stay, and 90-day complications, readmissions, reoperations, and mortality., Results: One hundred thirty-two patients with hip fracture admitted on DOACs were identified (107 factor Xa inhibitors, 25 dabigatran) and were matched to 262 "control" nonanticoagulated patients. There was no difference in overall transfusion rates between anticoagulation and control groups (43.2%; n = 57 DOAC vs. 39.7%; n = 104 control; P = 0.517). The median time from admission to surgery was 41.7 hours in the DOAC group and 26.0 hours in the control group (P < 0.001). There were no differences in 90-day complication, readmission, reoperation, or mortality rates between DOAC and control groups. Comparing DOAC patients undergoing surgery within 24 hours and after 24 hours, there were no differences in transfusion rates (P = 0.558) or overall complication rates (P = 0.179)., Conclusions: This study supports growing evidence that DOAC use should not be a determining factor in delaying surgery for patients with hip fracture who are otherwise medically optimized., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Meropenem is one of the most frequently used antibiotics to treat life-threatening infections in critically ill patients. This study aimed to develop a meropenem dosing algorithm for the treatment of Gram-negative infections based on intensive care unit (ICU)-specific resistance data. Antimicrobial susceptibility testing of Gram-negative bacteria obtained from critically ill patients was carried out from 2016 to 2020 at a tertiary care hospital. Based on the observed MIC distribution, stochastic simulations ( n  = 1,000) of an evaluated pharmacokinetic meropenem model, and a defined pharmacokinetic/pharmacodynamic target (100% T >4×MIC while minimum concentrations were <44.5 mg/L), dosing recommendations for patients with varying renal function were derived. Pathogen-specific MIC distributions were used to calculate the cumulative fraction of response (CFR), and the overall MIC distribution was used to calculate the local pathogen-independent mean fraction of response (LPIFR) for the investigated dosing regimens. A CFR/LPIFR of >90% was considered adequate. The observed MIC distribution significantly differed from the EUCAST database. Based on the 6,520 MIC values included, a three-level dosing algorithm was developed. If the pathogen causing the infection is unknown (level 1), known (level 2), known to be neither Pseudomonas aeruginosa nor Acinetobacter baumannii, or classified as susceptible (level 3), a continuous infusion of 1.5 g daily reached sufficient target attainment independent of renal function. In all other cases, dosing needs to be adjusted based on renal function. ICU-specific susceptibility data should be assessed regularly and integrated into dosing decisions. The presented workflow may serve as a blueprint for other antimicrobial settings.

Beta-lactam dosing is challenging in critically ill patients with slow extended daily dialysis (SLEDD). This prospective observational study aimed to investigate meropenem and piperacillin concentrations and half-lives during SLEDD and in SLEDD-free intervals. Critically ill patients with SLEDD-therapy and meropenem or piperacillin therapy were included. Breakpoints of target attainment were defined as 2 and 20.8 mg/L for meropenem and piperacillin, respectively. Daily TDM was performed and therapies were adapted based on the measured concentrations. Elimination rate constants were determined by using nonlinear regression analysis. Seventeen patients were included (48 SLEDD intervals; median SLEDD-duration: 7.25 h). The median antibiotic trough concentrations and half-lives were significantly (p < 0.001) lower during and after the SLEDD-therapy compared to SLEDD-free intervals (median meropenem: 22.3 (IQR: 12.8, 25.6) vs. 28.3 mg/L (IQR: 16.9, 37.4); median piperacillin: 55.8 (IQR: 45.1, 84.9) vs. 130 mg/L (IQR: 91.5, 154.5); relative change: -48.0% each, IQR meropenem: -33.3, -58.5%; IQR piperacillin: -36.3, -52.1%). However, none of the measured trough concentrations were subtherapeutic during SLEDD. SLEDD leads to a reduction in meropenem and piperacillin concentrations of approximately 50% independently of the initial concentration. If the concentration is twice as high as the breakpoint of target attainment before SLEDD-therapy, subtherapeutic levels can be avoided., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To investigate treatment patterns of women with isolated fever in labour and evaluate if variables in the sepsis in obstetrics score (SOS) or fetal tachycardia are associated with treatment differences. Our secondary objective was to compare women with isolated fever in labour with women with clinical chorioamnionitis to identify any clinicodemographic differences., Methods: A retrospective cohort study of 473 patients at BC Women's Hospital who presented with isolated fever in labour between January 2011 and April 2016 compared with a dataset of 1135 women with clinical chorioamnionitis from 2011 to 2016 in the same institution., Results: In our cohort of isolated fever in labour, antibiotics were given 74.2 % of the time, and the majority received cefazolin and metronidazole (80.9%, of those who received antibiotics). Higher maternal temperature and heart rate at time of first fever and fetal tachycardia were associated with more antibiotic use. Slightly higher maternal temperature was associated with use of a saline bolus and blood cultures. The proportion of women with a SOS greater than 5 increased 4.5-fold from time of first fever to time of maximum SOS. There were fewer cesarean deliveries in the isolated fever in labour group compared with the clinical chorioamnionitis group (22.4% vs. 54.0%; P < 0.0001)., Conclusions: Slightly higher maternal temperature was associated with increased treatment, including antibiotic use, saline bolus administration, and blood cultures. As evidenced by the higher proportion of women with an SOS over 5, women with isolated fever in labour may have a propensity to deteriorate clinically., (Copyright © 2021 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Background: Increasing incidence of invasive infections caused by rare fungi was observed over the recent years., Case: Here, we describe the first reported case of an infection caused by the thermophilic mold Talaromyces thermophilus. Cultivation and, hence, identification of this fastidious organism is challenging since standard incubation conditions are not sufficient. Retrospective analysis of patient samples and in vitro experiments demonstrated that testing for fungal antigens, i.e., the cell wall components galactomannan and β-1,3-D-glucan, is a promising tool., (© 2021. The Author(s).)

Pneumonia is one of the most common infections in intensive care patients, and it is often treated with beta-lactam antibiotics. Even if therapeutic drug monitoring in blood is available, it is unclear whether sufficient concentrations are reached at the target site: the lung. The present study was initiated to fill this knowledge gap. Various compartments from 10 patients' explanted lungs were subjected to laboratory analysis. Meropenem was quantified in serum, bronchoalveolar lavage (BAL) fluid, microdialysate, and homogenized lung tissue with isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS). BAL fluid represents diluted epithelial lining fluid (ELF), and microdialysate represents interstitial fluid (IF). Differences between target site and blood concentrations were investigated. The median meropenem concentration in blood, ELF, IF, and tissue were 26.8, 18.0, 12.1, and 9.1 mg/liter, respectively. A total of 37.5% of the target site ELF and IF meropenem concentrations were below the clinical EUCAST breakpoint of 8 mg/liter. The median ELF/serum quotient was 61.8% (interquartile range [IQR], 24.8% to 87.6%), the median IF/serum quotient was 35.4% (IQR, 23.8% to 54.3%), and the median tissue/serum quotient was 34.2% (IQR, 28.3% to 38.2%). We observed a substantial interindividual variability between the blood and the compartments (ELF and IF), whereas the intraindividual variability was relatively low. Target site measurement in different lung compartments was feasible and successfully applied in a clinical setting. A relevant amount of 37.5% of the target site concentrations were below the clinical EUCAST breakpoint, indicating subtherapeutic dosing in high-risk patients receiving perioperative antibiotic prophylaxis in lung transplantation. (This study has been registered at ClinicalTrials.gov under identifier NCT03970265.).

Modulating the activity of ion channels by blockers yields information on both the mode of drug action and on the biophysics of ion transport. Here we investigate the interplay between ions in the selectivity filter (SF) of K + channels and the release kinetics of the blocker tetrapropylammonium in the model channel Kcv NTS . A quantitative expression calculates blocker release rate constants directly from voltage-dependent ion occupation probabilities in the SF. The latter are obtained by a kinetic model of single-channel currents recorded in the absence of the blocker. The resulting model contains only two adjustable parameters of ion-blocker interaction and holds for both symmetric and asymmetric ionic conditions. This data-derived model is corroborated by 3D reference interaction site model (3D RISM) calculations on several model systems, which show that the K + occupation probability is unaffected by the blocker, a direct consequence of the strength of the ion-carbonyl attraction in the SF, independent of the specific protein background. Hence, Kcv NTS channel blocker release kinetics can be reduced to a small number of system-specific parameters. The pore-independent asymmetric interplay between K + and blocker ions potentially allows for generalizing these results to similar potassium channels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gabriel, Hansen, Urban, Drexler, Winterstein, Rauh, Thiel, Kast and Schroeder.)

Background: Posaconazole and itraconazole are commonly used for systemic antifungal prophylaxis after lung transplantation. The aim of this study on critically ill lung transplant recipients was to assess the rate of adequate plasma concentrations and the frequency of fungal-induced transitions from antifungal prophylaxis to therapy after the administration of either posaconazole or itraconazole for systemic prophylaxis., Methods: Critically ill lung transplant recipients with postoperative posaconazole or itraconazole prophylaxis and therapeutic drug monitoring from February 2016 to November 2019 were retrospectively included in the study. Positive fungal cultures or Aspergillus antigen tests resulting in a transition from antifungal prophylaxis to therapy were analyzed from the first day of prophylaxis until 7 days after the last sample for each patient. Adequate plasma concentrations were defined as ≥500 µg/L for itraconazole and ≥700 µg/L for posaconazole., Results: Two hundred seventy-five samples from 73 patients were included in the analysis. Overall, 60% of the posaconazole and 55% of the itraconazole concentrations were subtherapeutic. Administration of posaconazole suspension resulted significantly (P < .01) more often in subtherapeutic concentrations than tablets (68% vs 10%). Patients treated with posaconazole showed less positive fungal records resulting in a transition from prophylaxis to therapy than patients treated with itraconazole (10% vs 33%, P-value: .029). The detection of a fungal pathogen was not associated with the measured plasma concentrations or the achievement of the target concentrations., Conclusion: Our findings suggest that posaconazole should be used instead of itraconazole for systemic prophylaxis in critically ill lung transplant recipients., (© 2021 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Background: A cytokine storm is life threatening for critically ill patients and is mainly caused by sepsis or severe trauma. In combination with supportive therapy, the cytokine adsorber Cytosorb ® (CS) is increasingly used for the treatment of cytokine storm. However, it is questionable whether its use is actually beneficial in these patients., Methods: Patients with an interleukin-6 (IL-6) > 10,000 pg/ml were retrospectively included between October 2014 and May 2020 and were divided into two groups (group 1: CS therapy; group 2: no CS therapy). Inclusion criteria were a regularly measured IL-6 and, for patients allocated to group 1, CS therapy for at least 90 min. A propensity score (PS) matching analysis with significant baseline differences as predictors (Simplified Acute Physiology Score (SAPS) II, extracorporeal membrane oxygenation, renal replacement therapy, IL-6, lactate and norepinephrine demand) was performed to compare both groups (adjustment tolerance: < 0.05; standardization tolerance: < 10%). U-test and Fisher's-test were used for independent variables and the Wilcoxon test was used for dependent variables., Results: In total, 143 patients were included in the initial evaluation (group 1: 38; group 2: 105). Nineteen comparable pairings could be formed (mean initial IL-6: 58,385 vs. 59,812 pg/ml; mean SAPS II: 77 vs. 75). There was a significant reduction in IL-6 in patients with (p < 0.001) and without CS treatment (p = 0.005). However, there was no significant difference (p = 0.708) in the median relative reduction in both groups (89% vs. 80%). Furthermore, there was no significant difference in the relative change in C-reactive protein, lactate, or norepinephrine demand in either group and the in-hospital mortality was similar between groups (73.7%)., Conclusion: Our study showed no difference in IL-6 reduction, hemodynamic stabilization, or mortality in patients with Cytosorb ® treatment compared to a matched patient population., (© 2021. The Author(s).)

Background: In a pandemic situation the overall mortality rate is of considerable interest; however, these data must always be seen in relation to the given healthcare system and the availability of local level of care. A recently published German data evaluation of more than 10,000 COVID-19 patients treated in 920 hospitals showed a high mortality rate of 22% in hospitalized patients and of more than 50% in patients requiring invasive ventilation. Because of the high infection rates in Bavaria, a large number of COVID-19 patients with considerable severity of disease were treated at the intensive care units of the LMU hospital. The LMU hospital is a university hospital and a specialized referral center for the treatment of patients with acute respiratory distress syndrome (ARDS)., Objective: Data of LMU intensive care unit (ICU) patients were systematically evaluated and compared with the recently published German data., Methods: Data of all COVID-19 patients with invasive and noninvasive ventilation and with completed admission at the ICU of the LMU hospital until 31 July 2020 were collected. Data were processed using descriptive statistics., Results: In total 70 critically ill patients were included in the data evaluation. The median SAPS II on admission to the ICU was 62 points. The median age was 66 years and 81% of the patients were male. More than 90% were diagnosed with ARDS and received invasive ventilation. Treatment with extracorporeal membrane oxygenation (ECMO) was necessary in 10% of the patients. The median duration of ventilation was 16 days, whereby 34.3% of patients required a tracheostomy. Of the patients 27.1% were transferred to the LMU hospital from external hospitals with reference to our ARDS/ECMO program. Patients from external hospitals had ARDS of higher severity than the total study population. In total, nine different substances were used for virus-specific treatment of COVID-19. The most frequently used substances were hydroxychloroquine and azithromycin. Immunomodulatory treatment, such as Cytosorb® (18.6%) and methylprednisolone (25.7%) were also frequently used. The overall in-hospital mortality rate of ICU patients requiring ventilation was 28.6%. The mortality rates of patients from external hospitals, patients with renal replacement therapy and patients with ECMO therapy were 47.4%, 56.7% and 85.7%, respectively., Conclusion: The mortality rate in the ventilated COVID-19 intensive care patients was considerably different from the general rate in Germany. The data showed that treatment in an ARDS referral center could result in a lower mortality rate. Low-dose administration of steroids may be another factor to improve patient outcome in a preselected patient population. In the authors' opinion, critically ill COVID-19 patients should be treated in an ARDS center provided that sufficient resources are available.

Purpose: SARS-COV-2 infection can develop into a multi-organ disease. Although pathophysiological mechanisms of COVID-19-associated myocardial injury have been studied throughout the pandemic course in 2019, its morphological characterisation is still unclear. With this study, we aimed to characterise echocardiographic patterns of ventricular function in patients with COVID-19-associated myocardial injury., Methods: We prospectively assessed 32 patients hospitalised with COVID-19 and presence or absence of elevated high sensitive troponin T (hsTNT+ vs. hsTNT-) by comprehensive three-dimensional (3D) and strain echocardiography., Results: A minority (34.3%) of patients had normal ventricular function, whereas 65.7% had left and/or right ventricular dysfunction defined by impaired left and/or right ventricular ejection fraction and strain measurements. Concomitant biventricular dysfunction was common in hsTNT+ patients. We observed impaired left ventricular (LV) global longitudinal strain (GLS) in patients with myocardial injury (-13.9% vs. -17.7% for hsTNT+ vs. hsTNT-, p = 0.005) but preserved LV ejection fraction (52% vs. 59%, p = 0.074). Further, in these patients, right ventricular (RV) systolic function was impaired with lower RV ejection fraction (40% vs. 49%, p = 0.001) and reduced RV free wall strain (-18.5% vs. -28.3%, p = 0.003). Myocardial dysfunction partially recovered in hsTNT + patients after 52 days of follow-up. In particular, LV-GLS and RV-FWS significantly improved from baseline to follow-up (LV-GLS: -13.9% to -16.5%, p = 0.013; RV-FWS: -18.5% to -22.3%, p = 0.037)., Conclusion: In patients with COVID-19-associated myocardial injury, comprehensive 3D and strain echocardiography revealed LV dysfunction by GLS and RV dysfunction, which partially resolved at 2-month follow-up., Trial Registration: COVID-19 Registry of the LMU University Hospital Munich (CORKUM), WHO trial ID DRKS00021225.

There are different methods of artificial liver support for patients with acute liver dysfunction (ALD). However, CytoSorb (CS) might be a new approved option for those patients. Question of interest is whether the elimination performance of CS was comparable to that of advanced organ support (ADVOS). Patients, treated with CS (integrated into high-flux dialysis) or ADVOS and a total bilirubin > 10 mg/dl were included. Laboratory parameters were evaluated before starting therapy (d0) and 12-24 h thereafter (d1). The Wilcoxon-test with associated samples was used for statistical analysis. Thirty-nine patients (33 CS, 6 ADVOS) were included. The median bilirubin at d0 was 16.9 and 17.7 mg/dl and at d1 was 13.2 and 15.9 mg/dl, in the CS and ADVOS group, respectively. There was a significant bilirubin reduction as well in the CS group (p < 0.001, median relative reduction: 22.5%) as in the ADVOS group (p = 0.028, median relative reduction: 22.8%). There was no significant difference in the relative bilirubin reduction between CS and ADVOS therapies. The use of CytoSorb and ADVOS in patients with ALD led to a significant and comparable decrease in total bilirubin. The easy use of CS might be an advantage compared to other procedures.

Background: The MeroRisk-calculator, an easy-to-use tool to determine the risk of meropenem target non-attainment after standard dosing (1000 mg; q8h), uses a patient's creatinine clearance and the minimum inhibitory concentration (MIC) of the pathogen. In clinical practice, however, the MIC is rarely available. The objectives were to evaluate the MeroRisk-calculator and to extend risk assessment by including general pathogen sensitivity data., Methods: Using a clinical routine dataset (155 patients, 891 samples), a direct data-based evaluation was not feasible. Thus, in step 1, the performance of a pharmacokinetic model was determined for predicting the measured concentrations. In step 2, the PK model was used for a model-based evaluation of the MeroRisk-calculator: risk of target non-attainment was calculated using the PK model and agreement with the MeroRisk-calculator was determined by a visual and statistical (Lin's concordance correlation coefficient (CCC)) analysis for MIC values 0.125-16 mg/L. The MeroRisk-calculator was extended to include risk assessment based on EUCAST-MIC distributions and cumulative-fraction-of-response analysis., Results: Step 1 showed a negligible bias of the PK model to underpredict concentrations (-0.84 mg/L). Step 2 revealed a high level of agreement between risk of target non-attainment predictions for creatinine clearances >50 mL/min (CCC = 0.990), but considerable deviations for patients <50 mL/min. For 27% of EUCAST-listed pathogens the median cumulative-fraction-of-response for the observed patients receiving standard dosing was < 90%., Conclusions: The MeroRisk-calculator was successfully evaluated: For patients with maintained renal function it allows a reliable and user-friendly risk assessment. The integration of pathogen-based risk assessment substantially increases the applicability of the tool.

Background: Galactomannan antigen (GM) testing is widely used in the diagnosis of invasive aspergillosis (IA). Digestive enzymes play an important role in enzyme substitution therapy in exocrine pancreatic insufficiency. As digestive enzymes of fungal origin like Nortase contain enzymes from Aspergillus, a false-positive result of the test might be possible because of cross-reacting antigens of the cell wall of the producing fungi. We, therefore, asked whether the administration of fungal enzymes is a relevant cause of false-positive GM antigen test results., Methods: Patients with a positive GM antigen test between January 2016 and April 2020 were included in the evaluation and divided into two groups: group 1-Nortase-therapy, group 2-no Nortase-therapy. In addition, dissolved Nortase samples were analyzed in vitro for GM and β-1,3-D-glucan. For statistical analysis, the chi-squared and Mann‒Whitney U tests were used., Results: Sixty-five patients were included in this evaluation (30 patients receiving Nortase and 35 patients not receiving Nortase). The overall false positivity rate of GM testing was 43.1%. Notably, false-positive results were detected significantly more often in the Nortase group (73.3%) than in the control group (17.1%, p < 0.001). While the positive predictive value of GM testing was 0.83 in the control group, there was a dramatic decline to 0.27 in the Nortase group. In vitro analysis proved that the Nortase enzyme preparation was highly positive for the fungal antigens GM and β-1,3-D-glucan., Conclusions: Our data demonstrate that the administration of digestive enzymes of fungal origin like Nortase leads to a significantly higher rate of false-positive GM test results compared to that in patients without digestive enzyme treatment.

It has become increasingly apparent that the lipid composition of cell membranes affects the function of transmembrane proteins such as ion channels. Here, we leverage the structural and functional diversity of small viral K+ channels to systematically examine the impact of bilayer composition on the pore module of single K+ channels. In vitro-synthesized channels were reconstituted into phosphatidylcholine bilayers ± cholesterol or anionic phospholipids (aPLs). Single-channel recordings revealed that a saturating concentration of 30% cholesterol had only minor and protein-specific effects on unitary conductance and gating. This indicates that channels have effective strategies for avoiding structural impacts of hydrophobic mismatches between proteins and the surrounding bilayer. In all seven channels tested, aPLs augmented the unitary conductance, suggesting that this is a general effect of negatively charged phospholipids on channel function. For one channel, we determined an effective half-maximal concentration of 15% phosphatidylserine, a value within the physiological range of aPL concentrations. The different sensitivity of two channel proteins to aPLs could be explained by the presence/absence of cationic amino acids at the interface between the lipid headgroups and the transmembrane domains. aPLs also affected gating in some channels, indicating that conductance and gating are uncoupled phenomena and that the impact of aPLs on gating is protein specific. In two channels, the latter can be explained by the altered orientation of the pore-lining transmembrane helix that prevents flipping of a phenylalanine side chain into the ion permeation pathway for long channel closings. Experiments with asymmetrical bilayers showed that this effect is leaflet specific and most effective in the inner leaflet, in which aPLs are normally present in plasma membranes. The data underscore a general positive effect of aPLs on the conductance of K+ channels and a potential interaction of their negative headgroup with cationic amino acids in their vicinity., (© 2021 Winterstein et al.)

Background: Rhabdomyolysis is frequently occurring in critically ill patients, resulting in a high risk of acute kidney injury (AKI) and potentially permanent kidney damage due to increased myoglobin levels. The extracorporeal elimination of myoglobin might be an approach to prevent AKI, but its molecular weight of 17 kDa complicates an elimination with conventional dialysis membranes. Question of interest is, if myoglobin can be successfully eliminated with the cytokine adsorber Cytosorb® (CS) integrated in a high-flux dialysis system., Methods: Patients were included between 10/2014 and 05/2020 in the study population if they had an anuric renal failure with the need of renal replacement therapy, if CS therapy was longer than 90 min and if myoglobin level was > 5.000 ng/ml before treatment. The measurement times of the laboratory values were: d-1 = 24-36 h before CS, d0 = shortly before starting CS and d1 = 12-24 h after starting CS treatment. Statistical analysis were performed with Spearman's correlation coefficient, Wilcoxon test with associated samples and linear regression analysis., Results: Forty-three patients were included in the evaluation (median age: 56 years, 77% male patients, 32.6% ECMO therapy, median SAPS II: 80 points and in-hospital mortality: 67%). There was a significant equilateral correlation between creatine kinase (CK) and myoglobin at all measurement points. Furthermore, there was a significant reduction of myoglobin (p = 0.03, 95% confidence interval (CI): - 9030, - 908 ng/ml) during CS treatment, with a median relative reduction of 29%. A higher median reduction of 38% was seen in patients without ongoing rhabdomyolysis (CK decreased during CS treatment, n = 21). In contrast, myoglobin levels did not relevantly change in patients with increasing CK and therefore ongoing rhabdomyolysis (n = 22, median relative reduction 4%). Moreover, there was no significant difference in myoglobin elimination in patients with and without ECMO therapy., Conclusion: Blood purification with Cytosorb® during high-flux dialysis led to a significant reduction of myoglobin in patients with severe rhabdomyolysis. The effect might be obscured by sustained rhabdomyolysis, which was seen in patients with rising CK during treatment. Prospective clinical trials would be useful in investigating its benefits in avoiding permanent kidney damage.

Coarse-grained protein models approximate the first-principle physical potentials. Among those modeling approaches, the relative entropy framework yields promising and physically sound results, in which a mapping from the target protein structure and dynamics to a model is defined and subsequently adjusted by an entropy minimization of the model parameters. Minimization of the relative entropy is equivalent to maximization of the likelihood of reproduction of (configurational ensemble) observations by the model. In this study, we extend the relative entropy minimization procedure beyond parameter fitting by a second optimization level, which identifies the optimal mapping to a (dimension-reduced) topology. We consider anisotropic network models of a diverse set of ion channels and assess our findings by comparison to experimental results.

Background: Myocardial injury, defined by elevated troponin levels, is associated with adverse outcome in patients with coronavirus disease 2019 (COVID-19). The frequency of cardiac injury remains highly uncertain and confounded in current publications; myocarditis is one of several mechanisms that have been proposed., Methods: We prospectively assessed patients with myocardial injury hospitalized for COVID-19 using transthoracic echocardiography, cardiac magnetic resonance imaging, and endomyocardial biopsy., Results: Eighteen patients with COVID-19 and myocardial injury were included in this study. Echocardiography revealed normal to mildly reduced left ventricular ejection fraction of 52.5% (46.5%-60.5%) but moderately to severely reduced left ventricular global longitudinal strain of -11.2% (-7.6% to -15.1%). Cardiac magnetic resonance showed any myocardial tissue injury defined by elevated T1, extracellular volume, or late gadolinium enhancement with a nonischemic pattern in 16 patients (83.3%). Seven patients (38.9%) demonstrated myocardial edema in addition to tissue injury fulfilling the Lake-Louise criteria for myocarditis. Combining cardiac magnetic resonance with speckle tracking echocardiography demonstrated functional or morphological cardiac changes in 100% of investigated patients. Endomyocardial biopsy was conducted in 5 patients and revealed enhanced macrophage numbers in all 5 patients in addition to lymphocytic myocarditis in 1 patient. SARS-CoV-2 RNA was not detected in any biopsy by quantitative real-time polymerase chain reaction. Finally, follow-up measurements of left ventricular global longitudinal strain revealed significant improvement after a median of 52.0 days (-11.2% [-9.2% to -14.7%] versus -15.6% [-12.5% to -19.6%] at follow-up; P =0.041)., Conclusions: In this small cohort of COVID-19 patients with elevated troponin levels, myocardial injury was evidenced by reduced echocardiographic left ventricular strain, myocarditis patterns on cardiac magnetic resonance, and enhanced macrophage numbers but not predominantly lymphocytic myocarditis in endomyocardial biopsies.

Purpose: Optimization of antibiotic therapy is still urgently needed in critically ill patients. The aim of the ONTAI survey (online survey on the use of Therapeutic Drug Monitoring of antibiotics in intensive care units) was to evaluate which strategies intensive care physicians in Germany use to improve the quality of antibiotic therapy and what role a Therapeutic Drug Monitoring (TDM) plays., Methods: Among the members of the German Society for Anaesthesiology and the German Society for Medical Intensive Care Medicine and Emergency Medicine, a national cross-sectional survey was conducted using an online questionnaire., Results: The questionnaire was completely answered by 398 respondents. Without TDM, prolonged infusion was judged to be the most appropriate dosing regimen for beta lactams. A TDM for piperacillin, meropenem and vancomycin was performed in 17, 22 and 75% of respondents, respectively. For all beta lactams, a TDM was requested more often than it was available. There was great uncertainty as to the optimal pharmacokinetic/pharmacodynamic index for beta-lactams. 86% of the respondents who received minimal inhibitory concentrations adapted the therapy accordingly., Conclusion: German intensive care physicians are convinced of TDM for dose optimization. However, practical implementation, the determination of MICs and defined target values are still lacking., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Beta-lactam antibiotics are often subject to therapeutic drug monitoring, but breakpoints of target attainment are mostly based on expert opinions. Studies that show a correlation between target attainment and infection resolution are missing. This analysis investigated whether there is a difference in infection resolution based on two breakpoints of target attainment., Methods: An outcome group out of 1392 critically ill patients treated with meropenem or piperacillin-tazobactam was formed due to different selection criteria. Afterwards, three groups were created: group 1=free drug concentration (f) was < 100% of the time (T) above the minimal inhibitory concentration (MIC) (< 100% fT > MIC ), group 2=100% fT > MIC < 4xMIC , and group 3=100% fT > 4xMIC . Parameters for infection control, renal and liver function, and estimated and observed in-hospital mortality were compared between those groups. Statistical analysis was performed with one-way analysis of variance, Tukey post hoc test, U test, and bivariate logistic regression., Results: The outcome group consisted of 55 patients (groups 1-3, 17, 24, and 14 patients, respectively). Patients allocated to group 2 or 3 had a significantly faster reduction of the C-reactive protein in contrast to patients allocated to group 1 (p = 0.033 and p = 0.026). Patients allocated to group 3 had a worse renal function, a higher Acute Physiology and Chronic Health Evaluation (APACHE II) score, were older, and had a significantly higher in-hospital mortality compared to group 1 (p = 0.017) and group 2 (p = 0.001). The higher mortality was significantly influenced by worse liver function, higher APACHE II, and higher Sequential Organ Failure Assessment (SOFA) score and norepinephrine therapy., Conclusion: Achieving the target 100% fT > MIC leads to faster infection resolution in the critically ill. However, there was no benefit for patients who reached the highest target of 100% fT > 4xMIC , although the mortality rate was higher possibly due to confounding effects. In conclusion, we recommend the target 100% fT > MIC < 4xMIC for critically ill patients., Trial Registration: NCT03985605.

Various studies have reported insufficient beta-lactam concentrations in critically ill patients. The extent to which therapeutic drug monitoring (TDM) in clinical practice can reduce insufficient antibiotic concentrations is an ongoing matter of investigation. We retrospectively evaluated routine meropenem and piperacillin measurements in critically ill patients who received antibiotics as short infusions in the first year after initiating a beta-lactam TDM program. Total trough concentrations above 8.0 mg/L for meropenem and above 22.5 mg/L for piperacillin were defined as the breakpoints for target attainment. We included 1832 meropenem samples and 636 piperacillin samples. We found that 39.3% of meropenem and 33.6% of piperacillin samples did not reach the target concentrations. We observed a clear correlation between renal function and antibiotic concentration (meropenem, r = 0.53; piperacillin, r = 0.63). Patients with renal replacement therapy or creatinine clearance (CrCl) of <70 mL/min had high rates of target attainment with the standard dosing regimens. There was a low number of patients with a CrCl >100 mL/min that achieved the target concentrations with the maximum recommended dosage. Patients with impaired renal function only required TDM if toxic side effects were noted. In contrast, patients with normal renal function required different dosage regimens and TDM-guided therapy to reach the breakpoints of target attainment.

Some algal viruses have coding sequences for proteins with structural and functional characteristics of pore modules of complex K + channels. Here we exploit the structural diversity among these channel orthologs to discover new basic principles of structure/function correlates in K + channels. The analysis of three similar K + channels with ≤ 86 amino acids (AA) shows that one channel (Kmpv 1 ) generates an ohmic conductance in HEK293 cells while the other two (Kmpv SP1 , Kmpv PL1 ) exhibit typical features of canonical Kir channels. Like Kir channels, the rectification of the viral channels is a function of the K + driving force. Reconstitution of Kmpv SP1 and Kmpv PL1 in planar lipid bilayers showed rapid channel fluctuations only at voltages negative of the K + reversal voltage. This rectification was maintained in KCl buffer with 1 mM EDTA, which excludes blocking cations as the source of rectification. This means that rectification of the viral channels must be an inherent property of the channel. The structural basis for rectification was investigated by a chimera between rectifying and non-rectifying channels as well as point mutations making the rectifier similar to the ohmic conducting channel. The results of these experiments exclude the pore with pore helix and selectivity filter as playing a role in rectification. The insensitivity of the rectifier to point mutations suggests that tertiary or quaternary structural interactions between the transmembrane domains are responsible for this type of gating.

Recent high-resolution in situ mass spectrometry at comet 67P/Churyumov-Gerasimenko visited by European Space Agency's Rosetta spacecraft raised the question, if sublimating ammonium salts can unequivocally be detected in the cometary coma. In laboratory experiments with the twin model of the space instrument, two prototypic ammonium salts NH 4 B, namely, ammonium chloride (B = Cl - ) and ammonium formate (B = HCOO - ) (as well as methodologically relevant isotopologues), were allowed to sublimate in vacuum while mass spectra were collected. High-resolution electron-impact ionization mass spectrometry provides an outstanding experimental tool to investigate the complex physicochemical processes occurring during the sublimation of ammonium salts. Sublimation of ammonium chloride led to the observation of the ammonium cation NH 4 + and the chloramide molecule NH 2 Cl in the neutral gas mode of the instrument. These observations could be jointly interpreted as indirect evidence for the existence of a neutral gaseous parent species (either as the molecular complex NH 3 ···HB or the double-ionic species NH 4 + ···B - ). However, the qualitative fragmentation pattern we present for 13 C 15 N-ammonium formate suggests an alternative route of NH 4 + production within the ionization region of the instrument, namely, by protonation/hydrogenation. Besides NH 4 + , other species were observed that were formed in protonation/hydrogenation reactions. Moreover, together with the two major species from the decomposition of the salt, ammonia and formic acid, three minor species also contributed to the fragmentation pattern: HCN/HNC, HOCN/HNCO, and CH 3 NO. Like chloramide, formamide (CH 3 NO) also is a secondary species probably formed in a pseudo-intramolecular chemical reaction while ammonia and the respective acid are in a state of association. HCN/HNC and HOCN/HNCO are ternary products coming out of formamide decomposition reactions. We discuss our experimental findings, summarized in a tentative chemical reaction network, in light of the available theoretical literature and highlight their relevance for the interpretation of in situ measurements in space research.

Transport processes through ion-channel proteins, protein pores, or solid-state nanopores are traditionally recorded with commercial patch-clamp amplifiers. The bandwidth of these systems is typically limited to 10 kHz by signal-to-noise-ratio (SNR) considerations associated with these measurement platforms. At high bandwidth, the input-referred current noise in these systems dominates, determined by the input-referred voltage noise of the transimpedance amplifier applied across the capacitance at the input of the amplifier. This capacitance arises from several sources: the parasitic capacitance of the amplifier itself; the capacitance of the lipid bilayer harboring the ion channel protein (or the membrane used to form the solid-state nanopore); and the capacitance from the interconnections between the electronics and the membrane. Here, we review state-of-the-art applications of high-bandwidth conductance recordings of both ion channels and solid-state nanopores. These approaches involve tightly integrating measurement electronics fabricated in complementary metal-oxide semiconductors (CMOS) technology with lipid bilayer or solid-state membranes. SNR improvements associated with this tight integration push the limits of measurement bandwidths, in some cases in excess of 10 MHz. Recent case studies demonstrate the utility of these approaches for DNA sequencing and ion-channel recordings. In the latter case, studies with extended bandwidth have shown the potential for providing new insights into structure-function relations of these ion-channel proteins as the temporal resolutions of functional recordings matches time scales achievable with state-of-the-art molecular dynamics simulations., (Copyright © 2019 Elsevier B.V. All rights reserved.)