The antimicrobial fibupeptide lugdunin forms water-filled channel structures in lipid membranes.

Recently, a novel cyclo-heptapeptide composed of alternating D,L-amino acids and a unique thiazolidine heterocycle, called lugdunin, was discovered, which is produced by the nasal and skin commensal Staphylococcus lugdunensis. Lugdunin displays potent antimicrobial activity against a broad spectrum of Gram-positive bacteria, including challenging-to-treat methicillin-resistant Staphylococcus aureus (MRSA). Lugdunin specifically inhibits target bacteria by dissipating their membrane potential. However, the precise mode of action of this new class of fibupeptides remains largely elusive. Here, we disclose the mechanism by which lugdunin rapidly destabilizes the bacterial membrane potential using an in vitro approach. The peptide strongly partitions into lipid compositions resembling Gram-positive bacterial membranes but less in those harboring the eukaryotic membrane component cholesterol. Upon insertion, lugdunin forms hydrogen-bonded antiparallel ß-sheets by the formation of peptide nanotubes, as demonstrated by ATR-FTIR spectroscopy and molecular dynamics simulations. These hydrophilic nanotubes filled with a water wire facilitate not only the translocation of protons but also of monovalent cations as demonstrated by voltage-clamp experiments on black lipid membranes. Collectively, our results provide evidence that the natural fibupeptide lugdunin acts as a peptidic channel that is spontaneously formed by an intricate stacking mechanism, leading to the dissipation of a bacterial cell's membrane potential.

Impact of a simple non-invasive nasal mask device on intraprocedural hypoxemia in overweight individuals undergoing upper gastrointestinal endoscopy with sedation provided by a non-anesthesiologist provider.

BACKGROUND/AIMS: Hypoxemia is a common side effect of propofol sedation during endoscopy. Applying mild positive airway pressure (PAP) using a nasal mask may offer a simple way to reduce such events and optimize the conditions for diagnostic and therapeutic upper gastrointestinal endoscopies. METHODS: We compared overweight patients (body mass index >25 kg/m2) with a nasal PAP mask or standard nasal cannula undergoing upper gastrointestinal endoscopies by non-anesthesiologists who provided propofol sedation. Outcome parameters included the frequency and severity of hypoxemic episodes. RESULTS: We analyzed 102 procedures in 51 patients with nasal PAP masks and 51 controls. Episodes of hypoxemia (oxygen saturation [SpO2] <90% at any time during sedation) occurred in 25 (49.0%) controls compared to 8 (15.7%) patients with nasal PAP masks (p<0.001). Severe hypoxemia (SpO2 <80%) occurred in three individuals (5.9%) in both groups. The mean delta between baseline SpO2 and the lowest SpO2 recorded was significantly decreased among patients with nasal PAP mask compared to controls (3.7 and 8.2 percentage points difference, respectively). There were significantly fewer airway interventions performed in the nasal PAP mask group (15.7% vs. 41.2%, p=0.008). CONCLUSION: Using a nasal PAP mask may be a simple means of increasing patient safety and ease of examination.

Higher in-hospital mortality in SARS-CoV-2 omicron variant infection compared to influenza infection-Insights from the CORONA Germany study.

BACKGROUND: With the emergence of new subvariants, the disease severity of Severe Acute Respiratory Syndrome Coronavirus-2 has attenuated. This study aimed to compare the disease severity in patients hospitalized with omicron variant infection to those with influenza infection. METHODS: We compared data from the multicenter observational, prospective, epidemiological "CORONA Germany" (Clinical Outcome and Risk in hospitalized COVID-19 patients) study on patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 to retrospective data on influenza infection cases from November 2016 to August 2022. Severe Acute Respiratory Syndrome Coronavirus-2 cases were classified as wild-type/delta variant before January 2022, or omicron variant from January 2022 onward. The primary outcome was in-hospital mortality, adjusted for age, gender, and comorbidities. RESULTS: The study included 35,806 patients from 53 hospitals in Germany, including 4,916 patients (13.7%) with influenza infection, 16,654 patients (46.5%) with wild-type/delta variant infection, and 14,236 patients (39.8%) with omicron variant infection. In-hospital mortality was highest in patients with wild-type/delta variant infection (16.8%), followed by patients with omicron variant infection (8.4%) and patients with influenza infection (4.7%). In the adjusted analysis, higher age was the strongest predictor for in-hospital mortality (age 80 years vs. age 50 years: OR 4.25, 95% CI 3.10-5.83). Both, patients with wild-type/delta variant infection (OR 3.54, 95% CI 3.02-4.15) and patients with omicron variant infection (OR 1.56, 95% CI 1.32-1.84) had a higher risk for in-hospital mortality than patients with influenza infection. CONCLUSION: After adjusting for age, gender and comorbidities, patients with wild-type/delta variant infection had the highest risk for in-hospital mortality compared to patients with influenza infection. Even for patients with omicron variant infection, the adjusted risk for in-hospital mortality was higher than for patients with influenza infection. The adjusted risk for in-hospital mortality showed a strong age dependency across all virus types and variants. TRIAL REGISTRATION NUMBER: NCT04659187.

Age-adjusted high-dose chemotherapy followed by autologous stem cell transplantation or conventional chemotherapy with R-MP as first-line treatment in elderly primary CNS lymphoma patients - the randomized phase III PRIMA-CNS trial.

BACKGROUND: Older primary central nervous system lymphoma (PCNSL) patients have an inferior prognosis compared to younger patients because available evidence on best treatment is scarce and treatment delivery is challenging due to comorbidities and reduced performance status. High-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) after high-dose methotrexate (MTX)-based immuno-chemotherapy has become an increasingly used treatment approach in eligible elderly PCNSL patients with promising feasibility and efficacy, but has not been compared with conventional chemotherapy approaches. In addition, eligibility for HCT-ASCT in elderly PCNSL is not well defined. Geriatric assessment (GA) may be helpful in selecting patients for the best individual treatment choice, but no standardized GA exists to date. A randomized controlled trial, incorporating a GA and comparing age-adapted HCT-ASCT treatment with conventional chemotherapy is needed. METHODS: This open-label, multicenter, randomized phase III trial with two parallel arms will recruit 310 patients with newly diagnosed PCNSL > 65 years of age in 40 centers in Germany and Austria. The primary objective is to demonstrate that intensified chemotherapy followed by consolidating HCT-ASCT is superior to conventional chemotherapy with rituximab, MTX, procarbazine (R-MP) followed by maintenance with procarbazine in terms of progression free survival (PFS). Secondary endpoints include overall survival (OS), event free survival (EFS), (neuro-)toxicity and quality of life (QoL). GA will be conducted at specific time points during the course of the study. All patients will be treated with a pre-phase rituximab-MTX (R-MTX) cycle followed by re-assessment of transplant eligibility. Patients judged transplant eligible will be randomized (1:1). Patients in arm A will be treated with 3 cycles of R-MP followed by maintenance therapy with procarbazine for 6 months. Patients in arm B will be treated with 2 cycles of MARTA (R-MTX/AraC) followed by busulfan- and thiotepa-based HCT-ASCT. DISCUSSION: The best treatment strategy for elderly PCNSL patients remains unknown. Treatments range from palliative to curative but more toxic therapies, and there is no standardized measure to select patients for the right treatment. This randomized controlled trial will create evidence for the best treatment strategy with the focus on developing a standardized GA to help define eligibility for an intensive treatment approach. TRIAL REGISTRATION: German clinical trials registry DRKS00024085 registered March 29, 2023.

Liver surgery in the 2020s: ante-situm and in-situ resection are still indicated - A single-center study.

BACKGROUND: Tumor infiltration of the hepatic outflow comprising all three hepatic veins and the inferior vena cava remains a surgical challenge. Liver resection under total vascular exclusion with or without extracorporeal bypass has been described as a therapeutic option for these tumors. Here, we present our experience with these complex surgical methods. METHODS: We searched our database for patients treated with an in-situ or ante-situm liver resection (ISR and ASR, respectively) with extracorporeal bypass. We collected demographic and perioperative data. RESULTS: From January 2010 to December 2021, we performed 2122 liver resections. Nine patients were treated with ASR and five were treated with ISR. Out of these 14 patients, six had colorectal liver metastases, six had cholangiocarcinoma, and two had non-colorectal liver metastases. The median operative time and bypass time in all patients were 536.5 and 150 min, respectively. Compared with ISR, ASR required a longer operative time (ASR 586 min and ISR 495 min) and a longer bypass time (ASR 155 min and ISR 122 min). Morbidity (Clavien-Dindo grade > 3A adverse events) occurred in 78.5% of patients. 90-day postoperative mortality was 7%. Median overall survival was 33 months. Seven patients experienced recurrence. In these patients, median disease-free survival was 9 months. CONCLUSION: Resection of tumors infiltrating the hepatic outflow poses a high risk for patients. However, with rigorous selection and an experienced perioperative team, these patients can be treated surgically with reasonable oncological outcomes.

Distinct Lugdunins from a New Efficient Synthesis and Broad Exploitation of Its MRSA-Antimicrobial Structure.

A new solid-phase peptide synthesis and bioprofiling of the antimicrobial activity of lugdunin, a fibupeptide, enable a comprehensive structure-activity relationship (SAR) study (MRSA Staphylococcus aureus). Distinct lugdunin analogues with variation of the three important amino acids Val2, Trp3, and Leu4 are readily available based on the established high-output synthesis. This efficient synthesis concept takes advantage of the presynthesized thiazolidine building block. To gain further knowledge of SAR, d-Val2, and d-Leu4 were replaced with aliphatic amino acids. For l-Trp3 derivatization, a set of non-natural aromatic amino acids with manifold substitution and annulation patterns precisely shows structural imperatives, starting from the exchange of d-Val6 → d-Trp6 with a 2-fold improved biological activity. d-Trp6-lugdunin analogues with additional variation of d-Val2 and d-Leu4 residues were designed and synthesized followed by antimicrobial profiling. For the first time, these SAR studies deliver valuable information on the tolerance of other amino acids to d-Val2, l-Trp3, and d-Leu4 in the sequence of lugdunin.

[Inhalation of Flue Gases - Carbon Monoxide Intoxication]. / Vergiftung durch Rauchgase ­ Kohlenmonoxidintoxikation.

Most intoxications caused by inhalation are due to carbon monoxide (CO). Usually the reasons are fires in buildings from which people cannot escape quickly enough, open fire places or carbon monoxide emissions from combustion plants. In Germany, there are more than 4000 intoxications and over 600 fatalities resulting from CO poisining every year. Although there is a general awareness of the risks associated with CO, the specific risks and especially methods of protection are not sufficiently known.

Secretion of and Self-Resistance to the Novel Fibupeptide Antimicrobial Lugdunin by Distinct ABC Transporters in Staphylococcus lugdunensis.

Lugdunin is the first reported nonribosomally synthesized antibiotic from human microbiomes. Its production by the commensal Staphylococcus lugdunensis eliminates the pathogen Staphylococcus aureus from human nasal microbiomes. The cycloheptapeptide lugdunin is the founding member of the new class of fibupeptide antibiotics, which have a novel mode of action and represent promising new antimicrobial agents. How S. lugdunensis releases and achieves producer self-resistance to lugdunin has remained unknown. We report that two ABC transporters encoded upstream of the lugdunin-biosynthetic operon have distinct yet overlapping roles in lugdunin secretion and self-resistance. While deletion of the lugEF transporter genes abrogated most of the lugdunin secretion, the lugGH transporter genes had a dominant role in resistance. Yet all four genes were required for full-level lugdunin resistance. The small accessory putative membrane protein LugI further contributed to lugdunin release and resistance levels conferred by the ABC transporters. Whereas LugIEFGH also conferred resistance to lugdunin congeners with inverse structures or with amino acid exchange at position 6, they neither affected the susceptibility to a lugdunin variant with an exchange at position 2 nor to other cyclic peptide antimicrobials such as daptomycin or gramicidin S. The obvious selectivity of the resistance mechanism raises hopes that it will not confer cross-resistance to other antimicrobials or to optimized lugdunin derivatives to be used for the prevention and treatment of S. aureus infections.

Synthetic Lugdunin Analogues Reveal Essential Structural Motifs for Antimicrobial Action and Proton Translocation Capability.

Lugdunin, a novel thiazolidine cyclopeptide, exhibits micromolar activity against methicillin-resistant Staphylococcus aureus (MRSA). For structure-activity relationship (SAR) studies, synthetic analogues obtained from alanine and stereo scanning as well as peptides with modified thiazolidine rings were tested for antimicrobial activity. The thiazolidine ring and the alternating d- and l-amino acid backbone are essential. Notably, the non-natural enantiomer displays equal activity, thus indicating the absence of a chiral target. The antibacterial activity strongly correlates with dissipation of the membrane potential in S. aureus. Lugdunin equalizes pH gradients in artificial membrane vesicles, thereby maintaining membrane integrity, which demonstrates that proton translocation is the mode of action (MoA). The incorporation of extra tryptophan or propargyl moieties further expands the diversity of this class of thiazolidine cyclopeptides.

Prehospital non-invasive ventilation in acute respiratory failure is justified even if the distance to hospital is short.

AIMS: Evaluation of the efficacy of prehospital non-invasive ventilation (NIV) in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) and cardiogenic pulmonary edema (CPE). MATERIAL AND METHODS: Consecutive patients who were prehospitally treated by Emergency Physicians using NIV were prospectively included. A step-by-step approach escalating NIV-application from continuous positive airway pressure (CPAP) to continuous positive airway pressure supplemented by pressure support (CPAP-ASB) and finally bilevel inspiratory positive airway pressure (BIPAP) was used. Patients were divided into two groups according to the prehospital NIV-treatment-time (NIV-group 1: ≤15 min, NIV-group 2: >15 min). In addition, a historic control group undergoing standard care was created. Endpoints were heart rate, peripheral oxygen saturation, breathing rate, systolic blood pressure, and a dyspnea score. RESULTS: A total of 99 patients were analyzed (NIV-group 1: n = 41, NIV-group 2: n = 58). The control group consisted of 30 patients. The majority of NIV-patients (90%) received CPAP-ASB, while CPAP without ASB was conducted in 8% and BIPAP-ventilation in 2% of all cases. Technical application of NIV lasted 6.1 ±â€¯3.8 min. NIV-treatment-time was as follows: NIV-group 1: 13.1 ±â€¯3.2 min, NIV-group 2: 22.8 ±â€¯5.9 min. Differences between baseline- and hospital admission values of all endpoints showed significantly better improvement in NIV-groups compared to the control group (p < 0.001). The stabilizing effect of NIV in terms of vital parameters was comparable between both NIV-groups, independent of the duration of treatment (n.s.). CONCLUSION: Prehospital NIV-treatment should be performed in patients with COPD-exacerbation and CPE, even if the distance between emergency scene and hospital is short.

Development of A Low-Cost FPGA-Based Measurement System for Real-Time Processing of Acoustic Emission Data: Proof of Concept Using Control of Pulsed Laser Ablation in Liquids.

Today, the demand for continuous monitoring of valuable or safety critical equipment is increasing in many industrial applications due to safety and economical requirements. Therefore, reliable in-situ measurement techniques are required for instance in Structural Health Monitoring (SHM) as well as process monitoring and control. Here, current challenges are related to the processing of sensor data with a high data rate and low latency. In particular, measurement and analyses of Acoustic Emission (AE) are widely used for passive, in-situ inspection. Advantages of AE are related to its sensitivity to different micro-mechanical mechanisms on the material level. However, online processing of AE waveforms is computationally demanding. The related equipment is typically bulky, expensive, and not well suited for permanent installation. The contribution of this paper is the development of a Field Programmable Gate Array (FPGA)-based measurement system using ZedBoard devlopment kit with Zynq-7000 system on chip for embedded implementation of suitable online processing algorithms. This platform comprises a dual-core Advanced Reduced Instruction Set Computer Machine (ARM) architecture running a Linux operating system and FPGA fabric. A FPGA-based hardware implementation of the discrete wavelet transform is realized to accelerate processing the AE measurements. Key features of the system are low cost, small form factor, and low energy consumption, which makes it suitable to serve as field-deployed measurement and control device. For verification of the functionality, a novel automatically realized adjustment of the working distance during pulsed laser ablation in liquids is established as an example. A sample rate of 5 MHz is achieved at 16 bit resolution.

Association between Weather-Related Factors and Cardiac Arrest of Presumed Cardiac Etiology: A Prospective Observational Study Based on Out-of-Hospital Care Data.

OBJECTIVE: The objective of this study was to determine the association between weather-related factors and out-of-hospital cardiac arrest (OHCA) of presumed cardiac etiology. METHODS: This was a prospective observational study performed in a prehospital setting. Data from the Emergency Medical Service in Hamburg (Germany) and data from the local weather station were evaluated over a 5-year period. Weather data (temperature, humidity, air pressure, wind speed) were obtained every minute and matched with the associated rescue mission data. Lowess-Regression analysis was performed to assess the relationship between the above-mentioned weather-related factors and OHCA of presumed cardiac etiology. Additionally, varying measuring-ranges were defined for each weather-related factor in order to compare them with each other with regard to the probability of occurrence of OHCA. RESULTS: During the observation period 1,558 OHCA with presumed cardiac etiology were registered (age: 67 ± 19 yrs; 62% male; hospital admission: 37%; survival to hospital discharge: 6.7%). Compared to moderate temperatures (5 - 25°C), probability of OHCA-occurrence increased significantly at temperatures above 25°C (p = 0.028) and below 5°C p = 0.011). Regarding air humidity, probability of OHCA-occurrence increased below a threshold-value of 75% compared to values above this cut-off (p = 0.006). Decreased probability was seen at moderate atmospheric pressure (1000 hPa - 1020 hPa), whereas increased probability was seen above 1020 hPa (p = 0.023) and below 1000 hPa (p = 0.035). Probability of OHCA-occurrence increased continuously with increasing wind speed (p < 0.001). CONCLUSIONS: There are associations between several weather-related factors such as temperature, humidity, air pressure, and wind speed, and occurrence of OHCA of presumed cardiac etiology. Particularly dangerous seem to be cold weather, dry air and strong wind.

[First therapy of decompression injuries]. / Der Tauchunfall - Präklinische und klinische Behandlungsstrategien.

The diving accident is a rare incident for an emergency physician which requires special physical and patho-physiological knowledge. With increasing recreational activities and the fascination of diving also for older persons diving accidents are expected to occur more often. There can be several reasons for diving accidents such as the ignorance of the physics of diving, a trauma under water as well as internistical illnesses like heart attach, stroke or hypoglycaemia. The therapy of the underlying illness should not be left aside while dealing with the patient. The careful rescue and the immobilisation are most important for the initial therapy. The patient should receive oxygen, if possible via a demand valve, until a hyperbaric chamber is reached. There is no specific medical therapy for decompression illness. It is very important that a pre-information is sent to the closest hyperbaric chamber as soon as possible since often the chamber needs some time to be properly prepared for usage. In order to receive information regarding the depth where the diving incident occured, the duration of the diving trip and the decompression stops, it is important to secure the diving computer of the victim for the hyperbaric chamber. Also outside diving, decompression illness can occur, for example working in a tunnel under hyperbaric conditions. These accidents have to be treated according to the same guidelines.

[First therapy of drowning accident]. / Ertrinkungsunfälle - Präklinische und klinische Behandlungsstrategien.

Rescue and medical care of people in a drowning accident is a rather rare incident which still needs special attention. The rescue process can be technically challenging and only a well experienced team will be able to act professionally without any time loss. At a first step all team members have to protect themselves. Especially close collaboration of technical and medical rescue teams are of high significance and should be part of future exercises. Hypothermic persons should be protected from further cooling and gently rescued in a horizontally way. If a patient has no circulation continued cardiopulmonary resuscitation and immediate transport as soon as possible to the nearest hospital with an extracorporeal rewarming device is recommended. To avoid any time loss it is essential that the respective hospital is informed immediately and the fastest mode of transport selected. Astonishing cases show that this procedure is very promising even after long time submersion.

Transscalene brachial plexus block: a new posterolateral approach for brachial plexus block.

Depending on the approach to the upper brachial plexus, severe complications have been reported. We describe a novel posterolateral approach for brachial plexus block which, from an anatomical and theoretical point of view, seems to offer advantages. Twenty-seven patients were scheduled to undergo elective major surgery of the upper arm or shoulder using this new transscalene brachial plexus block. The success rate was 85.2% for surgery. Two patients required additional analgesia with IV sufentanil. In two others, regional anesthesia was inadequate. The side effects of this technique included reversible recurrent laryngeal nerve blockade in two patients and a reversible Horner syndrome in one patient. Further studies are needed to compare the transscalene brachial plexus block with other approaches to the brachial plexus.