LINAS-Score: prognostic model for mortality assessment in patients with cirrhotic liver and infected ascites.

BACKGROUND AND AIM: Patients with liver cirrhosis often face a grave threat from infected ascites (IA). However, a well-established prognostic model for this complication has not been established in routine clinical practice. Therefore, we aimed to assess mortality risk in patients with liver cirrhosis and IA. METHODS: We conducted a retrospective study across three tertiary hospitals, enrolling 534 adult patients with cirrhotic liver and IA, comprising 465 with spontaneous bacterial peritonitis (SBP), 34 with bacterascites (BA), and 35 with secondary peritonitis (SP). To determine the attributable mortality risk linked to IA, these patients were matched with 122 patients with hydropic decompensated liver cirrhosis but without IA. Clinical, laboratory, and microbiological parameters were assessed for their relation to mortality using univariable analyses and a multivariable random forest model (RFM). Least absolute shrinkage and selection operator (Lasso) regression model was used to establish an easy-to-use mortality prediction score. RESULTS: The in-hospital mortality risk was highest for SP (39.0%), followed by SBP (26.0%) and BA (25.0%). Besides illness severity markers, microbiological parameters, such as Candida spp., were identified as the most significant indicators for mortality. The Lasso model determined 15 parameters with corresponding scores, yielding good discriminatory power (area under the receiver operating characteristics curve = 0.89). Counting from 0 to 83, scores of 20, 40, 60, and 80 corresponded to in-hospital mortalities of 3.3%, 30.8%, 85.2%, and 98.7%, respectively. CONCLUSION: We developed a promising mortality prediction score for IA, highlighting the importance of microbiological parameters in conjunction with illness severity for assessing patient outcomes.

Nanoporous Gold Thin Films as Substrates to Analyze Liquids by Cryo-atom Probe Tomography.

Cryogenic atom probe tomography (cryo-APT) is being developed to enable nanoscale compositional analyses of frozen liquids. Yet, the availability of readily available substrates that allow for the fixation of liquids while providing sufficient strength to their interface is still an issue. Here, we propose the use of 1-2-µm-thick binary alloy film of gold-silver sputtered onto flat silicon, with sufficient adhesion without an additional layer. Through chemical dealloying, we successfully fabricate a nanoporous substrate, with an open-pore structure, which is mounted on a microarray of Si posts by lift-out in the focused-ion beam system, allowing for cryogenic fixation of liquids. We present cryo-APT results obtained after cryogenic sharpening, vacuum cryo-transfer, and analysis of pure water on the top and inside the nanoporous film. We demonstrate that this new substrate has the requisite characteristics for facilitating cryo-APT of frozen liquids, with a relatively lower volume of precious metals. This complete workflow represents an improved approach for frozen liquid analysis, from preparation of the films to the successful fixation of the liquid in the porous network, to cryo-APT.

The Roles of Impurities and Surface Area on Thermal Stability and Oxidation Resistance of BN Nanoplatelets.

This study considers the influence of purity and surface area on the thermal and oxidation properties of hexagonal boron nitride (h-BN) nanoplatelets, which represent crucial factors in high-temperature oxidizing environments. Three h-BN nanoplatelet-based materials, synthesized with different purity levels and surface areas (~3, ~56, and ~140 m2/g), were compared, including a commercial BN reference. All materials were systematically analyzed by various characterization techniques, including gas pycnometry, scanning electron microscopy, X-ray diffraction, Fourier-transform infrared radiation, X-ray photoelectron spectroscopy, gas sorption analysis, and thermal gravimetric analysis coupled with differential scanning calorimetry. Results indicated that the thermal stability and oxidation resistance of the synthesized materials were improved by up to ~13.5% (or by 120 °C) with an increase in purity. Furthermore, the reference material with its high purity and low surface area (~4 m2/g) showed superior performance, which was attributed to the minimized reactive sites for oxygen diffusion due to lower surface area availability and fewer possible defects, highlighting the critical roles of both sample purity and accessible surface area in h-BN thermo-oxidative stability. These findings highlight the importance of focusing on purity and surface area control in developing BN-based nanomaterials, offering a path to enhance their performance in extreme thermal and oxidative conditions.

Receptor transfer between immune cells by autoantibody-enhanced, CD32-driven trogocytosis is hijacked by HIV-1 to infect resting CD4 T cells.

Immune cell phenotyping frequently detects lineage-unrelated receptors. Here, we report that surface receptors can be transferred from primary macrophages to CD4 T cells and identify the Fcγ receptor CD32 as driver and cargo of this trogocytotic transfer. Filamentous CD32+ nanoprotrusions deposit distinct plasma membrane patches onto target T cells. Transferred receptors confer cell migration and adhesion properties, and macrophage-derived membrane patches render resting CD4 T cells susceptible to infection by serving as hotspots for HIV-1 binding. Antibodies that recognize T cell epitopes enhance CD32-mediated trogocytosis. Such autoreactive anti-HIV-1 envelope antibodies can be found in the blood of HIV-1 patients and, consistently, the percentage of CD32+ CD4 T cells is increased in their blood. This CD32-mediated, antigen-independent cell communication mode transiently expands the receptor repertoire and functionality of immune cells. HIV-1 hijacks this mechanism by triggering the generation of trogocytosis-promoting autoantibodies to gain access to immune cells critical to its persistence.

Herpes Simplex Virus Bronchopneumonitis in Critically Ill Patients with Acute on Chronic Liver Failure: A Retrospective Analysis.

(1) Background: Critically ill patients are frequently diagnosed with pulmonary Herpes simplex virus-1 (HSV) reactivation, which then can lead to HSV bronchopneumonitis and is associated with higher mortality and longer mechanical ventilation. For the particular subgroup of critically ill patients with acute on chronic liver failure (ACLF), however, the impact of HSV reactivation is unknown. We investigated the impact of HSV reactivation in these patients. (2) Methods: We conducted a retrospective analysis, evaluating data from 136 mechanically ventilated patients with ACLF between January 2016 and August 2023. Clinical parameters were compared between patients with and without HSV bronchopneumonitis. (3) Results: 10.3% were diagnosed with HSV bronchopneumonitis (HSV group). Mortality did not differ between the HSV and non-HSV group (85.7% vs. 75.4%, p = 0.52). However, the clinical course in the HSV group was more complicated as patients required significantly longer mechanical ventilation (14 vs. 21 days, p = 0.04). Furthermore, fungal superinfections were significantly more frequent in the HSV group (28.6% vs. 6.6%, p = 0.006). (4) Conclusions: Mortality of critically ill patients with ACLF with HSV bronchopneumonitis was not increased in spite of the cirrhosis-associated immune dysfunction. Their clinical course, however, was more complicated with significantly longer mechanical ventilation.

Perspective: The Impact of Fasting and Caloric Restriction on Neurodegenerative Diseases in Humans.

Neurodegenerative diseases (NDs) are characterized by the progressive functional and structural denaturation of neurons in the central and peripheral nervous systems. Despite the wide range of genetic predispositions, the increased emergence of these disorders has been associated with a variety of modifiable risk factors, including lifestyle factors. Diet has been shown to influence cognitive alterations in the elderly population with age-related brain pathologies, and specific dietary interventions might, therefore, confer preservatory protection to neural structures. Although Mediterranean and ketogenic diets have been studied, no clear guidelines have been implemented for the prevention or treatment of ND in clinical practice. Murine models have shown that intermittent fasting and caloric restriction (CR) can counteract disease processes in various age-related disorders, including NDs. The objective of this perspective is to provide a comprehensive, comparative overview of the available primary intervention studies on fasting and CR in humans with ND and to elucidate possible links between the mechanisms underlying the effects of fasting, CR, and the neuropathology of ND. We also included all currently available studies in older adults (with and without mild cognitive impairment) in which the primary endpoint was cognitive function to provide further insights into the feasibility and outcomes of such interventions. Overall, we conclude that nutritional intervention trials focusing on fasting and CR in humans with ND have been neglected, and more high-quality studies, including longitudinal clinical intervention trials, are urgently needed to elucidate the underlying immune-metabolic mechanisms in diet and ND.

Compositional defects in a MoAlB MAB phase thin film grown by high-power pulsed magnetron sputtering.

Various compositional defects such as Mo3Al2B4, Mo4Al3B4, Mo6Al5B6 and Al3Mo, together with MoB MBene, are observed to be coexisting in a MoAlB MAB phase thin film grown at 800 °C by high-power pulsed magnetron sputtering. An overall film composition of Mo0.29Al0.33B0.38 is measured by time-of-flight elastic recoil detection analysis. The concurrent formation of these compositional defects in the MoAlB matrix occurs during the synthesis without using any chemical reagent, and their coexistence with the MAB phase is thermodynamically possible, as elucidated by density functional theory simulations. These defect phases are imaged at the atomic scale by aberration-corrected scanning transmission electron microscopy. A rough estimation of defect populations of 0.073, 0.037, 0.042 and 0.039 nm-1 for Mo3Al2B4, Mo4Al3B4, Mo6Al5B6 and Al3Mo compositional defects, respectively, is performed within the MoAlB matrix. The calculated energies of formation reveal that the Mo4Al3B4 and Mo6Al5B6 defect phases form spontaneously in the MoAlB host matrix, while the energy barrier towards the formation of the metastable Mo3Al2B4 phase is approx. 20 meV per atom. The small magnitude of this barrier is easily overcome during vapor phase condensation, and the surface diffusion of adatoms during deposition leads to local compositional variations and the coexistence of the defect phases in the host matrix. Additionally, at grain boundaries, the presence of MoB MBene is observed, with an interlayer spacing between two Mo2B2 units increasing up to ∼50% compared to the pristine MoAlB phase.

Are enterococcal bloodstream infections an independent risk factor for a poorer 5-year survival or just a marker for severity of illness?-The Munich multicentric enterococci cohort.

IMPORTANCE: The present study provides a substantial contribution to literature, showing that patients with enterococcal bloodstream infections (BSI) have a lower survival rate than those with Escherichia coli (E. coli) bloodstream infections after adjusting for 17 limiting prognostic factors and excluding patients with a limited life expectancy [metastatic tumor disease, Charlson Comorbidity Index (CCI) (greater than or equal to) 5]. This difference in the 5-year long-term survival was mainly driven by Enterococcus faecium (ECFM) bloodstream infections, with vancomycin resistance not being a significant contributing factor. Our findings imply that E. faecium bloodstream infections seem to be an independent risk factor for poor long-term outcomes. As such, future research should confirm this relationship and prioritize investigating its causality through prospective studies.

Influence of a Structured Microbiological Endotracheal Monitoring Program on the Outcome of Critically Ill COVID-19 Patients: An Observational Study.

BACKGROUND: In past influenza pandemics and the current COVID-19 pandemic, bacterial endotracheal superinfections are a well-known risk factor for higher morbidity and mortality. The goal of this study was to investigate the influence of a structured, objective, microbiological monitoring program on the prognosis of COVID-19 patients with mechanical ventilation. METHODS: A structured microbiological monitoring program (at intubation, then every 3 days) included collection of endotracheal material. Data analysis focused on the spectrum of bacterial pathogens, mortality, as well as intensive care unit (ICU), hospital, and mechanical ventilation duration. RESULTS: A total of 29% of the patients showed bacterial coinfection at the time of intubation, and within 48 h, 56% developed ventilator-associated pneumonia (VAP). Even though patients with VAP had significantly longer ICU, hospital, and mechanical ventilation durations, there was no significant difference in mortality between patients with VAP pneumonia and patients without bacterial infection. CONCLUSION: VAP is a common complication in COVID-19 patients. In contrast to already published studies, in our study implementing a structured microbiological monitoring program, COVID-19 patients with bacterial coinfection or VAP did not show higher mortality. Thus, a standardized, objective, microbiological screening can help detect coinfection and ventilator-associated infections, refining anti-infective therapy and positively influencing patient outcomes.

Evaluation of Self-Collected Versus Health Care Professional (HCP)-Performed Sampling and the Potential Impact on the Diagnostic Results of Asymptomatic Sexually Transmitted Infections (STIs) in High-Risk Individuals.

Sexually transmitted infections (STIs) are increasing among men who have sex with men (MSM). Screening can improve the detection and outcome of asymptomatic STIs in high-risk populations. Self-sampling may be a resource-optimized strategy; however, its diagnostic reliability compared to testing by healthcare professionals (HCPs) requires further investigation. In this prospective, multicenter cohort study in a high-income country, asymptomatic MSM with a sexual risk profile for STIs were included. Sequential swabs for STI nucleic acid-based diagnosis of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) were performed after randomization, either through self-sampling or HCP-performed sampling. Baseline demographic information, sexual risk behavior, and acceptance and feedback on self-sampling were recorded using an electronic questionnaire. Out of 236 asymptomatic MSM, 47 individuals (19.9%) tested positive for CT and/or NG through self- or HCP-performed sampling. For CT, the sensitivity was 93.3% for both sampling methods, while for NG, it was 90.0% for self-sampling and 95.0% for HCP-performed sampling. Our study demonstrates that self-sampling for asymptomatic STIs has a comparable diagnostic outcome to HCP-performed sampling, with high acceptance in high-risk MSM.

Improving Spatial and Elemental Associations in Analytical Field Ion Microscopy.

Chemically resolved atomic resolution imaging can give fundamental information about material properties. However, even today, a technique capable of such achievement is still only an ambition. Here, we take further steps in developing the analytical field ion microscopy (aFIM), which combines the atomic spatial resolution of field ion microscopy (FIM) with the time-of-flight spectrometry of atom probe tomography (APT). To improve the performance of aFIM that are limited in part by a high level of background, we implement bespoke flight path time-of-flight corrections normalized by the ion flight distances traversed in electrostatic simulations modeled explicitly for an atom probe chamber. We demonstrate effective filtering in the field evaporation events upon spatially and temporally correlated multiples, increasing the mass spectrum's signal-to-background. In an analysis of pure tungsten, mass peaks pertaining to individual W isotopes can be distinguished and identified, with the signal-to-background improving by three orders of magnitude over the raw data. We also use these algorithms for the analysis of a CoTaB amorphous film to demonstrate application of aFIM beyond pure metals and binary alloys. These approaches facilitate elemental identification of the FIM-imaged surface atoms, making analytical FIM more precise and reliable.

Protocol for a multicentre cross-sectional, longitudinal ambulatory clinical trial in rheumatoid arthritis and Parkinson's disease patients analysing the relation between the gut microbiome, fasting and immune status in Germany (ExpoBiome).

INTRODUCTION: Chronic inflammatory diseases like rheumatoid arthritis (RA) and neurodegenerative disorders like Parkinson's disease (PD) have recently been associated with a decreased diversity in the gut microbiome, emerging as key driver of various diseases. The specific interactions between gut-borne microorganisms and host pathophysiology remain largely unclear. The microbiome can be modulated by interventions comprising nutrition.The aim of our clinical study is to (1) examine effects of prolonged fasting (PF) and time-restricted eating (TRE) on the outcome parameters and the immunophenotypes of RA and PD with (2) special consideration of microbial taxa and molecules associated with changes expected in (1), and (3) identify factors impacting the disease course and treatment by in-depth screening of microorganisms and molecules in personalised HuMiX gut-on-chip models, to identify novel targets for anti-inflammatory therapy. METHODS AND ANALYSIS: This trial is an open-label, multicentre, controlled clinical trial consisting of a cross-sectional and a longitudinal study. A total of 180 patients is recruited. For the cross-sectional study, 60 patients with PD, 60 patients with RA and 60 healthy controls are recruited at two different, specialised clinical sites. For the longitudinal part, 30 patients with PD and 30 patients with RA undergo 5-7 days of PF followed by TRE (16:8) for a period of 12 months. One baseline visit takes place before the PF intervention and 10 follow-up visits will follow over a period of 12 months (April 2021 to November 2023). ETHICS AND DISSEMINATION: Ethical approval was obtained to plan and conduct the trial from the institutional review board of the Charité-Universitätsmedizin Berlin (EA1/204/19), the ethics committee of the state medical association (Landesärztekammer) of Hessen (2021-2230-zvBO) and the Ethics Review Panel (ERP) of the University of Luxembourg (ERP 21-001 A ExpoBiome). The results of this study will be disseminated through peer-reviewed publications, scientific presentations and social media. TRIAL REGISTRATION NUMBER: NCT04847011.

Prevalence, characteristics and challenges of late HIV diagnosis in Germany: an expert narrative review.

PURPOSE: We aimed to review the landscape of late HIV diagnosis in Germany and discuss persisting and emerging barriers to earlier diagnosis alongside potential solutions. METHODS: We searched PubMed for studies informing the prevalence, trends, and factors associated with late HIV diagnosis in Germany. Author opinions were considered alongside relevant data. RESULTS: In Germany, older individuals, heterosexuals, and migrants living with HIV are more likely to be diagnosed late. The rate of late diagnosis in men who have sex with men (MSM), however, continues to decrease. Indicator conditions less often prompt HIV testing in women and non-MSM. During the COVID-19 pandemic, the absolute number of late diagnoses fell in Germany, but the overall proportion increased, probably reflecting lower HIV testing rates. The Ukraine war and subsequent influx of Ukrainians living with HIV may have substantially increased undiagnosed HIV cases in Germany. Improved indicator testing (based on unbiased assessments of patient risk) and universal testing could help reduce late diagnoses. In patients who receive a late HIV diagnosis, rapid treatment initiation with robust ART regimens, and management and prevention of opportunistic infections, are recommended owing to severely compromised immunity and increased risks of morbidity and mortality. CONCLUSION: Joint efforts are needed to ensure that UNAIDS 95-95-95 2030 goals are met in Germany. These include greater political will, increased funding of education and testing campaigns (from government institutions and the pharmaceutical industry), continued education about HIV testing by HIV experts, and broad testing support for physicians not routinely involved in HIV care.

Seroconversion rate of SARS-CoV-2 IgG antibodies and dating behaviour in HIV-PrEP users in a German metropolis during the COVID-19 pandemic.

BACKGROUND: At the beginning of the COVID-19 pandemic, when mortality was high, social distance was the only option to prevent transmission of SARS-CoV-2 and prohibit uncontrolled spreading. As the impact of social distancing on sexual behavior was unclear, we aimed to assess the influence of sexual risk behavior on SARS-CoV-2 seroconversion in HIV pre-exposition prophylaxis (PrEP) users after declaration of the pandemic. METHODS: Prospective study on SARS-CoV-2 IgG-antibody seroconversion rate over time in men having sex with men (MSM) using PrEP at a single tertiary university hospital in Munich, Germany, during quarterly (Q) routine HIV-PrEP visits over 1 year per participant (May 2020 - September 2021). Seroconversion was defined as at least one positive anti-nucleocapsid (anti-N) SARS-CoV-2 IgG antibody test as surrogate for past infection. In addition, sexually transmitted infections (STIs), personal estimated risk behavior and sexual contacts were assessed. RESULTS: Seroconversion rate during the full observation period was 7.3% (9/124 subjects) by September 2021. Percentage of subjects with symptomatic STIs (T. pallidum, N. gonorrhoeae, C. trachomatis and M. genitalium) was 18.7% in Q3-20, 8.1% in Q4-20, 11.1% in Q1-21, 11.6% in Q2-21 and 9.5% in Q3-21. Perception of subjective threat of SARS-CoV-2 infection and adequacy of preventive measures decreased during the observation period. However, self-reported sex behavior remained stable during the observation period. CONCLUSIONS: Our cohort showed low proportion of PrEP-users with anti-N IgG by September 2021, comparable to the local incidence. Sexual behavior in this cohort did not change, despite local recommendations for social distancing.

Lower gastric sensitivity in quiescent inflammatory bowel disease than in irritable bowel syndrome.

OBJECTIVE: Visceral hypersensitivity is considered a key symptom in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), both of which seriously affect health-related quality of life (HrQoL). Previous findings are mostly based on invasive procedures that may interfere with the assessment of visceral perception. The current study, therefore, investigates whether IBD and IBS are characterized by altered perception of 'natural' gastric distensions ('interoception'). METHODS: Twenty IBD patients in remission (13 Crohn's disease, 7 ulcerative colitis), 12 IBS patients, and 20/12 matched healthy control (HC) individuals, respectively, underwent the water load test, in which they could drink ad libitum until the subjective thresholds of satiation (stage 1) and fullness (stage 2) were reached. Gastric motility was assessed using electrogastrography. RESULTS: IBD patients drank significantly more water until satiation than IBS patients, whereas no differences between patients and HC groups were observed. Electrogastrographic patterns were comparable between groups, suggesting no pathologies in gastric motility in IBD or IBS. The amount of water consumed until satiation negatively correlated with HrQoL related to bowel symptoms in IBD patients, but was positively associated with emotional well-being in IBS patients. CONCLUSION: Our findings implicate relative gastric hypersensitivity in IBS, and relative hyposensitivity in IBD patients, which are both related to specific HrQoL aspects.

Englerin A Inhibits T-Type Voltage-Gated Calcium Channels at Low Micromolar Concentrations.

Englerin A (EA) is a potent agonist of tetrameric transient receptor potential canonical (TRPC) ion channels containing TRPC4 and TRPC5 subunits. TRPC proteins form cation channels that are activated by plasma membrane receptors. They convert extracellular signals such as angiotensin II into cellular responses, whereupon Na+ and Ca2+ influx and depolarization of the plasma membrane occur. Via depolarization, voltage-gated Ca2+ (CaV) channels can be activated, further increasing Ca2+ influx. We investigated the extent to which EA also affects the functions of CaV channels using the high-voltage-activated L-type Ca2+ channel CaV1.2 and the low-voltage-activated T-type Ca2+ channels CaV3.1, CaV3.2, and CaV3.3. After expression of cDNAs in human embryonic kidney (HEK293) cells, EA inhibited currents through all T-type channels at half-maximal inhibitory concentrations (IC50) of 7.5 to 10.3 µM. In zona glomerulosa cells of the adrenal gland, angiotensin II-induced elevation of cytoplasmic Ca2+ concentration leads to aldosterone release. We identified transcripts of low- and high-voltage-activated CaV channels and of TRPC1 and TRPC5 in the human adrenocortical (HAC15) zona glomerulosa cell line. Although no EA-induced TRPC activity was measurable, Ca2+ channel blockers distinguished T- and L-type Ca2+ currents. EA blocked 60% of the CaV current in HAC15 cells and T- and L-type channels analyzed at -30 mV and 10 mV were inhibited with IC50 values of 2.3 and 2.6 µM, respectively. Although the T-type blocker Z944 reduced basal and angiotensin II-induced 24-hour aldosterone release, EA was not effective. In summary, we show here that EA blocks CaV1.2 and T-type CaV channels at low-micromolar concentrations. SIGNIFICANCE STATEMENT: In this study we showed that englerin A (EA), a potent agonist of tetrameric transient receptor potential canonical (TRPC)4- or TRPC5-containing channels and currently under investigation to treat certain types of cancer, also inhibits the L-type voltage-gated Ca2+ (CaV) channel CaV1.2 and the T-type CaV channels CaV3.1, CaV3.2, and CaV3.3 channels at low micromolar concentrations.

Convective Flow Redistribution of Oxygen by Laser Melting of a Zr-Based Amorphous Alloy.

Oxygen impurities play a crucial role in the glass-forming ability and crystallisation behaviour of metallic glasses. In the present work, single laser tracks were produced on Zr59.3-xCu28.8 Al10.4Nb1.5Ox substrates (x = 0.3, 1.3) to study the redistribution of oxygen in the melt pool under laser melting, which provides the basis for laser powder bed fusion additive manufacturing. Since such substrates are commercially not available, they were fabricated by arc melting and splat quenching. X-ray diffraction revealed that the substrate with 0.3 at.% oxygen was X-ray amorphous, while the substrate with 1.3 at.% oxygen was partially crystalline. Hence, it is evident that the oxygen content affects the crystallisation kinetics. Subsequently, single laser tracks were produced on the surface of these substrates, and the melt pools attained from the laser processing were characterised by atom probe tomography and transmission electron microscopy. Surface oxidation and subsequent convective flow redistribution of oxygen by laser melting were identified as causes of the presence of CuOx and crystalline ZrO nanoparticles in the melt pool. Bands of ZrO likely originate from surface oxides that were moved deeper into the melt pool by convective flow. The findings presented here highlight the influence of oxygen redistribution from the surface into the melt pool during laser processing.