Search

Luciana Mascarenhas Fonseca,1,2,* Juliana Janeiro Schmidt,3,* Frank J Snoek,4 Ruth S Weinstock,5 Naomi Chaytor,1 Heather Stuckey,6 Christopher M Ryan,7 Eelco van Duinkerken3,4 1Department of Community and Behavioral Health, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA; 2Programa Terceira Idade (PROTER, Old Age Research Group), Department and Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, Brazil; 3Post-Graduate Program in Neurology, Universidade Federal Do Estado Do Rio de Janeiro, Rio de Janeiro, Brazil; 4Department of Medical Psychology, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, the Netherlands; 5Department of Medicine, Upstate Medical University, Syracuse, NY, USA; 6Department of Medicine, Penn State University College of Medicine, Hershey, PA, USA; 7Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA*These authors contributed equally to this workCorrespondence: Eelco van Duinkerken, Amsterdam University Medical Centers, Vrije Universiteit, Department of Medical Psychology, De Boelelaan 1117, Amsterdam, 1081 HV, the Netherlands, Email e.vanduinkerken@amsterdamumc.nlAbstract: Over the past decades, life expectancy of people with type 1 diabetes has increased considerably, which brings potential challenges due to the process of aging. Cognitive aging and dementia, as well as reductions in visual acuity, hearing and dexterity, can influence the frequency and quality of daily self-management activities, including medication taking and insulin dosing, glucose self-monitoring, and healthy eating. This can increase the risk for hypo- and hyperglycemic events, which, in turn, may contribute to cognitive decline. Because there is a gap in understanding the barriers and facilitators of self-management in older adults with type 1 diabetes and the relationship to cognitive functioning, the authors 1) review the available literature on cognitive aging and type 1 diabetes, 2) describe what self-management in later adulthood entails and the cognitive functions required for effective self-management behaviors, 3) analyze the interaction between type 1 diabetes, cognition, aging, and self-management behaviors, and 4) describe the barriers and facilitators for self-management throughout the life span and how they may differ for older people. Potential evidence-based practices that could be developed for older adults with type 1 diabetes are discussed. There is need for further studies that clarify the impact of aging on T1D self-management, ultimately to improve diabetes care and quality of life.Keywords: type 1 diabetes, self-management, cognition, aging

Sergio L Schmidt,1,2 Michele Santos da Silva,2 Juliana J Schmidt,2 Ana Lucia Novais Carvalho,3 Claudia Cristina Ferreira Vasconcelos,2 Renata Alves Paes,2 Yolanda EM Boechat,4 Rafael Neder,2 Regina P Alvarenga2 1Department of Neurophysiology, State University of Rio de Janeiro, RJ, Brazil; 2Neurology Department, Federal University of the State of Rio de Janeiro, RJ, Brazil; 3Department of Psychology, Fluminense Federal University, Niteroi, Brazil; 4Department of Internal Medicine, Fluminense Federal University, Niteroi, Brazil Background: In the early phases of multiple sclerosis (MS), patients exhibit slight neuropsychiatric deficits that can only be detected using reliable tools. Aim: The present investigation aimed to examine neuropsychological performance in 35 patients with incipient MS. Patients and methods: For the MS group, the inclusion criteria included time of disease

Emerging antibiotic resistance requires continual improvement in the arsenal of antimicrobial drugs, especially the critical macrolide antibiotics. Formation of the macrolactone scaffold of these polyketide natural products is catalyzed by a modular polyketide synthase (PKS) thioesterase (TE). The TE accepts a linear polyketide substrate from the termina PKS acyl carrier protein to generate an acyl-enzyme adduct that is resolved by attack of a substrate hydroxyl group to form the macrolactone. Our limited mechanistic understanding of TE selectivity for a substrate nucleophile and/or water has hampered development of TEs as biocatalysts that accommodate a variety of natural and non-natural substrates. To understand how TEs direct the substrate nucleophile for macrolactone formation, acyl-enzyme intermediates were trapped as stable amides by substituting the natural serine OH with an amino group. Incorporation of the unnatural amino acid, 1,3-diaminopropionic acid (DAP), was tested with five PKS TEs. DAP-modified TEs (TE DAP ) from the pikromycin and erythromycin pathways were purified and tested with six full-length polyketide intermediates from three pathways. The erythromycin TE had permissive substrate selectivity, whereas the pikromycin TE was selective for its native hexaketide and heptaketide substrates. In a crystal structure of a native substrate trapped in pikromycin TE DAP , the linear heptaketide was curled in the active site with the nucleophilic hydroxyl group positioned 4 Å from the amide-enzyme linkage. The curled heptaketide displayed remarkable shape complementarity with the TE acyl cavity. The strikingly different shapes of acyl cavities in TEs of known structure, including those reported here for juvenimicin, tylosin and fluvirucin biosynthesis, provide new insights to facilitate TE engineering and optimization.

Introduction: The Seraph® 100 Microbind® Affinity blood filter (Seraph® 100) has been in use since 2019 for the treatment of fulminant or difficult to treat blood stream infections as an adjunct to pharmacotherapy. In 2020 the device received emergency use authorization by the US Food and Drug Administration for the treatment of critically ill COVID-19 patients with confirmed or imminent respiratory failure. Results of an international registry showed that the Seraph® 100 was operated under blood flow rates of 100-350 mL/min. As those conditions require a large bore central line, a dialysis catheter is currently considered indispensable to operate the Seraph® 100. The use of smaller catheter lumina has neither been evaluated in vitro nor in vivo., Methods: In vitro pressure data before and after the Seraph® 100 at various blood pump rates (prepump line 16 G, postpump line 18 G) with saline and human plasma were obtained. Further, anecdotal flow and pressure data of two patients treated with the Seraph® 100 for a COVID-19 infection are reported., Results: At a pump speed of 50 mL/min pre-Seraph® pressure using saline was -70 [-70 to -60] mm Hg. In comparison, using plasma pre-Seraph® pressure was lower at -120 [-120 to -105] mm Hg; p  < 0.001 ( t -test). The post-Seraph® pressure at 50 mL/min using saline of 120 [110-130] mm Hg was not different from plasma at 130 [120-140] mm Hg, p  = 0.152 ( t -test). Blood flow rates of 50 mL/min did not lead to preAP levels below -250 mm Hg in the two clinical cases., Conclusion: Seraph® 100 blood flow rate of 50 mL/min may be achieved using low flow vascular access, allowing to treat a blood volume 72 L in 24 h., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MTS, JJS, and JTK received research funding from ExThera Medical. MTS and JTK received travel support from ExThera Medical. All other authors: none to declare.

Background: Artificial intelligence (AI) and game-based methods such as serious games or gamification are both emerging technologies and methodologies in health care. The merging of the two could provide greater advantages, particularly in the field of therapeutic interventions in medicine., Objective: This scoping review sought to generate an overview of the currently existing literature on the connection of AI and game-based approaches in health care. The primary objectives were to cluster studies by disease and health topic addressed, level of care, and AI or games technology., Methods: For this scoping review, the databases PubMed, Scopus, IEEE Xplore, Cochrane Library, and PubPsych were comprehensively searched on February 2, 2022. Two independent authors conducted the screening process using Rayyan software (Rayyan Systems Inc). Only original studies published in English since 1992 were eligible for inclusion. The studies had to involve aspects of therapy or education in medicine and the use of AI in combination with game-based approaches. Each publication was coded for basic characteristics, including the population, intervention, comparison, and outcomes (PICO) criteria; the level of evidence; the disease and health issue; the level of care; the game variant; the AI technology; and the function type. Inductive coding was used to identify the patterns, themes, and categories in the data. Individual codings were analyzed and summarized narratively., Results: A total of 16 papers met all inclusion criteria. Most of the studies (10/16, 63%) were conducted in disease rehabilitation, tackling motion impairment (eg, after stroke or trauma). Another cluster of studies (3/16, 19%) was found in the detection and rehabilitation of cognitive impairment. Machine learning was the main AI technology applied and serious games the main game-based approach used. However, direct interaction between the technologies occurred only in 3 (19%) of the 16 studies. The included studies all show very limited quality evidence. From the patients' and healthy individuals' perspective, generally high usability, motivation, and satisfaction were found., Conclusions: The review shows limited quality of evidence for the combination of AI and games in health care. Most of the included studies were nonrandomized pilot studies with few participants (14/16, 88%). This leads to a high risk for a range of biases and limits overall conclusions. However, the first results present a broad scope of possible applications, especially in motion and cognitive impairment, as well as positive perceptions by patients. In future, the development of adaptive game designs with direct interaction between AI and games seems promising and should be a topic for future reviews., (©Daniel Tolks, Johannes Jeremy Schmidt, Sebastian Kuhn. Originally published in JMIR Serious Games (https://games.jmir.org), 15.01.2024.)

Agrobacterium tumefaciens is a plant pathogen, broadly known as the causal agent of the crown gall disease. The soil bacterium is naturally resistant to beta-lactam antibiotics by utilizing the inducible beta-lactamase AmpC. Our picture on the condition-dependent regulation of ampC expression is incomplete. A known regulator is AmpR controlling the transcription of ampC in response to unrecycled muropeptides as a signal for cell wall stress. In our study, we uncovered the global transcriptional regulator LsrB as a critical player acting upstream of AmpR. Deletion of lsrB led to severe ampicillin and penicillin sensitivity, which could be restored to wild-type levels by lsrB complementation. By transcriptome profiling via RNA-Seq and qRT-PCR and by electrophoretic mobility shift assays, we show that ampD coding for an anhydroamidase involved in peptidoglycan recycling is under direct negative control by LsrB. Controlling AmpD levels by the LysR-type regulator in turn impacts the cytoplasmic concentration of cell wall degradation products and thereby the AmpR-mediated regulation of ampC. Our results substantially expand the existing model of inducible beta-lactam resistance in A. tumefaciens by establishing LsrB as higher-level transcriptional regulator., (© 2023 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)

Goal: Rising incidents of violence and mistreatment of healthcare workers by patients and visitors have been reported. U.S. healthcare workers are five times more likely to experience nonfatal workplace violence (WPV) than workers in any other profession. However, less is known about the national trends in the incidence of violence and mistreatment in healthcare. The specific organizational and individual-level factors that relate to stress arising from these occurrences specifically by patients and family members are also not fully understood. The goals of this study were to examine national trends of violence toward healthcare workers, understand which populations are most vulnerable to stress from violence and mistreatment, and explore organizational factors that are related to these occurrences., Methods: Data were collected from three sources: (1) The Bureau of Labor Statistics Intentional Injury by Another Person data for the period 2011-2020, (2) data from a large national workers' compensation claim services provider for the period 2018-2022, and (3) results from a survey distributed at a large medical center in June and July 2022. Data were represented graphically and analyzed using multivariate regression and dominance analysis to identify specific predictors of WPV and mistreatment among healthcare workers., Principal Findings: Of the total surveyed sample, 23.7% of participants reported mistreatment from patients or visitors as a major stressor and 14.6% reported WPV from patients or visitors as a major stressor. Stress from mistreatment and WPV was most frequently reported by nurses, employees aged 18 to 24 years other than nurses, those who identified as White, and those who identified as female or a gender minority. The emergency room (ER) showed the highest percentages of stress from mistreatment (61.8%) and violence (55.9%) from patients or visitors. The top predictors of stress from WPV and mistreatment by patients or visitors among healthcare workers ranked high to low were working in the ER, working as a nurse, a lack of necessary supplies or equipment, patient or visitor attitudes or beliefs about COVID-19, and working in a hospital-based unit., Practical Applications: In addition to protecting employees as a moral imperative, preventing WPV is critical for organizational performance. Employee productivity is estimated to decrease up to 50% in the 6 to 18 weeks following an incident of violence, while turnover can increase 30% to 40%. An effective WPV prevention plan and a proactive approach to supporting the physical and mental health conditions that may result from WPV can mitigate the potential costs and exposures from these incidents. Organizations must also set clear expectations of behavior with patients and visitors by refusing to tolerate violence and mistreatment of caregivers. The impact of WPV can remain present and active for up to 8 years following an incident. Policy-level interventions are also needed. Currently, there are no federal protections for healthcare workers related to violence, though some states have made it a felony to abuse healthcare workers., Competing Interests: This research was supported in part with funding from ProAssurance. Dr. Meese has received speaking honoraria from the American College of Healthcare Executives. Dr. Boitet has received funding from an NIH/NIGMS Institutional Research and Academic Career Development Award. The other authors declare no conflicts of interest., (Copyright © 2023 Foundation of the American College of Healthcare Executives.)

Background: Immune cell recruitment, endothelial cell barrier disruption, and platelet activation are hallmarks of lung injuries caused by COVID-19 or other insults which can result in acute respiratory distress syndrome (ARDS). Basement membrane (BM) disruption is commonly observed in ARDS, however, the role of newly generated bioactive BM fragments is mostly unknown. Here, we investigate the role of endostatin, a fragment of the BM protein collagen XVIIIα1, on ARDS associated cellular functions such as neutrophil recruitment, endothelial cell barrier integrity, and platelet aggregation in vitro ., Methods: In our study we analyzed endostatin in plasma and post-mortem lung specimens of patients with COVID-19 and non-COVID-19 ARDS. Functionally, we investigated the effect of endostatin on neutrophil activation and migration, platelet aggregation, and endothelial barrier function in vitro. Additionally, we performed correlation analysis for endostatin and other critical plasma parameters., Results: We observed increased plasma levels of endostatin in our COVID-19 and non-COVID-19 ARDS cohort. Immunohistochemical staining of ARDS lung sections depicted BM disruption, alongside immunoreactivity for endostatin in proximity to immune cells, endothelial cells, and fibrinous clots. Functionally, endostatin enhanced the activity of neutrophils, and platelets, and the thrombin-induced microvascular barrier disruption. Finally, we showed a positive correlation of endostatin with soluble disease markers VE-Cadherin, c-reactive protein (CRP), fibrinogen, and interleukin (IL)-6 in our COVID-19 cohort., Conclusion: The cumulative effects of endostatin on propagating neutrophil chemotaxis, platelet aggregation, and endothelial cell barrier disruption may suggest endostatin as a link between those cellular events in ARDS pathology., 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 © 2023 Jandl, Berg, Birnhuber, Fliesser, Borek, Seeliger, David, Schmidt, Gorkiewicz, Zacharias, Welte, Olschewski, Heinemann, Wygrecka and Kwapiszewska.)

Background: Acute kidney injury (AKI) is a frequent complication in patients with decompensated cirrhosis. Studies reported conflicting results regarding the nephrotoxic potential of iodinated contrast medium (CM) for computer tomography (CT)., Aim: To investigate the impact of diagnostic CM application on kidney function in patients with decompensated cirrhosis., Methods: First, we evaluated the impact of diagnostic CM-CT on AKI incidence in a cross-sectional approach. Second, we analysed 28-day AKI incidence post-CM-CT in patients with impaired kidney function (i.e., creatinine >133 μmoL/L). Third, we excluded all patients with relevant interventions besides CM-CT. All remaining patients were matched via propensity score matching (PPSM) and further analysed. Last, we validated the results in an independent dataset of prospectively collected registry data of 118 patients with decompensated cirrhosis. Here, plasma samples were analysed regarding neutrophil-gelatinase-associated-lipocalin (NGAL)., Results: Of the 611 included patients, 98 (16%) received CM-CT. CM-CT was not associated with AKI in the cross-sectional approach (CM-CT:8% vs. no CM-CT:15%; p = 0.08). Furthermore, CM-CT was not associated with higher 28-day AKI incidence among patients with impaired kidney function (HR:0.79; 95% CI 0.45-1.38; p = 0.40). The PPSM cohort revealed no association between CM-CT and AKI or severe AKI (HR:1.28, p = 0.45 and HR:1.62; p = 0.43). Moreover, CM-CT did not result in worsening of kidney function after CM application. In the validation cohort, CM-CT was also not linked to AKI (p = 0.85) and NGAL levels were not increased in those with CM-CT (CM-CT:309 ng/ml vs. No CM-CT:266 ng/ml, p = 0.35)., Conclusion: Decompensated cirrhosis per se should not preclude diagnostic CM-CT., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Cerebellar manifestations have been described in patients with gluten sensitivity (GS)-related disorders. A better understanding of the neurological manifestations of GS requires the use of neuroimaging techniques. We performed a systematic review on neuroimaging findings in GS patients with cerebellar symptoms. We also included a specific search on neuroimaging findings in GS patients with cerebellar manifestations on a gluten-free diet (GFD). PubMed, Embase, and Bireme were systematically searched to identify studies assessing neuroimaging features of adults with cerebellar manifestations and GS with or without enteropathy on a GFD. Ten studies with a total of 222 adult-GS patients were included. Magnetic resonance imaging was used in 100% of the studies. Cerebellar atrophy was evaluated in 7 studies and observed in 63% of the patients. White matter abnormalities were described in 2 studies. Single-photon emission computed tomography was used in 2 studies, and decreased cerebellar perfusion was detected in 92% of the included patients. No study employed nuclear medicine after the start of GFD. Magnetic resonance spectroscopy (MRS) was performed in 2 studies before and after GFD. An increase in the Naa/Cr ratio in cerebellar vermis was seen in 98% of the cases on a strict GFD. Cerebellar atrophy was found to be a prevalent condition in GS patients. MRS demonstrated to be useful in the follow-up of GS patients with cerebellar manifestations on a GFD. Prospective studies using nuclear medicine imaging are needed to study brain changes in GS patients on a GFD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

An amplification-free, nanopore-based nucleic acid detection platform has been demonstrated for rapid, 16S rRNA sequence-specific detection of Neisseria gonorrhoeae at 10-100 CFU mL -1 in human urine against background bacterial flora at 1000 CFU mL -1 . Gonorrhea is a very common notifiable communicable disease, antibiotic resistant strains have emerged, and the rate of reported gonococcal infections continues to increase. Since rapid clinical identification of bacterial pathogens in clinical samples is needed to guide proper antibiotic treatment and to control disease spread, it is important to engineer rapid, sensitive, selective, and inexpensive point-of-care (POC) diagnostic devices for pathogens such as N. gonorrhoeae . Our detector technology is based on straightforward conductometric detection of sustained blockage of a glass nanopore. Charge neutral, complementary peptide nucleic acid probes are conjugated to polystyrene beads to capture N. gonorrhoeae 16S rRNA selectively. In the presence of an electric field applied externally through a glass nanopore, the PNA-microbead conjugates that acquire substantial negative charge upon target hybridization are driven to the smaller diameter nanopore. At least partial blockage of the nanopore results in a sustained drop in ionic current that can be measured easily with simple electronics. The ability to detect N. gonorrhoeae over the range of 10 to 100 CFU mL -1 spiked in human urine was demonstrated successfully with estimated sensitivity and specificity of ∼98% and ∼100%, respectively. No false positives were observed for the control group of representative background flora ( E. coli , K. pneumoniae , and E. faecalis ) at 1000 CFU mL -1 . Also, N. gonorrhoeae at 50 CFU mL -1 was successfully detected against 1000 CFU mL -1 of background flora in urine. These results suggest that this amplification-free technology may serve as the basis for rapid, inexpensive, low-power detection of pathogens in clinical samples at the POC., Competing Interests: H. G. Monbouquette and J. J. Schmidt report holding equity in and Director positions at ElectroNucleics Inc., a company formed to commercialize the technology described in this publication. O. B. Garner serves in an advisory role to ElectroNucleics Inc., (This journal is © The Royal Society of Chemistry.)

Modification of polyketides with fluorine offers a promising approach to develop new pharmaceuticals. While synthetic chemical methods for site-selective incorporation of fluorine in complex molecules have improved in recent years, approaches for the biosynthetic incorporation of fluorine in natural compounds are still rare. Here, we report a strategy to introduce fluorine into complex polyketides during biosynthesis. We exchanged the native acyltransferase domain of a polyketide synthase, which acts as the gatekeeper for the selection of extender units, with an evolutionarily related but substrate tolerant domain from metazoan type I fatty acid synthase. The resulting polyketide-synthase/fatty-acid-synthase hybrid can utilize fluoromalonyl coenzyme A and fluoromethylmalonyl coenzyme A for polyketide chain extension, introducing fluorine or fluoro-methyl units in polyketide scaffolds. We demonstrate the feasibility of our approach in the chemoenzymatic synthesis of fluorinated 12- and 14-membered macrolactones and fluorinated derivatives of the macrolide antibiotics YC-17 and methymycin., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Bacterial burden as well as duration of bacteremia influence the outcome of patients with bloodstream infections. Promptly decreasing bacterial load in the blood by using extracorporeal devices in addition to anti-infective therapy has recently been explored. Preclinical studies with the Seraph® 100 Microbind® Affinity Blood Filter (Seraph® 100), which consists of heparin that is covalently bound to polymer beads, have demonstrated an effective binding of bacteria and viruses. Pathogens adhere to the heparin coated polymer beads in the adsorber as they would normally do to heparan sulfate on cell surfaces. Using this biomimetic principle, the Seraph® 100 could help to decrease bacterial burden in vivo., Methods: This first in human, prospective, multicenter, non-randomized interventional study included patients with blood culture positive bloodstream infection and the need for kidney replacement therapy as an adjunctive treatment for bloodstream infections. We performed a single four-hour hemoperfusion treatment with the Seraph® 100 in conjunction with a dialysis procedure. Post procedure follow up was 14 days., Results: Fifteen hemodialysis patients (3F/12 M, age 74.0 [68.0-78.5] years, dialysis vintage 28.0 [11.0-45.0] months) were enrolled. Seraph® 100 treatment started 66.4 [45.7-80.6] hours after the initial positive blood culture was drawn. During the treatment with the Seraph® 100 with a median blood flow of 285 [225-300] ml/min no device or treatment related adverse events were reported. Blood pressure and heart rate remained stable while peripheral oxygen saturation improved during the treatment from 98.0 [92.5-98.0] to 99.0 [98.0-99.5] %; p = 0.0184. Four patients still had positive blood culture at the start of Seraph® 100 treatment. In one patient blood cultures turned negative during treatment. The time to positivity (TTP) was increased between inflow and outflow blood cultures by 36 [- 7.2 to 96.3] minutes. However, overall TTP increase was not statistical significant., Conclusions: Seraph® 100 treatment was well tolerated. Adding Seraph® 100 to antibiotics early in the course of bacteremia might result in a faster resolution of bloodstream infections, which has to be evaluated in further studies., Trail Registration: ClinicalTrials.gov Identifier: NCT02914132 , first posted September 26, 2016., (© 2022. The Author(s).)

Objectives: Extracorporeal membrane oxygenation (ECMO) is a potentially lifesaving procedure in acute respiratory distress syndrome (ARDS) due to COVID-19. Previous studies have shown a high prevalence of clinically silent cerebral microbleeds in patients with COVID-19. Based on this fact, together with the hemotrauma and the requirement of therapeutic anticoagulation on ECMO support, we hypothesized an increased risk of intracranial hemorrhages (ICHs). We analyzed ICH occurrence rate, circumstances and clinical outcome in patients that received ECMO support due to COVID-19-induced ARDS in comparison to viral non-COVID-19-induced ARDS intracerebral hemorrhage., Design: Multicenter, retrospective analysis between January 2010 and May 2021., Setting: Three tertiary care ECMO centers in Germany and Switzerland., Patients: Two-hundred ten ARDS patients on ECMO support (COVID-19, n = 142 vs viral non-COVID, n = 68)., Interventions: None., Measurements and Main Results: Evaluation of ICH occurrence rate, parameters of coagulation and anticoagulation strategies, inflammation, and ICU survival. COVID-19 and non-COVID-19 ARDS patients showed comparable disease severity regarding Sequential Organ Failure Assessment score, while the oxygenation index before ECMO cannulation was higher in the COVID group (82 vs 65 mm Hg). Overall, ICH of any severity occurred in 29 of 142 COVID-19 patients (20%) versus four of 68 patients in the control ECMO group (6%). Fifteen of those 29 ICH events in the COVID-19 group were classified as major (52%) including nine fatal cases (9/29, 31%). In the control group, there was only one major ICH event (1/4, 25%). The adjusted subhazard ratio for the occurrence of an ICH in the COVID-19 group was 5.82 (97.5% CI, 1.9-17.8; p = 0.002). The overall ICU mortality in the presence of ICH of any severity was 88%., Conclusions: This retrospective multicenter analysis showed a six-fold increased adjusted risk for ICH and a 3.5-fold increased incidence of ICH in COVID-19 patients on ECMO. Prospective studies are needed to confirm this observation and to determine whether the bleeding risk can be reduced by adjusting anticoagulation strategies., Competing Interests: Dr. Seeliger is supported by Program of Hannover Medical School for Clinician Scientists (PRACTIS), funded by the Deutsche Forschungsgemeinschaft (DFG, ME 3696/3-1) and the German Center for Lung Research (DZL). Dr. David received funding from the German Centre for Lung Research. Dr. Hoeper received funding from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, and Pfizer. Dr. Putensen’s institution received funding from the DFG (PU 219/2-3); he received funding from Pluristem Ltd and Dräger Medical. Dr. Bode is supported by the DFG (BO 3640/2-1) and the Federal Ministry of Education and Research (01KI20343). Dr. David’s institution received funding from the German Research Foundation (DA1209/4-3), DFG, DZL, Cytobsorbents, Octapharma, and Terumo; he received funding from Terumo, Octapharma, and Cytosorbents. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy., Methods: In the original RCT, patients with septic shock of < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 μg/kg/min received standard of care (SOC) or SOC + one single TPE. Here, we report all clinical and biological endpoints of this study. Multivariate mixed-effects modeling of NE reduction was performed to investigate characteristics that could be associated with clinical response to TPE., Results: A continuous effect of TPE on the reduction in NE doses over the initial 24 h was observed (SOC group: estimated NE dose reduction of 0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004). Similarly, under TPE, serum lactate levels, continuously decreased over the initial 24 h in the TPE group, whereas lactate levels increased under SOC (p = 0.001). A reduction in biomarkers and disease mediators (such as PCT (p = 0.037), vWF:Ag (p < 0.001), Angpt-2 (p = 0.009), sTie-2 (p = 0.005)) along with a repletion of exhausted protective factors (such as AT-III (p = 0.026), Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but not in the SOC group. In a multivariate mixed effects model, increasing baseline lactate levels led to greater NE dose reduction effects with TPE as opposed to SOC (p = 0.004)., Conclusions: Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. We identified that baseline lactate concentration as a potential response predictor might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints. Trial registration Retrospectively registered 18th January 2020 at clinicaltrials.gov (Identifier: NCT04231994 )., (© 2022. The Author(s).)

Background: The Seraph® 100 Microbind® Affinity Blood Filter is a haemoperfusion device that is licensed for the reduction of pathogens, including several viruses, in the blood. It received Emergency Use Authorization for the treatment of severe coronavirus disease 2019 (COVID-19) by the Food and Drug Administration (FDA). Several studies have shown that the blood viral load of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) correlates with adverse outcomes and removal of the nucleocapsid of the SARS-CoV-2 virus by the Seraph® 100 has been recently demonstrated. The aim of this registry was to evaluate the safety and efficacy of Seraph® 100 treatment for COVID-19 patients., Methods: Twelve hospitals from six countries representing two continents documented patient and treatment characteristics as well as outcome parameters without reimbursement. Additionally, mortality and safety results of the device were reported. A total of 102 treatment sessions in 82 patients were documented in the registry. Four patients were excluded from mortality analysis due to incomplete outcome data, which were available in the other 78 patients., Results: Overall, a 30-day mortality rate of 46.2% in the 78 patients with complete follow-up was reported. The median treatment time was 5.00 h (4.00-13.42) and 43.1% of the treatments were performed as haemoperfusion only. Adverse events of the Seraph® 100 treatment were reported in 8.8% of the 102 treatments and represented the premature end of treatment due to circuit failure. Patients who died were treated later in their intensive care unit (ICU) stay and onset of COVID symptoms. They also had higher ferritin levels. Multivariate Cox regression revealed that delayed Seraph® 100 treatment after ICU admission (>60 h), as well as bacterial superinfection, were associated with mortality. While average predicted mortality rate according to Sequential Organ Failure Assessment (SOFA) score in ICU patients was 56.7%, the observed mortality was 50.7%. In non-ICU patients, Coronavirus Clinical Characterisation Consortium (4C) score average predicted a mortality rate of 38.0%, while the observed mortality rate was 11.1%., Conclusions: The treatment of COVID-19 patients with Seraph® 100 is well tolerated and the circuit failure rate was lower than previously reported for kidney replacement therapy (KRT) in COVID-19 patients. Mortality correlated with late initiation of Seraph treatment after ICU admission and bacterial superinfection. Compared with predicted mortality according to 4C and SOFA scores, mortality of Seraph® 100-treated patients reported in the registry was lower., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Many cases of Clostridium perfringens sepsis prove to be fatal. We present a case of C. perfringens sepsis with a liver abscess as the focus of infection, which was successfully treated by an interdisciplinary intensive medical care management. The sepsis with this rare pathogen was favored by the presence of a bilioenteric anastomosis and immunosuppressive treatment of a pre-existing Crohn's disease. Antibiotic treatment with clindamycin and penicillin G was initiated and the abscess was drained. Hemodialysis with high cut-off filters was started because of acute kidney failure in the Acute Kidney Injury Network (AKIN) stage III, hemolysis and rhabdomyolysis. Therapeutic plasma exchange was performed due to sepsis and acute liver failure., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. In this study, we determined the altered levels of factor XII (FXII) and its activation products in critically ill patients with COVID-19 in comparison with patients with severe acute respiratory distress syndrome related to the influenza virus (acute respiratory distress syndrome [ARDS]-influenza). Compatible with those data, we found rapid consumption of FXII in COVID-19 but not in ARDS-influenza plasma. Interestingly, the lag phase in fibrin formation, triggered by the FXII activator kaolin, was not prolonged in COVID-19, as opposed to that in ARDS-influenza. Confocal and electron microscopy showed that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggered formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, clot lysis was markedly impaired in COVID-19 as opposed to that in ARDS-influenza. Dysregulated fibrinolytic system, as evidenced by elevated levels of thrombin-activatable fibrinolysis inhibitor, tissue-plasminogen activator, and plasminogen activator inhibitor-1 in COVID-19 potentiated this effect. Analysis of lung tissue sections revealed widespread extra- and intravascular compact fibrin deposits in patients with COVID-19. A compact fibrin network structure and dysregulated fibrinolysis may collectively contribute to a high incidence of thrombotic events in COVID-19., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Fosfomycin is used increasingly in the treatment of MDR bacteria. It is eliminated by renal excretion, but data regarding dosing recommendations for patients undergoing modern means of renal replacement therapies are scarce., Objectives: Evaluation of the pharmacokinetics (PK) of fosfomycin in patients undergoing prolonged intermittent renal replacement therapy (PIRRT) to guide dosing recommendations., Methods: Fosfomycin was given in 11 (7 female) patients with severe infections undergoing PIRRT. Plasma levels were measured at several timepoints on the first day of fosfomycin therapy, as well as 5-6 days into therapy, before and after the dialyser, to calculate its clearance. Fosfomycin was measured in the collected spent dialysate., Results: The median (IQR) plasma dialyser clearance for fosfomycin was 183.4 (156.9-214.9) mL/min, eliminating a total amount of 8834 (4556-10 440) mg of fosfomycin, i.e. 73.9% (45.3%-93.5%) of the initial dose. During PIRRT, the fosfomycin half-life was 2.5 (2.2-3.4) h. Data from multiple-dose PK showed an increase in fosfomycin Cmax from 266.8 (166.3-438.1) to 926.1 (446.8-1168.0) mg/L and AUC0-14 from 2540.5 (1815.2-3644.3) to 6714 (4060.6-10612.6) mg·h/L. Dialysis intensity during the study was 1.5 L/h. T>MIC was 100% in all patients., Conclusions: Patients undergoing PIRRT experience significant fosfomycin elimination, requiring a dose of 5 g/8 h to reach adequate plasma levels. However, drug accumulation may occur, depending on dialysis frequency and intensity., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Deficiency of immunoglobulins of the classes IgG, IgG1, IgA and IgM is associated with severity of disease and mortality in sepsis and septic shock. Therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) has recently gained attention as an adjunctive therapeutic option in early septic shock. We hypothesized that TPE might modulate immunoglobulin deficiencies besides sole elimination of circulating injurious molecules., Methods: We conducted a prospective single center study with TPE in 33 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE > 0.4μg/kg/min). Clinical and biochemical data, including measurement of immunoglobulin subgroups IgG, IgG1, IgM and IgA were obtained before and after TPE. The following immunoglobulin cut-off values were used to analyze subgroups with low immunoglobulin concentrations at baseline (IgG ≤ 6.5, IgG1 ≤ 3, IgM ≤ 1.5 and IgA ≤ 0.35 g/L)., Results: At inclusion, median (IQR) SOFA score was 18 (15-20) and NE dose was 0.8 (0.6-1.2) μg/kg/min. The majority of patients demonstrated profound reductions in immunoglobulins levels of all classes. Globally, immunoglobulin levels were not significantly changed after a single TPE session. However, in patients with low baseline immunoglobulin levels a significant increase in all classes was observed (IgG 1.92 (0.96-3) g/L (+41%), IgG1 2.1 (1.46-2.32) g/L (+96%), IgA 0.44 (0.12-0.62) g/L (59%) and IgM 0.18 (0.14-0.34) g/L (+55%), p < 0.001 for comparison to patients above cut-off)., Conclusions: The majority of early and severe septic shock patients had reduced immunoglobulin levels and a single TPE could attenuate immunoglobulin deficiencies of all classes. The clinical relevance of this observation has to be investigated in a proper designed trial.

Background: Disruption of the endothelial glycocalyx (eGC) is observed in septic patients and its injury is associated with multiple-organ failure and inferior outcomes. Besides this biomarker function, increased blood concentrations of shedded eGC constituents might play a mechanistic role in septic organ failure. We hypothesized that therapeutic plasma exchange (TPE) using fresh frozen plasma might influence eGC-related pathology by removing injurious mediators of eGC breakdown while at the time replacing eGC protective factors., Methods: We enrolled 20 norepinephrine-dependent (NE > 0.4 μg/kg/min) patients with early septic shock (onset < 12 h). Sublingual assessment of the eGC via sublingual sidestream darkfield (SDF) imaging was performed. Plasma eGC degradation products, such as heparan sulfate (HS) and the eGC-regulating enzymes, heparanase (Hpa)-1 and Hpa-2, were obtained before and after TPE. A 3D microfluidic flow assay was performed to examine the effect of TPE on eGC ex vivo. Results were compared to healthy controls., Results: SDF demonstrated a decrease in eGC thickness in septic patients compared to healthy individuals (p = 0.001). Circulating HS levels were increased more than sixfold compared to controls and decreased significantly following TPE [controls: 16.9 (8-18.6) vs. septic patients before TPE: 105.8 (30.8-143.4) μg/ml, p < 0.001; vs. after TPE: 70.7 (36.9-109.5) μg/ml, p < 0.001]. The Hpa-2 /Hpa-1 ratio was reduced in septic patients before TPE but normalized after TPE [controls: 13.6 (6.2-21.2) vs. septic patients at inclusion: 2.9 (2.1-5.7), p = 0.001; vs. septic patients after TPE: 13.2 (11.2-31.8), p < 0.001]. Ex vivo stimulation of endothelial cells with serum from a septic patient induced eGC damage that could be attenuated with serum from the same patient following TPE., Conclusions: Septic shock results in profound degradation of the eGC and an acquired deficiency of the protective regulator Hpa-2. TPE removed potentially injurious eGC degradation products and partially attenuated Hpa-2 deficiency. Trial registration clinicaltrials.gov NCT04231994, retrospectively registered 18 January 2020., (© 2021. The Author(s).)

The EXTRIP (EXtracorporeal Treatments In Poisoning) workgroup is a collaborative international effort of pharmacologists, toxicologists, critical care physicians and nephrologists reviewing all available evidence in extracorporeal procedures for the treatment of intoxications in a standardized way to distill treatment recommendations for the physician at the bedside. The second round of guidelines will include recommendations for ethylenglycol intoxication. The case reported here is of a 60-year old man with a body weight of 65 kg who ingested approximately half a bottle (500 mL) of Aral Antifreeze in a suicidal attempt and presented around 12 h later with severe metabolic acidosis (venous blood gas analysis: pH 7.13; lactate 30 mmol/l, anion gap 23.3 mmol/l). As fomepizole, the inhibitor of the alcohol dehydrogenase, was not readily available, therapy with intermittent hemodialysis was started, as well as ethanol infusion. The first available ethylenglycol concentration before prolonged intermittent hemodialysis was 1230 mg/L. The total removed amount of ethylenglycol during intermittent hemodialysis, as well as following prolonged intermittent renal replacement therapy, was quantified (102 and 65 g). Based on this case report, the new EXRIP recommendations for the role of extracorporeal treatment in the case of ethylenglycol intoxication are discussed., (© 2020. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Melkersson-Rosenthal syndrome is a rare disease characterized by the triad of recurrent orofacial swelling with facial paralysis and fissured dorsal tongue. Histologically, noncaseating granulomatous inflammation occurs that confirms the diagnosis. Overlaps between granulomatous diseases such as sarcoidosis and Crohn's disease are described. Systemic corticosteroid therapy is the treatment of choice for acute attacks., Case Presentation: We here present a case of a 59-year-old White woman suffering from Melkersson-Rosenthal syndrome with a past history of sarcoidosis on therapy with leflunomide in combination with low-dose tacrolimus successfully treated with the anti-leprosy drug clofazimine after failure of systemic steroid therapy., Conclusions: We propose clofazimine as an alternative treatment in steroid-refractory cases., (© 2021. The Author(s).)

Macrolides have been effective clinical antibiotics for over 70 years. They inhibit protein biosynthesis in bacterial pathogens by narrowing the nascent protein exit tunnel in the ribosome. The macrolide class of natural products consist of a macrolactone ring linked to one or more sugar molecules. Most of the macrolides used currently are semi-synthetic erythromycin derivatives, composed of a 14- or 15-membered macrolactone ring. Rapidly emerging resistance in bacterial pathogens is among the most urgent global health challenges, which render many antibiotics ineffective, including next-generation macrolides. To address this threat and advance a longer-term plan for developing new antibiotics, we demonstrate how 16-membered macrolides overcome erythromycin resistance in clinically isolated Staphylococcus aureus strains. By determining the structures of complexes of the large ribosomal subunit of Deinococcus radiodurans (D50S) with these 16-membered selected macrolides, and performing anti-microbial studies, we identified resistance mechanisms they may overcome. This new information provides important insights toward the rational design of therapeutics that are effective against drug resistant human pathogens., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Iterative P450 enzymes are powerful biocatalysts for selective late-stage C-H oxidation of complex natural product scaffolds. These enzymes represent useful tools for selectivity and cascade reactions, facilitating direct access to core structure diversification. Recently, we reported the structure of the multifunctional bacterial P450 TamI and elucidated the molecular basis of its substrate binding and strict reaction sequence at distinct carbon atoms of the substrate. Here, we report the design and characterization of a toolbox of TamI biocatalysts, generated by mutations at Leu101, Leu244, and/or Leu295, that alter the native selectivity, step sequence, and number of reactions catalyzed, including the engineering of a variant capable of catalyzing a four-step oxidative cascade without the assistance of the flavoprotein and oxidative partner TamL. The tuned enzymes override inherent substrate reactivity, enabling catalyst-controlled C-H functionalization and alkene epoxidation of the tetramic acid-containing natural product tirandamycin. Five bioactive tirandamycin derivatives (6-10) were generated through TamI-mediated enzymatic synthesis. Quantum mechanics calculations and MD simulations provide important insights into the basis of altered selectivity and underlying biocatalytic mechanisms for enhanced continuous oxidation of the iterative P450 TamI., Competing Interests: The authors declare no competing financial interest.

Many biologically active natural products are synthesized by nonribosomal peptide synthetases (NRPSs), polyketide synthases (PKSs) and their hybrids. These megasynthetases contain modules possessing distinct catalytic domains that allow for substrate initiation, chain extension, processing and termination. At the end of a module, a terminal domain, usually a thioesterase (TE), is responsible for catalyzing the release of the NRPS or PKS as a linear or cyclized product. In this review, we address the general cyclization mechanism of the TE domain, including oligomerization and the fungal C-C bond forming Claisen-like cyclases (CLCs). Additionally, we include examples of cyclization catalysts acting within or at the end of a module. Furthermore, condensation-like (C T ) domains, terminal reductase (R) domains, reductase-like domains that catalyze Dieckmann condensation (R D ), thioesterase-like Dieckmann cyclases, trans -acting TEs from the penicillin binding protein (PBP) enzyme family, product template (PT) domains and others will also be reviewed. The studies summarized here highlight the remarkable diversity of NRPS and PKS cyclization catalysts for the production of biologically relevant, complex cyclic natural products and related compounds.

Polyketides, one of the largest classes of natural products, are often clinically relevant. The ability to engineer polyketide biosynthesis to produce analogs is critically important. Acyltransferases (ATs) of modular polyketide synthases (PKSs) catalyze the installation of malonyl-CoA extenders into polyketide scaffolds. ATs have been targeted extensively to site-selectively introduce various extenders into polyketides. Yet, a complete inventory of AT residues responsible for substrate selection has not been established, limiting the scope of AT engineering. Here, molecular dynamics simulations are used to prioritize ~50 mutations within the active site of EryAT6 from erythromycin biosynthesis, leading to identification of two previously unexplored structural motifs. Exchanging both motifs with those from ATs with alternative extender specificities provides chimeric PKS modules with expanded and inverted substrate specificity. Our enhanced understanding of AT substrate selectivity and application of this motif-swapping strategy are expected to advance our ability to engineer PKSs towards designer polyketides.

Celiac disease (CD) is an immune-mediated systemic disorder triggered by gluten and related prolamins in genetically predisposed individuals. Here, we described a case of a 31-year-old Caucasian woman who exhibited cerebellar and psychiatric dysfunctions. The patient underwent single-photon emission computed tomography (SPECT-CT) before and after a gluten-free diet (GFD). There was an improvement in cerebellar perfusion accompanied by a remission of cerebellar manifestations. The maintenance of the psychiatric manifestations was related to the persistence of the hypoperfusion in the frontal lobes. The patient's psychiatric symptoms did not change after 4 months under a GFD in the hospital. To our knowledge, this is the first case that shows the relationship between improvement in cerebellar perfusion and remission of cerebellar clinical manifestations in a CD patient under a GFD.

On April 17 2020, the United States Food and Drug Administration granted Coronavirus Disease 2019 (COVID-19) emergency use authorizations for the Seraph 100 Microbind Affinity Blood Filter. The medical device is aimed to treat critically ill COVID-19 patients with confirmed or imminent respiratory failure. The aim of this life size in vitro pharmacokinetic study was to investigate the in vitro adsorption of chloroquine and hydroxychloroquine from human plasma using equipment that is also used at the bedside. After start of the hemoperfusion, Pre (C pre ) Seraph plasma levels were obtained at 5 (C 5 ), 10 (C 10 ), 15 (C 15 ), 30 (C 30 ), 60 (C 60 ), and 120 (C 120 ) minutes into the procedure. At two timepoints (5 and 120 minutes) post (C post ) Seraph plasma levels were determined that were used to calculate the plasma clearance of the Seraph. Both drugs were determined using a validated HPLC method. Median [IQR] plasma clearance of the Seraph for chloroquine/hydroxychloroquine was 1.71 [0.51-4.38] mL/min/1.79 [0.21-3.68] mL/min respectively. The lack of elimination was also confirmed by the fact that plasma levels did not change over the 120 minutes treatment. As neither chloroquine nor hydroxychloroquine were removed by the treatment with the Seraph dose adjustments in COVID-19 patients undergoing this treatment are not necessary., (© 2020 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Objective: To analyze continuous 1- or 2-channel electroencephalograms (EEGs) of mechanically ventilated patients with coronavirus disease 2019 (COVID-19) with regard to occurrence of epileptiform potentials. Design: Single-center retrospective analysis. Setting: Intensive care unit of Hannover Medical School, Hannover, Germany. Patients: Critically ill COVID-19 patients who underwent continuous routine EEG monitoring (EEG monitor: Narcotrend-Compact M) during sedation. Measurements and Main Results: Data from 15 COVID-19 patients (11 men, four women; age: 19-75 years) were evaluated. Epileptiform potentials occurred in 10 of 15 patients (66.7%). Conclusions: The results of the evaluation regarding the occurrence of epileptiform potentials show that there is an unusually high percentage of cerebral involvement in patients with severe COVID-19. EEG monitoring can be used in COVID-19 patients to detect epileptiform potentials., 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 Schultz, Krauß, Schmidt, Schultz, Schneider, Wiesner, Schmidt, Stahl, David, Hoeper and Busch.)

Myxococcus xanthus kills other species to use their biomass as energy source. Its predation mechanisms allow feeding on a broad spectrum of bacteria, but the identity of predation effectors and their mode of action remains largely unknown. We initially focused on the role of hydrolytic enzymes for prey killing and compared the activity of secreted M. xanthus proteins against four prey strains. 72 secreted proteins were identified by mass spectrometry, and among them a family 19 glycoside hydrolase that displayed bacteriolytic activity in vivo and in vitro This enzyme, which we name LlpM (lectin/lysozyme-like protein of M. xanthus ), was not essential for predation, indicating that additional secreted components are required to disintegrate prey. Furthermore, secreted proteins lysed only Gram-positive, but not Gram-negative species. We thus compared the killing of different preys by cell-associated mechanisms: Individual M. xanthus cells killed all four test strains in a cell-contact dependent manner, but were only able to disintegrate Gram-negative, not Gram-positive cell envelopes. Thus, our data indicate that M. xanthus uses different, multifactorial mechanisms for killing and degrading different preys. Besides secreted enzymes, cell-associated mechanisms that have not been characterized so far, appear to play a major role for prey killing. IMPORTANCE Predation is an important survival strategy of the widespread myxobacteria, but it remains poorly understood on the mechanistic level. Without a basic understanding of how prey cell killing and consumption is achieved, it also remains difficult to investigate the role of predation for the complex myxobacterial lifestyle, reciprocal predator-prey relationships or the impact of predation on complex bacterial soil communities.We study predation in the established model organism Myxococcus xanthus , aiming to dissect the molecular mechanisms of prey cell lysis. In this study, we addressed the role of secreted bacteriolytic proteins, as well as potential mechanistic differences in the predation of Gram-positive and Gram-negative bacteria. Our observation shows that secreted enzymes are sufficient for killing and degrading Gram-positive species, but that cell-associated mechanisms may play a major role for killing Gram-negative and Gram-positive prey on fast timescales., (Copyright © 2020 American Society for Microbiology.)

Cellular and humoral immunity to SARS-CoV-2 is critical to control primary infection and correlates with severity of disease. The role of SARS-CoV-2-specific T cell immunity, its relationship to antibodies, and pre-existing immunity against endemic coronaviruses (huCoV), which has been hypothesized to be protective, were investigated in 82 healthy donors (HDs), 204 recovered (RCs), and 92 active COVID-19 patients (ACs). ACs had high amounts of anti-SARS-CoV-2 nucleocapsid and spike IgG but lymphopenia and overall reduced antiviral T cell responses due to the inflammatory milieu, expression of inhibitory molecules (PD-1, Tim-3) as well as effector caspase-3, -7, and -8 activity in T cells. SARS-CoV-2-specific T cell immunity conferred by polyfunctional, mainly interferon-γ-secreting CD4 + T cells remained stable throughout convalescence, whereas humoral responses declined. Immune responses toward huCoV in RCs with mild disease and strong cellular SARS-CoV-2 T cell reactivity imply a protective role of pre-existing immunity against huCoV., Competing Interests: Declaration of interests The authors declare that they have no competing interests. The funders played no role in designing the study, in collecting, analyzing, or interpreting the data, in writing the manuscript, or in the decision to publish the results., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hannah Arendt developed a twofold account of 'being earthbound' directly relevant to Anthropocene debates regarding the political. For Arendt, both senses of 'being earthbound' arose as humans began to act into nature, not merely upon it. The first sense is oriented to a political ontology of process, which arose as human actions - political, technological, scientific - nullified modernist conceits separating humans from nature. The second sense is one of earth alienation, which is referenced specifically to a scientific praxis coincident with advances in science and technology that alienates common sense experiences in politics. Though not unqualified, these two senses of being earthbound anchor our argument that Arendt offered prescient resources for understanding the political in the Anthropocene at the intersection of science, capital and world. The article ends by contrasting Arendt's account of being earthbound with Bruno Latour's recent interventions on the politics of Gaia., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: The Clinical Dementia Rating (CDR) scale is commonly used to stage cognitive impairment, despite having educational limitations. In elderly with low education, a previous study has shown that intraindividual variability of reaction time (CV) and commission errors (CE), measured using a culture-free Go/No-Go task, can reliably distinguish early Alzheimer's disease (AD) from mild cognitive impairment (MCI) and healthy controls., Objective: We aimed to extend the clinical utility of this culture-free Go/No-Go task in a sample with high educational disparity., Methods: One hundred and ten participants with a wide range of years of formal education (0-14 years) were randomly selected from a geriatric unit and divided based on their CDR scores into cognitively unimpaired (CDR = 0), MCI (CDR = 0.5), and early AD (CDR = 1). All underwent a 90-s reaction-time test that measured the variables previously found to predict CDR in low educated elderly. Here we added years of formal education (educational level) to the model. Multivariate analyses compared differences in group means using educational level as confounding factor. A confirmatory discriminant analyses was performed, to assess if CDR scores could be predicted by the two Go/No-Go variables in a sample with high educational disparity., Results: Over all three groups, differences in both CE and CV reached statistical significance (p < 0.05). The discriminant analysis demonstrated that CV and CE discriminated cognitively impaired from cognitively normal elderly. These results remained similar when discriminating MCI from cognitively unimpaired elderly., Conclusion: The Go/No-Go task reliably discriminates elderly with MCI from elderly without cognitive impairment independent of educational disparity.