Large neutral amino acid levels tune perinatal neuronal excitability and survival.

Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes, but what are the consequences of perturbing this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state, leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction.

Prognostic Impact of the International Society on Thrombosis and Hemostasis Disseminated Intravascular Coagulation Score in Sepsis: A Systematic Review.

The International Society on Thrombosis and Haemostasis (ISTH) diagnostic criteria for disseminated intravascular coagulation (DIC) are widely used for DIC diagnosis. However, the prognostic value of the score may vary between different patient populations and settings. This systematic review investigated the association between the ISTH DIC score and mortality in sepsis patients. A literature search was conducted in PubMed and Embase. Inclusion criteria were studies including adult and pediatric patients hospitalized with sepsis, using any sepsis definition, and investigating the association between mortality and the ISTH DIC score. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. In total, 42 studies were included. A positive association between the ISTH DIC score and mortality was consistently reported, with odds ratios of death in DIC versus non-DIC patients ranging from 1.125 (95% confidence interval [CI]: 0.838-1.511) to 21.008 (95% CI: 1.408-313.405) in adults and from 1.378 (95% CI: 1.004-1.893) to 2.99 (95% CI: 0.54-16.6) in pediatric populations. However, the DIC score only had a low-moderate positive predictive value for mortality, as area under receiver-operator characteristics ranged from 0.602 (95% CI: 0.575-0.630) to 0.815 (95% CI: 0.676-0.954) in adults. Of note, only few studies adjusted for potential confounders such as age, gender, and comorbidity. The ISTH DIC score is consistently associated with sepsis-related mortality but is not a strong positive predictor for mortality. Nevertheless, the score may still have a prognostic value and its use in sepsis is encouraged.

Involving Health Professionals in the Development of Quality and Safety Dashboards: Qualitative Study.

BACKGROUND: Dashboards are an important tool for hospitals to improve quality and safety performance. However, implementing quality and safety dashboards often does not increase performance due to a lack of use by health professionals. Including health professionals in the development process of quality and safety dashboards can improve their use in practice. Yet, it remains unclear how a development process involving health professionals can be executed successfully. OBJECTIVE: The aim of this study is twofold: (1) to delineate how a process whereby health professionals are included in the development of quality and safety dashboards can be facilitated and (2) to identify the factors that are important to consider in order to make that process successful. METHODS: We conducted a qualitative, in-depth exploratory case study in which we analyzed 150 pages of internal documents and interviewed 13 staff members regarding the development of quality and safety dashboards within 2 care pathways of a hospital that has experience in such development. The data were analyzed inductively using the constant comparative method. RESULTS: We found that the development of quality and safety dashboards in collaboration with health professionals was facilitated through a five-stage process: (1) familiarizing participants with dashboards and the development process; (2) brainstorming about potential indicators to be included in the dashboard; (3) prioritizing, defining, and selecting indicators to be included in the dashboard; (4) examining how the indicators can be visualized; and (5) implementing the dashboard and following up on its use. To enhance the success of the process, 3 factors were deemed important. The first is to create and maintain broad involvement, ensuring that various professions are represented and take ownership of the dashboard. Here, potential barriers include gaining engagement from peers not directly involved in the process and maintaining involvement after the initial implementation of the dashboard. Second, unburdening, whereby quality and safety staff facilitate a structured process that has little additional burden for professionals. For this, time management and a lack of collaboration with departments responsible for delivering the data might be an issue. Lastly, focusing on relevance for health professionals, which refers to the inclusion of indicators with value for health professionals. For this factor, a lack of consensus on how indicators should be defined and registered might be a barrier. CONCLUSIONS: Health care organizations seeking to develop quality and safety dashboards in collaboration with health professionals can use a 5-stage process. To enhance the success of the process, organizations are advised to focus on 3 key factors. For each of the key factors, potential barriers should be taken into account. Engaging in this process and attaining the key factors could increase the likelihood that the dashboards are used in practice.

Gold-Catalyzed Cycloisomerization of Sulfur Ylides to Dihydrobenzothiepines.

The metal-promoted nucleophilic addition of sulfur ylides to π-systems is a well-established reactivity. However, the driving force of such transformations, elimination of a sulfide moiety, entails stoichiometric byproducts making them unfavorable in terms of atom economy. In this work, a new take on sulfur ylide chemistry is reported, an atom-economical gold(I)-catalyzed synthesis of dihydrobenzo[b]thiepines. The reaction proceeds under mild conditions at room temperature.

Deciphering tissue-induced Klebsiella pneumoniae lipid A structure.

The outcome of an infection depends on host recognition of the pathogen, hence leading to the activation of signaling pathways controlling defense responses. A long-held belief is that the modification of the lipid A moiety of the lipopolysaccharide could help Gram-negative pathogens to evade innate immunity. However, direct evidence that this happens in vivo is lacking. Here we report the lipid A expressed in the tissues of infected mice by the human pathogen Klebsiella pneumoniae. Our findings demonstrate that Klebsiella remodels its lipid A in a tissue-dependent manner. Lipid A species found in the lungs are consistent with a 2-hydroxyacyl-modified lipid A dependent on the PhoPQ-regulated oxygenase LpxO. The in vivo lipid A pattern is lost in minimally passaged bacteria isolated from the tissues. LpxO-dependent modification reduces the activation of inflammatory responses and mediates resistance to antimicrobial peptides. An lpxO mutant is attenuated in vivo thereby highlighting the importance of this lipid A modification in Klebsiella infection biology. Colistin, one of the last options to treat multidrug-resistant Klebsiella infections, triggers the in vivo lipid A pattern. Moreover, colistin-resistant isolates already express the in vivo lipid A pattern. In these isolates, LpxO-dependent lipid A modification mediates resistance to colistin. Deciphering the lipid A expressed in vivo opens the possibility of designing novel therapeutics targeting the enzymes responsible for the in vivo lipid A pattern.

Economy of Catalyst Synthesis-Convenient Access to Libraries of Di- and Tetranaphtho Azepinium Compounds.

Efficient optimization procedures in chiral catalysis are usually linked to a straightforward strategy to access groups of structurally similar catalysts required for fine-tuning. The ease of building up such ligand libraries can be increased when the structure-modifying step (introduction of a substituent) is done at a later stage of the synthesis. This is demonstrated for the extended family of di- and tetranaphtho azepinium compounds, widely used as chiral phase transfer catalysts (PTC). Using 2,6-diiodo-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine and 4,8-diiodo-6,7-dihydro-5H-dibenzo[c,e]azepine, respectively, as key intermediates, 18 spiro-azepinium compounds were synthesized in a total yield of 25-42% over 6-7 steps from 1,1'-binaphthyl-2,2'-dicarboxylic acid or diphenic acid, respectively. The replacement of iodo groups with aryl substituents was performed as the last or the penultimate step of the synthesis.

C-H Activation Enables a Concise Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity.

We report a novel approach to the classical natural product quinine that is based on two stereoselective key steps, namely a C-H activation and an aldol reaction, to unite the two heterocyclic moieties of the target molecule. This straightforward and flexible strategy enables a concise synthesis of natural (-)-quinine, the first synthesis of unnatural (+)-quinine, and also provides access to unprecedented C3-aryl analogues, which were prepared in only six steps. We additionally demonstrate that these structural analogues exhibit improved antimalarial activity compared with (-)-quinine both in vitro and in mice infected with Plasmodium berghei.

In vitro pharmacokinetics/pharmacodynamics of the combination of avibactam and aztreonam against MDR organisms.

OBJECTIVES: The combination of aztreonam and avibactam has been proposed for the treatment of infections caused by metallo-ß-lactamase-producing Gram-negative organisms, given the stability of aztreonam against metallo-ß-lactamases plus the broad coverage of avibactam against AmpC ß-lactamases and ESBLs. This study aimed to evaluate the efficacy of the combination against four clinical isolates with defined but diverse ß-lactamase profiles. METHODS: The MICs of aztreonam were determined without and with avibactam (1, 2, 4, 8 and 16 mg/L). Using the MIC values, the static time-kill kinetic studies were designed to encompass aztreonam concentrations of 0.25, 0.5, 1, 2 and 4 times the MIC at the respective avibactam concentrations from 0 to 8 mg/L. Aztreonam and avibactam concentrations were determined by LC-MS/MS during the course of the time-kill kinetic studies to evaluate whether avibactam protects aztreonam from degradation. RESULTS: Three of the four isolates had aztreonam MICs ≥128 mg/L in monotherapy. Dramatically increasing susceptibility associated with a decrease in aztreonam MIC was observed with increasing avibactam concentration. Against all isolates, the combinations resulted in greater killing with a much lower dose requirement for aztreonam. The resulting changes in base-10 logarithm of cfu/mL at both the 10 h and 24 h references (versus 0 h) were synergistic. In contrast, a significantly higher concentration of aztreonam in the monotherapy was required to produce the same kill as that in the combination therapy, due to rapid aztreonam degradation in two isolates. CONCLUSIONS: The aztreonam/avibactam combination protects aztreonam from hydrolysis and provides synergy in antimicrobial activity against multiple ß-lactamase-expressing strains with a wide MIC range.

Association between biomarkers of endothelial injury and hypocoagulability in patients with severe sepsis: a prospective study.

INTRODUCTION: Patients with severe sepsis often present with concurrent coagulopathy, microcirculatory failure and evidence of vascular endothelial activation and damage. Given the critical role of the endothelium in balancing hemostasis, we investigated single-point associations between whole blood coagulopathy by thrombelastography (TEG) and plasma/serum markers of endothelial activation and damage in patients with severe sepsis. METHODS: A post-hoc multicenter prospective observational study in a subgroup of 184 patients from the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) Trial. Study patients were admitted to two Danish intensive care units. Inclusion criteria were severe sepsis, pre-intervention whole blood TEG measurement and a plasma/serum research sample available from baseline (pre-intervention) for analysis of endothelial-derived biomarkers. Endothelial-derived biomarkers were measured in plasma/serum by enzyme-linked immunosorbent assay (syndecan-1, thrombomodulin, protein C (PC), tissue-type plasminogen activator and plasminogen activator inhibitor-1). Pre-intervention TEG, functional fibrinogen (FF) and laboratory and clinical data, including mortality, were retrieved from the trial database. RESULTS: Most patients presented with septic shock (86%) and pulmonary (60%) or abdominal (30%) focus of infection. The median (IQR) age was 67 years (59 to 75), and 55% were males. The median SOFA and SAPS II scores were 8 (6 to 10) and 56 (41 to 68), respectively, with 7-, 28- and 90-day mortality rates being 21%, 39% and 53%, respectively. Pre-intervention (before treatment with different fluids), TEG reaction (R)-time, angle and maximum amplitude (MA) and FF MA all correlated with syndecan-1, thrombomodulin and PC levels. By multivariate linear regression analyses, higher syndecan-1 and lower PC were independently associated with TEG and FF hypocoagulability at the same time-point: 100 ng/ml higher syndecan-1 predicted 0.64 minutes higher R-time (SE 0.25), 1.78 mm lower TEG MA (SE 0.87) and 0.84 mm lower FF MA (SE 0.42; all P < 0.05), and 10% lower protein C predicted 1.24 mm lower TEG MA (SE 0.31). CONCLUSIONS: In our cohort of patients with severe sepsis, higher circulating levels of biomarkers of mainly endothelial damage were independently associated with hypocoagulability assessed by TEG and FF. Endothelial damage is intimately linked to coagulopathy in severe sepsis. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT00962156. Registered 13 July 2009.

Mycophenolic acid reverses TGF beta-induced cell motility, collagen matrix contraction and cell morphology in vitro.

The aim of this study was to elucidate functional and molecular effects of mycophenolic acid (MPA) on non-lymphatic, kidney epithelial cells treated with transforming growth factor (TGF). MPA effects were studied using HK2 cells incubated with EGF and TGF. The reversibility of these effects was verified using guanosine and 8-aminoguanosine. The following assays were applied: cell proliferation, viability, collagen matrix contraction, scratch wound closure, spindle index, FACS with anti-CD29 and anti-CD326, promoter demethylation of RAS protein activator like 1 (RASAL1), as well as gene expression of RASAL1, integrin 1ß (ITGB1) (CD29) and epithelial cell adhesion molecule (EpCam) (CD326). Cell proliferation was inhibited by increasing concentrations of MPA, whereas neither apoptosis nor cytotoxicity was detected. Stimulation with EGF and/or TGF led to a significant collagen matrix contraction that was successfully inhibited by MPA. In addition, scratch wound closure was inhibited by incubation with TGF alone or with EGF. Under the same conditions, cell morphology (spindle shape) and molecular phenotype (ITGB1(High)EpCam(Low)/ITGB1(Low)EpCam(High)) were both significantly changed, suggesting an epithelial to mesenchymal transformation. Cell morphology and motility, as well as molecular phenotype, were reversible after MPA treatment with TGF transformation in both presence/absence of EGF, thereby suggesting a correlation with the previously described antifibrotic effects of MPA. Dysregulation of TGF signal transduction appears to be related to progression of fibrosis. A TGF-transformed kidney epithelial cell line derived from human proximal tubules was used to study whether the immunosuppressive drug: MPA possesses any functional or molecular antifibrotic effects. Functional and morphological in vitro changes induced by both the TGF and epithelial-growth-factor were reversible by treatment with MPA. An inhibitory effect of MPA on the TGF pathway appears to be responsible for the previously described antifibrotic effects of the MPA in the COL4A3-deficient mouse model of renal fibrosis.

Effects of mycophenolate mofetil on kidney function and phosphorylation status of renal proteins in Alport COL4A3-deficient mice.

BACKGROUND: We investigated the effects of mycophenolate mofetil (MMF) on kidney function and on protein phosphorylation in a mouse model for the human Alport syndrome. METHODS: COL4A3-deficient (COL4A3-/-) mice were randomly allocated to receive a placebo (PLC COL4A3-/-) or MMF treatment (MMF COL4A3-/-). Wild type mice (WT) were used as controls. Changes in serum creatinine, total protein and blood urea nitrogen (BUN), concentrations of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG), serum protein electrophoresis, urine dipstick chemistry and sediment were measured. Changes in the phosphorylation status of renal proteins and histology were analyzed. RESULTS: MMF influenced kidney function and protein phosphorylation. Serum creatinine and BUN were lower in MMF treated compared to PLC treated COL4A3-/- mice. Serum albumin and alpha-1 globulins were significantly decreased while serum creatinine, alpha-2 globulins, urine dipstick protein, leukocyte esterase, hemoglobin and red blood cells were all increased in both COL4A3-/- groups compared to WT. Differential 2DE-gel analysis identified six phosphorylated kidney protein spots that were significantly altered by MMF. CONCLUSIONS: These data suggest that the MMF treatment in this murine model moderately improved kidney function and reversed the phosphorylation status of six renal phosphoprotein spots to that seen in WT mice.

Klebsiella pneumoniae targets an EGF receptor-dependent pathway to subvert inflammation.

The NF-κB transcriptional factor plays a key role governing the activation of immune responses. Klebsiella pneumoniae is an important cause of community-acquired and nosocomial pneumonia. Evidence indicates that K. pneumoniae infections are characterized by lacking an early inflammatory response. Recently, we have demonstrated that Klebsiella antagonizes the activation of NF-κB via the deubiquitinase CYLD. In this work, by applying a high-throughput siRNA gain-of-function screen interrogating the human kinome, we identified 17 kinases that when targeted by siRNA restored IL-1ß-dependent NF-κB translocation in infected cells. Further characterization revealed that K. pneumoniae activates an EGF receptor (EGFR)-phosphatidylinositol 3-OH kinase (PI3K)-AKT-PAK4-ERK-GSK3ß signalling pathway to attenuate the cytokine-dependent nuclear translocation of NF-κB. Our data also revealed that CYLD is a downstream effector of K. pneumoniae-induced EGFR-PI3K-AKT-PAK4-ERK-GSK3ß signalling pathway. Our efforts to identify the bacterial factor(s)responsible for EGFR activation demonstrate that a capsule (CPS) mutant did not activate EGFR hence suggesting that CPS could mediate the activation of EGFR. Supporting this notion, purified CPS did activate EGFR as well as the EGFR-dependent PI3K-AKT-PAK4-ERK-GSK3ß signalling pathway. CPS-mediated EGFR activation was dependent on a TLR4-MyD88-c-SRC-dependent pathway. Several promising drugs have been developed to antagonize this cascade. We propose that agents targeting this signalling pathway might provide selective alternatives for the management of K. pneumoniae pneumonias.

Does Rft1 flip an N-glycan lipid precursor?

Protein N-glycosylation requires flipping of the glycolipid Man(5)GlcNAc(2)-diphosphate dolichol (Man(5)GlcNAc(2)-PP-Dol) across the endoplasmic reticulum (ER). Helenius et al. report genetic evidence suggesting that Rft1, an essential ER membrane protein in yeast, is required directly to translocate Man(5)GlcNAc(2)-PP-Dol. We now show that a specific ER protein(s), but not Rft1, is required to flip Man(5)GlcNAc(2)-PP-Dol in reconstituted vesicles. Rft1 may have a critical accessory role in translocating Man(5)GlcNAc(2)-PP-Dol in vivo, but the Man(5)GlcNAc(2)-PP-Dol flippase itself remains to be identified.

Emission properties of ns and ps laser-induced soft x-ray sources using pulsed gas jets.

The influcence of the pulse duration on the emission characteristics of nearly debris-free laser-induced plasmas in the soft x-ray region (λ ≈ 1-5 nm) was investigated, using six different target gases from a pulsed jet. Compared to ns pulses of the same energy, a ps laser generates a smaller, more strongly ionized plasma, being about 10 times brighter than the ns laser plasma. Moreover, the spectra are considerably shifted towards shorter wavelengths. Electron temperatures and densities of the plasma are obtained by comparing the spectra with model calculations using a magneto-hydrodynamic code.

Klebsiella pneumoniae subverts the activation of inflammatory responses in a NOD1-dependent manner.

Klebsiella pneumoniae is an important cause of community-acquired and nosocomial pneumonia. Subversion of inflammation is essential for pathogen survival during infection. Evidence indicates that K. pneumoniae infections are characterized by lacking an early inflammatory response although the molecular bases are currently unknown. Here we unveil a novel strategy employed by a pathogen to counteract the activation of inflammatory responses. K. pneumoniae attenuates pro-inflammatory mediators-induced IL-8 secretion. Klebsiella antagonizes the activation of NF-κB via the deubiquitinase CYLD and blocks the phosphorylation of mitogen-activated protein kinases (MAPKs) via the MAPK phosphatase MKP-1. Our studies demonstrate that K. pneumoniae has evolved the capacity to manipulate host systems dedicated to control the immune balance. To exert this anti-inflammatory effect, Klebsiella engages NOD1. In NOD1 knock-down cells, Klebsiella neither induces the expression of CYLD and MKP-1 nor blocks the activation of NF-κB and MAPKs. Klebsiella inhibits Rac1 activation; and inhibition of Rac1 activity triggers a NOD1-mediated CYLD and MKP-1 expression which in turn attenuates IL-1ß-induced IL-8 secretion. A capsule (CPS) mutant does not attenuate the inflammatory response. However, purified CPS neither reduces IL-1ß-induced IL-8 secretion nor induces the expression of CYLD and MKP-1 thereby indicating that CPS is necessary but not sufficient to attenuate inflammation.

The detection and prevention of adverse drug events in nursing home and home care patients: Study protocol of a quasi-experimental study.

AIM: To estimate the cost-effectiveness of an intervention facilitating the early detection of adverse drug events through the means of health professional training and the application of a digital screening tool. DESIGN: Multi-centred non-randomized controlled trial from August 2018 to March 2020 including 65 nursing homes or home care providers. METHODS: We aim to estimate the effect of the intervention on the rate of adverse drug events as primary outcome through a quasi-experimental empirical study design. As secondary outcomes, we use hospital admissions and falls. All outcomes will be measured on patient-month level. Once the causal effect of the intervention is estimated, cost-effectiveness will be calculated. For cost-effectiveness, we include all patient costs observed by the German statutory health insurance. RESULTS: The results of this study will inform about the cost-effectiveness of the optimized drug supply intervention and provide evidence for potential reimbursement within the German statutory health insurance system.

Intraoperative subcutaneous wound closing culture sample: a predicting factor for periprosthetic infection after hip- and knee-replacement?

INTRODUCTION: It is unknown whether intraoperative subcutaneous wound closing culture samples (WCCS) are useful to predict periprosthetic joint infection (PJI). METHOD: Here we prospectively followed 167 out of a total of 175 consecutive patients with primary total hip (THR) or knee replacement (TKR) between 01/2002 and 12/2002 for a mean follow-up period of 5 years; of those patients, n = 159 (96.8%) underwent WCCS. RESULTS: The results showed a positive WCCS in n = 9 cases (5.8%). Nine patients developed postoperative wound complication and required revision surgery. Two patients developed signs of a deep periprosthetic infection; however, only one out of nine patients had initial positive WCCS. CONCLUSION: Our results thus indicate that WCCS during primary joint replacement is not an appropriate predictive method to identify patients at risk for periprosthetic joint infections.

Isolated Pectoralis Minor Tendon Rupture with Subclavian Vein Thrombosis.

Isolated insertional ruptures of the pectoralis minor tendon at the coracoid process are a rare condition. Hitherto, very few cases have been reported in the literature. A precise diagnosis is often difficult to obtain and commonly requires advanced imaging to confirm the suspicion and rule out concomitant injuries. All cases reported in the literature to date have been treated conservatively, with excellent results and no further complications. Here, however, we present the case of a patient who had developed a subclavian vein thrombosis. Furthermore, we provide an overview over and draw comparisons to the cases described in the literature. Despite the effectiveness of the conservative treatment, physicians should be aware that adverse events may occur.

Klebsiella pneumoniae Reduces SUMOylation To Limit Host Defense Responses.

Klebsiella pneumoniae is an important cause of multidrug-resistant infections worldwide. Understanding the virulence mechanisms of K. pneumoniae is a priority and timely to design new therapeutics. Here, we demonstrate that K. pneumoniae limits the SUMOylation of host proteins in epithelial cells and macrophages (mouse and human) to subvert cell innate immunity. Mechanistically, in lung epithelial cells, Klebsiella increases the levels of the deSUMOylase SENP2 in the cytosol by affecting its K48 ubiquitylation and its subsequent degradation by the ubiquitin proteasome. This is dependent on Klebsiella preventing the NEDDylation of the Cullin-1 subunit of the ubiquitin ligase complex E3-SCF-ßTrCP by exploiting the CSN5 deNEDDylase. Klebsiella induces the expression of CSN5 in an epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-extracellular signal-regulated kinase (ERK)-glycogen synthase kinase 3 beta (GSK3ß) signaling pathway-dependent manner. In macrophages, Toll-like receptor 4 (TLR4)-TRAM-TRIF-induced type I interferon (IFN) via IFN receptor 1 (IFNAR1)-controlled signaling mediates Klebsiella-triggered decrease in the levels of SUMOylation via let-7 microRNAs (miRNAs). Our results revealed the crucial role played by Klebsiella polysaccharides, the capsule, and the lipopolysaccharide (LPS) O-polysaccharide, to decrease the levels of SUMO-conjugated proteins in epithelial cells and macrophages. A Klebsiella-induced decrease in SUMOylation promotes infection by limiting the activation of inflammatory responses and increasing intracellular survival in macrophages.IMPORTANCEKlebsiella pneumoniae has been singled out as an urgent threat to human health due to the increasing isolation of strains resistant to "last-line" antimicrobials, narrowing the treatment options against Klebsiella infections. Unfortunately, at present, we cannot identify candidate compounds in late-stage development for treatment of multidrug-resistant Klebsiella infections; this pathogen is exemplary of the mismatch between unmet medical needs and the current antimicrobial research and development pipeline. Furthermore, there is still limited evidence on K. pneumoniae pathogenesis at the molecular and cellular levels in the context of the interactions between bacterial pathogens and their hosts. In this research, we have uncovered a sophisticated strategy employed by Klebsiella to subvert the activation of immune defenses by controlling the modification of proteins. Our research may open opportunities to develop new therapeutics based on counteracting this Klebsiella-controlled immune evasion strategy.

Sepsis-related Organ Failure Assessment Score is a strong predictor of survival in acute-on-chronic liver failure.

INTRODUCTION: The mortality of patients with an exacer-bation of decompensated liver cirrhosis is high even if treated in the intensive care unit (ICU), and the criteria for referral to ICU are not well defined. The objective of this study was to identify variables associated with mortality. METHODS: A single-centre retrospective cohort analysis was conducted in a university-affiliated ICU. A total of 53 adult patients with decompensated alcoholic liver cirrhosis were admitted from January 2012 to June 2015. Variables associated with survival were identified using Cox regression analysis. RESULTS: The ten-day, 30-day, 90-day, and one-year mortality were 36%, 57%, 66%, and 80%, respectively. Univariate Cox regression analysis showed that mortality was significantly associated with a low oxygen saturation, low diastolic blood pressure, terlipressin treatment, high Acute Physiology And Chronic Health Evaluation II score, high Simplified Acute Physiology Score II score, high Sepsis-related Organ Failure Assessment (SOFA) score and high Model For End-Stage Liver Disease score, but only a high SOFA score and old age were independently associated with increased mortality. These two variables were combined to the Age-SOFA index to predict the probability of surviving a given period. CONCLUSIONS: The mortality was high in these severely ill patients, even when they received optimum supportive therapy in the ICU. The finding that the SOFA score and age best predicted mortality shows that the increased mortality was caused mainly by insufficiency of organs other than the liver. FUNDING: none. TRIAL REGISTRATION: not relevant.