Meningococcal carriage in children and young adults: a cross-sectional and longitudinal study, Iceland, 2019 to 2021.

BackgroundNeisseria meningitidis is a commensal bacterium which can cause invasive disease. Colonisation studies are important to guide vaccination strategies.AimThe study's aim was to determine the prevalence of meningococcal colonisation, duration of carriage and distribution of genogroups in Iceland.MethodsWe collected samples from 1 to 6-year-old children, 15-16-year-old adolescents and 18-20-year-old young adults. Carriers were sampled at regular intervals until the first negative swab. Conventional culture methods and qPCR were applied to detect meningococci and determine the genogroup. Whole genome sequencing was done on groupable meningococci.ResultsNo meningococci were detected among 460 children, while one of 197 (0.5%) adolescents and 34 of 525 young adults (6.5 %) carried meningococci. Non-groupable meningococci were most common (62/77 isolates from 26/35 carriers), followed by genogroup B (MenB) (12/77 isolates from 6/35 carriers). Genogroup Y was detected in two individuals and genogroup W in one. None carried genogroup C (MenC). The longest duration of carriage was at least 21 months. Serial samples from persistent carriers were closely related in WGS.ConclusionsCarriage of pathogenic meningococci is rare in young Icelanders. Non-groupable meningococci were the most common colonising meningococci in Iceland, followed by MenB. No MenC were found. Whole genome sequencing suggests prolonged carriage of the same strains in persistent carriers.

Dissecting distinct proteolytic activities of FMDV Lpro implicates cleavage and degradation of RLR signaling proteins, not its deISGylase/DUB activity, in type I interferon suppression.

The type I interferon response is an important innate antiviral pathway. Recognition of viral RNA by RIG-I-like receptors (RLRs) activates a signaling cascade that leads to type I interferon (IFN-α/ß) gene transcription. Multiple proteins in this signaling pathway (e.g. RIG-I, MDA5, MAVS, TBK1, IRF3) are regulated by (de)ubiquitination events. Most viruses have evolved mechanisms to counter this antiviral response. The leader protease (Lpro) of foot-and-mouth-disease virus (FMDV) has been recognized to reduce IFN-α/ß gene transcription; however, the exact mechanism is unknown. The proteolytic activity of Lpro is vital for releasing itself from the viral polyprotein and for cleaving and degrading specific host cell proteins, such as eIF4G and NF-κB. In addition, Lpro has been demonstrated to have deubiquitination/deISGylation activity. Lpro's deubiquitination/deISGylation activity and the cleavage/degradation of signaling proteins have both been postulated to be important for reduced IFN-α/ß gene transcription. Here, we demonstrate that TBK1, the kinase that phosphorylates and activates the transcription factor IRF3, is cleaved by Lpro in FMDV-infected cells as well as in cells infected with a recombinant EMCV expressing Lpro. In vitro cleavage experiments revealed that Lpro cleaves TBK1 at residues 692-694. We also observed cleavage of MAVS in HeLa cells infected with EMCV-Lpro, but only observed decreasing levels of MAVS in FMDV-infected porcine LFPK αVß6 cells. We set out to dissect Lpro's ability to cleave RLR signaling proteins from its deubiquitination/deISGylation activity to determine their relative contributions to the reduction of IFN-α/ß gene transcription. The introduction of specific mutations, of which several were based on the recently published structure of Lpro in complex with ISG15, allowed us to identify specific amino acid substitutions that separate the different proteolytic activities of Lpro. Characterization of the effects of these mutations revealed that Lpro's ability to cleave RLR signaling proteins but not its deubiquitination/deISGylation activity correlates with the reduced IFN-ß gene transcription.

Small molecule ISRIB suppresses the integrated stress response within a defined window of activation.

Activation of the integrated stress response (ISR) by a variety of stresses triggers phosphorylation of the α-subunit of translation initiation factor eIF2. P-eIF2α inhibits eIF2B, the guanine nucleotide exchange factor that recycles inactive eIF2•GDP to active eIF2•GTP. eIF2 phosphorylation thereby represses translation. Persistent activation of the ISR has been linked to the development of several neurological disorders, and modulation of the ISR promises new therapeutic strategies. Recently, a small-molecule ISR inhibitor (ISRIB) was identified that rescues translation in the presence of P-eIF2α by facilitating the assembly of more active eIF2B. ISRIB enhances cognitive memory processes and has therapeutic effects in brain-injured mice without displaying overt side effects. While using ISRIB to investigate the ISR in picornavirus-infected cells, we observed that ISRIB rescued translation early in infection when P-eIF2α levels were low, but not late in infection when P-eIF2α levels were high. By treating cells with varying concentrations of poly(I:C) or arsenite to induce the ISR, we provide additional proof that ISRIB is unable to inhibit the ISR when intracellular P-eIF2α concentrations exceed a critical threshold level. Together, our data demonstrate that the effects of pharmacological activation of eIF2B are tuned by P-eIF2α concentration. Thus, ISRIB can mitigate undesirable outcomes of low-level ISR activation that may manifest neurological disease but leaves the cytoprotective effects of acute ISR activation intact. The insensitivity of cells to ISRIB during acute ISR may explain why ISRIB does not cause overt toxic side effects in vivo.

International Classification of Retinopathy of Prematurity, Third Edition.

PURPOSE: The International Classification of Retinopathy of Prematurity is a consensus statement that creates a standard nomenclature for classification of retinopathy of prematurity (ROP). It was initially published in 1984, expanded in 1987, and revisited in 2005. This article presents a third revision, the International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), which is now required because of challenges such as: (1) concerns about subjectivity in critical elements of disease classification; (2) innovations in ophthalmic imaging; (3) novel pharmacologic therapies (e.g., anti-vascular endothelial growth factor agents) with unique regression and reactivation features after treatment compared with ablative therapies; and (4) recognition that patterns of ROP in some regions of the world do not fit neatly into the current classification system. DESIGN: Review of evidence-based literature, along with expert consensus opinion. PARTICIPANTS: International ROP expert committee assembled in March 2019 representing 17 countries and comprising 14 pediatric ophthalmologists and 20 retinal specialists, as well as 12 women and 22 men. METHODS: The committee was initially divided into 3 subcommittees-acute phase, regression or reactivation, and imaging-each of which used iterative videoconferences and an online message board to identify key challenges and approaches. Subsequently, the entire committee used iterative videoconferences, 2 in-person multiday meetings, and an online message board to develop consensus on classification. MAIN OUTCOME MEASURES: Consensus statement. RESULTS: The ICROP3 retains current definitions such as zone (location of disease), stage (appearance of disease at the avascular-vascular junction), and circumferential extent of disease. Major updates in the ICROP3 include refined classification metrics (e.g., posterior zone II, notch, subcategorization of stage 5, and recognition that a continuous spectrum of vascular abnormality exists from normal to plus disease). Updates also include the definition of aggressive ROP to replace aggressive-posterior ROP because of increasing recognition that aggressive disease may occur in larger preterm infants and beyond the posterior retina, particularly in regions of the world with limited resources. ROP regression and reactivation are described in detail, with additional description of long-term sequelae. CONCLUSIONS: These principles may improve the quality and standardization of ROP care worldwide and may provide a foundation to improve research and clinical care.

Frailty leads to poor long-term survival in patients undergoing elective vascular surgery.

OBJECTIVE: Frailty has persistently been associated with unfavorable short-term outcomes after vascular surgery, including an increased complication risk, greater readmission rate, and greater short-term mortality. However, a knowledge gap remains concerning the association between preoperative frailty and long-term mortality. In the present study, we aimed to determine this association in elective vascular surgery patients. METHODS: The present study was a part of a large prospective cohort study initiated in 2010 in our tertiary referral teaching hospital to study frailty in elderly elective vascular surgery patients (Vascular Ageing Study). A total of 639 patients with a minimal follow-up of 5 years, who had been treated from 2010 to 2014, were included in the present study. The Groningen Frailty Indicator, a 15-item self-administered questionnaire, was used to determine the presence and degree of frailty. RESULTS: Of the 639 patients, 183 (28.6%) were considered frail preoperatively. For the frail patients, the actuarial survival after 1, 3, and 5 years was 81.4%, 66.7%, and 55.7%, respectively. For the nonfrail patients, the corresponding survival was 93.6%, 83.3%, and 75.2% (log-rank test, P < .001). Frail patients had a significantly greater risk of 5-year mortality (unadjusted hazard ratio, 2.09; 95% confidence interval, 1.572-2.771; P < .001). After adjusting for surgical- and patient-related risk factors, the hazard ratio was 1.68 (95% confidence interval, 1.231-2.286; P = .001). CONCLUSIONS: The results of our study have shown that preoperative frailty is associated with significantly increased long-term mortality after elective vascular surgery. Knowledge of a patient's preoperative frailty state could, therefore, be helpful in shared decision-making, because it provides more information about the procedural benefits and risks.

Risk Factors for Delirium after Vascular Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Vascular surgery is considered a risk factor for the development of postoperative delirium (POD). In this systematic review we provide a report on the incidence and risk-factors of POD after vascular surgery. METHODS: A systematic literature search was conducted using Pubmed with the MeSH terms and key words "delirium" or "confusion", "vascular surgery procedures" and "risk factors or "risk assessment". Studies were selected for review after meeting the following inclusion criteria: vascular surgery, POD diagnosed using validated screening tools, and DSM-derived criteria to assess delirium. A meta-analysis was performed for each endpoint if at least two studies could be combined. RESULTS: Sixteen articles met the abovementioned criteria. The incidence of delirium ranged from 5% to 39%. Various preoperative risk factors were identified that is, age (Random MD 3.96, CI 2.57-5.35), hypertension (Fixed OR 1.30, CI 1.05-1.59), diabetes mellitus (Random OR 2.15, CI 1.30-3.56), hearing impairment (Fixed OR 1.89, CI 1.28-2.81), history of cerebrovascular incident or transient ischemic attack (Fixed OR 2.20, CI 1.68-2.88), renal failure (Fixed OR 1.61, CI 1.19-2.17), and pre-operative low haemoglobin level (fixed MD -0.76, CI -1.04 to -0.47). Intra-operative risk factors were duration of surgery (Random MD 15.68; CI 2.79-28.57), open aneurysm repair (Fixed OR 4.99, CI 3.10-8.03), aortic cross clamping time (fixed MD 7.99, CI 2.56-13.42), amputation surgery (random OR 3.77, CI 2.13-6.67), emergency surgery (Fixed OR 4.84, CI 2.81-8.32) and total blood loss (Random MD 496.5, CI 84.51-908.44) and need for blood transfusion (Random OR 3.72, CI 1.57-8.80). Regional anesthesia on the other hand, had a protective effect. Delirium was associated with longer ICU and hospital length of stay, and more frequent discharge to a care facility. CONCLUSIONS: POD after vascular surgery is a frequent complication and effect-size pooling supports the concept that delirium is a heterogeneous disorder. The risk factors identified can be used to either design a validated risk factor model or individual preventive strategies for high-risk patients.

Irreversible inactivation of ISG15 by a viral leader protease enables alternative infection detection strategies.

In response to viral infection, cells mount a potent inflammatory response that relies on ISG15 and ubiquitin posttranslational modifications. Many viruses use deubiquitinases and deISGylases that reverse these modifications and antagonize host signaling processes. We here reveal that the leader protease, Lbpro, from foot-and-mouth disease virus (FMDV) targets ISG15 and to a lesser extent, ubiquitin in an unprecedented manner. Unlike canonical deISGylases that hydrolyze the isopeptide linkage after the C-terminal GlyGly motif, Lbpro cleaves the peptide bond preceding the GlyGly motif. Consequently, the GlyGly dipeptide remains attached to the substrate Lys, and cleaved ISG15 is rendered incompetent for reconjugation. A crystal structure of Lbpro bound to an engineered ISG15 suicide probe revealed the molecular basis for ISG15 proteolysis. Importantly, anti-GlyGly antibodies, developed for ubiquitin proteomics, are able to detect Lbpro cleavage products during viral infection. This opens avenues for infection detection of FMDV based on an immutable, host-derived epitope.

[Differential Stability and Interrater-Dependencies in the Assessment of Psychopathological Symptoms: Longitudinal Analyses Based on the SDQ in Children with and without Specific Learning Disabilities]. / Differentielle Stabilität und Interrater-Dependenzen bei der Beurteilung psychischer Auffälligkeiten: Längsschnittliche Analysen mit dem SDQ bei Kindern mit und ohne Lernstörungen.

Differential Stability and Interrater-Dependencies in the Assessment of Psychopathological Symptoms: Longitudinal Analyses Based on the SDQ in Children with and without Specific Learning Disabilities A widely used open access instrument for screening of internalising and externalising problem behaviour is the Strengths and Difficulties Questionnaire (SDQ). For the use of the SDQ in clinical practice, information about its differential validity and applicability for follow-up assessments is relevant. Therefore, the aim was to study the SDQ regarding differential stability in the repeatedly collected child, parent and teacher reports. As the social context influences the perception of symptoms, we additionally explored the extent to which the child, parent and teacher reports influenced each other. Also, we studied differences in problem behaviour between children with and without specific learning disabilities and between girls and boys. To this end, 60 children from 5th and 6th grade with and without specific learning disabilities and their parents and teachers filled in the SDQ at three time points during secondary school. The results of the cross-lagged-panel-analyses showed substantial stability for almost all subscales. This shows that in their SDQ-reports, parents, children and teachers can separate the stable parts of problem behaviour from situational variations therein. Inter-rater dependencies between the different reports in the form of cross-delayed effects could be identified mainly from the adult to the child reports and clarify the caregiver's influence on the children's symptom perception. With respect to specific learning disabilities, the results showed differences only for the subscale related to hyperactivity: children with specific learning disabilities had more parent-reported, but less self-reported hyperactive symptoms than children without. Girls reported more emotional problems and boys more conduct problems and less prosocial behavior. Teacher and parents reported almost no differences between boys and girls. The results support the usefulness of the SDQ for repeated assessments in clinical practice.

Essential Role of Enterovirus 2A Protease in Counteracting Stress Granule Formation and the Induction of Type I Interferon.

Most viruses have acquired mechanisms to suppress antiviral alpha/beta interferon (IFN-α/ß) and stress responses. Enteroviruses (EVs) actively counteract the induction of IFN-α/ß gene transcription and stress granule (SG) formation, which are increasingly implicated as a platform for antiviral signaling, but the underlying mechanisms remain poorly understood. Both viral proteases (2Apro and 3Cpro) have been implicated in the suppression of these responses, but these conclusions predominantly rely on ectopic overexpression of viral proteases or addition of purified viral proteases to cell lysates. Here, we present a detailed and comprehensive comparison of the effect of individual enterovirus proteases on the formation of SGs and the induction of IFN-α/ß gene expression in infected cells for representative members of the enterovirus species EV-A to EV-D. First, we show that SG formation and IFN-ß induction are suppressed in cells infected with EV-A71, coxsackie B3 virus (CV-B3), CV-A21, and EV-D68. By introducing genes encoding CV-B3 proteases in a recombinant encephalomyocarditis virus (EMCV) that was designed to efficiently activate antiviral responses, we show that CV-B3 2Apro, but not 3Cpro, is the major antagonist that counters SG formation and IFN-ß gene transcription and that 2Apro's proteolytic activity is essential for both functions. 2Apro efficiently suppressed SG formation despite protein kinase R (PKR) activation and α subunit of eukaryotic translation initiation factor 2 phosphorylation, suggesting that 2Apro antagonizes SG assembly or promotes its disassembly. Finally, we show that the ability to suppress SG formation and IFN-ß gene transcription is conserved in the 2Apro of EV-A71, CV-A21, and EV-D68. Collectively, our results indicate that enterovirus 2Apro plays a key role in inhibiting innate antiviral cellular responses.IMPORTANCE Enteroviruses are important pathogens that can cause a variety of diseases in humans, including aseptic meningitis, myocarditis, hand-foot-and-mouth disease, conjunctivitis, and acute flaccid paralysis. Like many other viruses, enteroviruses must counteract antiviral cellular responses to establish an infection. It has been suggested that enterovirus proteases cleave cellular factors to perturb antiviral pathways, but the exact contribution of viral proteases 2Apro and 3Cpro remains elusive. Here, we show that 2Apro, but not 3Cpro, of all four human EV species (EV-A to EV-D) inhibits SG formation and IFN-ß gene transcription. Our observations suggest that enterovirus 2Apro has a conserved function in counteracting antiviral host responses and thereby is the main enterovirus "security protein." Understanding the molecular mechanisms of enterovirus immune evasion strategies may help to develop countermeasures to control infections with these viruses.

Foot-and-Mouth Disease Virus Leader Protease Cleaves G3BP1 and G3BP2 and Inhibits Stress Granule Formation.

Like other viruses, the picornavirus foot-and-mouth disease virus (FMDV; genus Aphthovirus), one of the most notorious pathogens in the global livestock industry, needs to navigate antiviral host responses to establish an infection. There is substantial insight into how FMDV suppresses the type I interferon (IFN) response, but it is largely unknown whether and how FMDV modulates the integrated stress response. Here, we show that the stress response is suppressed during FMDV infection. Using a chimeric recombinant encephalomyocarditis virus (EMCV), in which we functionally replaced the endogenous stress response antagonist by FMDV leader protease (Lpro) or 3Cpro, we demonstrate an essential role for Lpro in suppressing stress granule (SG) formation. Consistently, infection with a recombinant FMDV lacking Lpro resulted in SG formation. Additionally, we show that Lpro cleaves the known SG scaffold proteins G3BP1 and G3BP2 but not TIA-1. We demonstrate that the closely related equine rhinitis A virus (ERAV) Lpro also cleaves G3BP1 and G3BP2 and also suppresses SG formation, indicating that these abilities are conserved among aphthoviruses. Neither FMDV nor ERAV Lpro interfered with phosphorylation of RNA-dependent protein kinase (PKR) or eIF2α, indicating that Lpro does not affect SG formation by inhibiting the PKR-triggered signaling cascade. Taken together, our data suggest that aphthoviruses actively target scaffolding proteins G3BP1 and G3BP2 and antagonize SG formation to modulate the integrated stress response.IMPORTANCE The picornavirus foot-and-mouth disease virus (FMDV) is a notorious animal pathogen that puts a major economic burden on the global livestock industry. Outbreaks have significant consequences for animal health and product safety. Like many other viruses, FMDV must manipulate antiviral host responses to establish infection. Upon infection, viral double-stranded RNA (dsRNA) is detected, which results in the activation of the RNA-dependent protein kinase (PKR)-mediated stress response, leading to a stop in cellular and viral translation and the formation of stress granules (SG), which are thought to have antiviral properties. Here, we show that FMDV can suppress SG formation via its leader protease (Lpro). Simultaneously, we observed that Lpro can cleave the SG scaffolding proteins G3BP1 and G3BP2. Understanding the molecular mechanisms of the antiviral host response evasion strategies of FMDV may help to develop countermeasures to control FMDV infections in the future.

Transition in Frailty State Among Elderly Patients After Vascular Surgery.

BACKGROUND: Frailty in the vascular surgical ward is common and predicts poor surgical outcomes. The aim of this study was to analyze transitions in frailty state in elderly patients after vascular surgery and to evaluate influence of patient characteristics on this transition. METHODS: Between 2014 and 2018, 310 patients, ≥65 years and scheduled for elective vascular surgery, were included in this cohort study. Transition in frailty state between preoperative and follow-up measurement was determined using the Groningen Frailty Indicator (GFI), a validated tool to measure frailty in vascular surgery patients. Frailty is defined as a GFI score ≥4. Patient characteristics leading to a transition in frailty state were analyzed using multivariable Cox regression analysis. RESULTS: Mean age was 72.7 ± 5.2 years, and 74.5% were male. Mean follow-up time was 22.7 ± 9.5 months. At baseline measurement, 79 patients (25.5%) were considered frail. In total, 64 non-frail patients (20.6%) shifted to frail and 29 frail patients (9.4%) to non-frail. Frail patients with a high Charlson Comorbidity Index (HR = 0.329 (CI: 0.133-0.812), p = 0.016) and that underwent a major vascular intervention (HR = 0.365 (CI: 0.154-0.865), p = 0.022) had a significantly higher risk to remain frail after the intervention. CONCLUSIONS: The results of this study, showing that after vascular surgery almost 21% of the non-frail patients become frail, may lead to a more effective shared decision-making process when considering treatment options, by providing more insight in the postoperative frailty course of patients.

Vascular Surgery Patients at Risk for Malnutrition Are at an Increased Risk of Developing Postoperative Complications.

BACKGROUND: Malnutrition is an important risk factor for adverse postoperative outcomes such as infection and delayed wound healing, often resulting in longer hospital stay and higher readmission and mortality rates. The aim of this study is to assess the relationship between the risk for malnutrition prior to elective vascular surgery and postoperative complications. METHODS: In this observational cross-sectional study, elective vascular surgery patients were included from January 2015 until November 2018. Included were percutaneous, carotid, endovascular, peripheral bypass, abdominal, lower extremity amputation, and other interventions. The patients were assessed for risk for malnutrition using the Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF), whereby <4 points was defined as low risk, 4-8 points as medium risk, and ≥9 points as high risk for malnutrition. Postoperative complications were registered using the Comprehensive Complication Index. Univariate and multivariate analyses were performed to evaluate the relationship between risk for malnutrition and postoperative complications. RESULTS: Of 468 patients, 113 (24.1%) were found to be at risk for malnutrition (PG-SGA SF ≥4 points). Occurrence of postoperative complications (23.9% in the low risk vs. 51.9% in the high risk group, P = 0.006), length of hospital stay (5.5 ± 4.3 days in the low risk vs. 8.2 ± 5.1 in the high risk group, P = 0.005), 30-day readmission (4.7% in the low risk vs. 19.2% in the high risk group, P = 0.009), and Comprehensive Complication Index (median score of 0 in the low risk vs. 8.7 in the high risk group, P = 0.018) varied significantly between the 3 PG-SGA SF groups. After multivariate analysis, the medium risk for malnutrition group had a 1.39 (95% confidence interval 1.05-1.84) times higher Comprehensive Complication Index than the low risk for malnutrition group (P = 0.02). CONCLUSIONS: Electively operated vascular surgery patients at risk for malnutrition are more likely to develop postoperative complications. This finding suggests that improving the nutritional status of vascular surgery patients prior to surgery has the potential to reduce the risk of complications.

The Effect of Frailty on Outcome After Vascular Surgery.

OBJECTIVES: Frailty is a state of increased vulnerability and is a stronger predictor for post-operative outcome than age alone. The aim of this study was to determine whether frailty is associated with adverse 30 day outcome in vascular surgery patients. METHODS: This was a prospective cohort study. All electively operated vascular surgery patients between March 2010 and October 2017 (n = 1201), aged ≥ 60 years were evaluated prospectively. Exclusion criteria were arteriovenous access surgery, percutaneous interventions and minor amputations, resulting in 825 patients for further analysis whereas 195 had incomplete data on Groningen Frailty Indicator (GFI) and were excluded. Frailty was measured using the GFI, a screening tool covering 16 items in the domains of functioning. Patients with a total score of ≥4 were classified as frail. The primary outcome parameter was 30 day morbidity (based on the Comprehensive Complication Index). Secondary outcome measures were 30 day mortality, hospital readmission, and type of care facility after discharge. Outcomes were adjusted for sex, body mass index, smoking status, hypertension, Charlson Comorbidity Index, and type of intervention. RESULTS: There was an unequal sex distribution (77.6% male). The mean age was 72.1 years. One hundred and eighty-four patients (22.3%) were considered frail. The mean Comprehensive Complication Index was 8.5. Frail patients had a significantly higher Comprehensive Complication Index (3.7 point increase, p = .005). Patients with impaired cognition and reduced psychosocial condition, two domains of the GFI, had a significantly higher Comprehensive Complication Index. Also, the 30 day mortality rate was higher in frail patients (2.7 point increase; p = .05), and they were discharged to a care facility more often (7.7 point increase; p < .001). There was no significant difference in readmission rates between frail and non-frail patients. CONCLUSIONS: Frailty is associated with a higher risk of post-operative complications and discharge to a nursing home after vascular surgery. Some frailty domains (mobility, nutrition, cognition and psychosocial condition) appear to have a more pronounced impact.

The Effect of Metabolic Syndrome on the Occurrence of Restenosis After Carotid Endarterectomy.

OBJECTIVES: The metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular disease. The effect of MetS on clinical outcome in patients with cerebrovascular disease remains largely unknown because conflicting results have been published. This study aimed to determine the influence of MetS on the occurrence of restenosis after carotid endarterectomy (CEA). METHODS: All patients who underwent CEA between June 2003 and December 2014 in two tertiary academic referral centres in The Netherlands were included. MetS was defined if three or more of the following criteria were present: hypertension, obesity, high fasting serum blood glucose, high serum triglycerides, or low serum high density lipoprotein cholesterol. The primary outcome measure was the occurrence of ipsilateral restenosis after index surgery. The secondary outcome measure was (all cause) mortality during follow up. For the primary analysis, missing data were multiply imputed using multivariable imputation by chained equations. A Cox proportional hazards model was used to perform an adjusted analysis on the multiply imputed data sets. RESULTS: A total of 1668 CEA procedures (in 1577 patients) were performed. The presence or absence of MetS could not be determined in 263 patients because of missing data. There was no significant difference in freedom from restenosis in the MetS group vs. the no-MetS group (hazard ratio [HR], 1.10; 95% confidence interval [CI] 0.98-1.23; p = .10) or in all cause mortality (HR 1.20; 95% CI 0.94-1.54; p = .14). CONCLUSION: This study shows that MetS does not predict restenosis after CEA. Also, the presence of MetS did not influence patient survival negatively.

Knockout of cGAS and STING Rescues Virus Infection of Plasmid DNA-Transfected Cells.

It is well known that plasmid DNA transfection, prior to virus infection, negatively affects infection efficiency. Here, we show that cytosolic plasmid DNA activates the cGAS/STING signaling pathway, which ultimately leads to the induction of an antiviral state of the cells. Using a transient one-plasmid clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system, we generated cGAS/STING-knockout cells and show that these cells can be infected after plasmid DNA transfection as efficiently as nontransfected cells.

Predicting postoperative delirium after vascular surgical procedures.

OBJECTIVE: The objective of this study was to determine the incidence of and specific preoperative and intraoperative risk factors for postoperative delirium (POD) in electively treated vascular surgery patients. METHODS: Between March 2010 and November 2013, all vascular surgery patients were included in a prospective database. Various preoperative, intraoperative, and postoperative risk factors were collected during hospitalization. The primary outcome variable was the incidence of POD. Secondary outcome variables were any surgical complication, hospital length of stay, and mortality. RESULTS: In total, 566 patients were prospectively evaluated; 463 patients were 60 years or older at the time of surgery and formed our study cohort. The median age was 72 years (interquartile range, 66-77), and 76.9% were male. Twenty-two patients (4.8%) developed POD. Factors that differed significantly by univariate analysis included current smoking (P = .001), increased comorbidity (P = .001), hypertension (P = .003), diabetes mellitus (P = .001), cognitive impairment (P < .001), open aortic surgery or amputation surgery (P < .001), elevated C-reactive protein level (P < .001), and blood loss (P < .001). Multivariate logistic regression analysis revealed preoperative cognitive impairment (odds ratio [OR], 16.4; 95% confidence interval [CI], 4.7-57.0), open aortic surgery or amputation surgery (OR, 14.0; 95% CI, 3.9-49.8), current smoking (OR, 10.5; 95% CI, 2.8-40.2), hypertension (OR, 7.6; 95% CI, 1.9-30.5) and age ≥80 years (OR, 7.3; 95% CI, 1.8-30.1) to be independent predictors of the occurrence of POD. The combination of these parameters allows us to predict delirium with a sensitivity of 86% and a specificity of 92%. The area under the curve of the corresponding receiver operating characteristics was 0.93. Delirium was associated with longer hospital length of stay (P < .001), more frequent and increased intensive care unit stays (P = .008 and P = .003, respectively), more surgical complications (P < .001), more postdischarge institutionalization (P < .001), and higher 1-year mortality rates (P = .0026). CONCLUSIONS: In vascular surgery patients, preoperative cognitive impairment and open aortic or amputation surgery were highly significant risk factors for the occurrence of POD. In addition, POD was significantly associated with a higher mortality and more institutionalization. Patients with these risk factors should be considered for high-standard delirium care to improve these outcomes.

A limited and customized follow-up seems justified after endovascular abdominal aneurysm repair in octogenarians.

OBJECTIVE: The objective of this study was to determine whether long-term follow-up after endovascular aneurysm repair (EVAR) is justified in octogenarians. METHODS: Between September 1996 and October 2011, all patients, including octogenarians, treated for an abdominal aortic aneurysm (AAA) by EVAR were included in a prospective database. Patients older than 80 years and with a nonruptured infrarenal aneurysm treated electively or urgently were included in the study (study group [SG]). Patients with ruptured aneurysms and patients who died during surgery or within the first postoperative month were excluded from further analysis. The control group (CG) consisted of patients younger than 80 years, matched for gender and AAA diameter. All patients were evaluated 4 to 8 weeks after EVAR and then annually thereafter. Follow-up data were complemented by review of the computerized hospital registry and charts and by contact of the patient's general practitioner or referring hospital. Primary outcomes were stent- or aneurysm-related complications and interventions. Secondary outcomes were additional surgical complications and patient survival. RESULTS: A total number of 193 patients (SG, n = 97; CG, n = 96) were included for analysis. Median age was 80 years, and 88.6% were male. Median follow-up time was 33.6 months (interquartile range [IQR], 12.9-68.3). Stent- and procedure-related postoperative complications were comparable between groups (SG, 41.2%; CG, 39.6%; P = .82). Median time to complication was 2.3 months (IQR, 0.2-19.4) in the SG compared with 18.1 months (IQR, 6.8-50.5) in the CG. The 2-year complication-free survival rates were 58% (SG) and 60% (CG). Interventions were performed significantly less frequently in octogenarians (SG, 8.2%; CG, 19.8%; P < .05). Median time to intervention was 11.1 months (IQR, 2.0-31.0) in the SG compared with 54.3 months (IQR, 15.0-93.2) in the CG. The 2-year intervention-free survival rates were 90% (SG) and 92% (CG). During follow-up, 98 patients died (SG, n = 54; CG, n = 44); median time to death was 31.8 months (IQR, 13.3-66.0) in the SG compared with 44.4 months (IQR, 15.0-77.7) in the CG. One aneurysm-related death occurred in the CG. The 2- and 5-year survival rates were 71% and 32% for the SG compared with 77% and 66% for the CG (P < .05). CONCLUSIONS: Because of the low incidence of secondary procedures and AAA-related deaths in octogenarians, long-term and frequent follow-up after EVAR seems questionable. An adapted and shortened follow-up seems warranted in this patient group.

C-reactive protein predicts postoperative delirium following vascular surgery.

BACKGROUND: The etiology of postoperative delirium (POD) following vascular surgery is generally unknown. The incidence, however, can be as high as 35%. A possible neuroinflammatory basis for delirium is likely and C-reactive protein (CRP) as a marker for inflammation can possibly play a predictive role. METHODS: Between March 2010 and September 2012, 277 consecutive elective vascular surgery patients were prospectively evaluated for the diagnosis of POD. Various potential risk factors, including postoperative CRP values, were collected. RESULTS: The mean age of the patients was 69 ± 11 years (range 21-92). The mean hospital length of stay was 6 ± 4 days (range 1-33). Sixteen patients (6%) developed POD during hospital stay. Univariate analysis revealed multiple comorbidities (P = 0.001), postoperative elevated CRP levels (P = 0.001), intensive care unit admittance (P = 0.01), and open aortic surgery or amputation procedures (P = 0.0001) to be significantly related to the diagnosis POD. Multivariate logistic regression analysis confirmed the relationship between an elevated CRP value and POD (odds ratio [OR] 1.01, 95% confidence interval 1.00-1.03, P = 0.04). The sensitivity analyses yielded essentially similar results. Based on OR, it can be calculated that the risk of POD is increased by approximately 35% if the CRP concentration is 50 mg/L, and by approximately 90% if the CRP concentration is 100 mg/L (compared with a CRP concentration of 5 mg/L). Thirty-one percent (5/16) of patients with POD needed a long-stay care facility after discharge (P = 0.0001). CONCLUSIONS: In this study, CRP can be used as a marker for an increased risk of POD after vascular surgery. In addition, it was found that POD was associated with a 10-fold increase in the need of long-stay care after discharge.

Accommodating the Bayley-III for motor and/or visual impairment: a comparative pilot study.

PURPOSE: This study assessed the validity and usefulness of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) Low Motor/Vision accommodated version. Accommodations are adaptations to minimize impairment bias, without altering what the test measures. Of the items, 66% have Low Motor accommodations like enlarged materials; 62% have Low Vision accommodations. METHODS: Using a within-subject design, we tested 19 children with the accommodated and standard Bayley-III, in a randomly counterbalanced order. The children had motor and/or visual impairment and a chronological age between 22 and 90 months. The test administrators completed an evaluation form. RESULTS: A subgroup of children benefited from the accommodations; 2 children obtained a large raw score difference. Test administrators considered the accommodations as practical, and advantageous for most children. CONCLUSION: The Low Motor/Vision accommodated version seems to validly assess the development of this population. Future, larger-scale research should study whether the accommodations improve the construct validity of the Bayley-III.