Phage-Encoded Sigma Factors Alter Bacterial Dormancy.

By entering a reversible state of reduced metabolic activity, dormant microorganisms are able to tolerate suboptimal conditions that would otherwise reduce their fitness. Dormancy may also benefit bacteria by serving as a refuge from parasitic infections. Here, we focus on dormancy in the Bacillota, where endospore development is transcriptionally regulated by the expression of sigma factors. A disruption of this process could influence the survivorship or reproduction of phages that infect spore-forming hosts with implications for coevolutionary dynamics. We characterized the distribution of sigma factors in over 4,000 genomes of diverse phages capable of infecting hosts that span the bacterial domain. From this, we identified homologs of sporulation-specific sigma factors in phages that infect spore-forming hosts. Unlike sigma factors required for phage reproduction, we provide evidence that sporulation-like sigma factors are nonessential for lytic infection. However, when expressed in the spore-forming Bacillus subtilis, some of these phage-derived sigma factors can activate the bacterial sporulation gene network and lead to a reduction in spore yield. Our findings suggest that the acquisition of host-like transcriptional regulators may allow phages to manipulate a complex and ancient trait in one of the most abundant cell types on Earth. IMPORTANCE As obligate parasites, phages exert strong top-down pressure on host populations with eco-evolutionary implications for community dynamics and ecosystem functioning. The process of phage infection, however, is constrained by bottom-up processes that influence the energetic and nutritional status of susceptible hosts. Many phages have acquired auxiliary genes from bacteria, which can be used to exploit host metabolism with consequences for phage fitness. In this study, we demonstrate that phages infecting spore-forming bacteria carry homologs of sigma factors, which their hosts use to orchestrate gene expression during spore development. By tapping into regulatory gene networks, phages may manipulate the physiology and survival strategies of nongrowing bacteria in ways that influence host-parasite coevolution.

BCI learning induces core-periphery reorganization in M/EEG multiplex brain networks.

Objective.Brain-computer interfaces (BCIs) constitute a promising tool for communication and control. However, mastering non-invasive closed-loop systems remains a learned skill that is difficult to develop for a non-negligible proportion of users. The involved learning process induces neural changes associated with a brain network reorganization that remains poorly understood.Approach.To address this inter-subject variability, we adopted a multilayer approach to integrate brain network properties from electroencephalographic and magnetoencephalographic data resulting from a four-session BCI training program followed by a group of healthy subjects. Our method gives access to the contribution of each layer to multilayer network that tends to be equal with time.Main results.We show that regardless the chosen modality, a progressive increase in the integration of somatosensory areas in theαband was paralleled by a decrease of the integration of visual processing and working memory areas in theßband. Notably, only brain network properties in multilayer network correlated with future BCI scores in theα2band: positively in somatosensory and decision-making related areas and negatively in associative areas.Significance.Our findings cast new light on neural processes underlying BCI training. Integrating multimodal brain network properties provides new information that correlates with behavioral performance and could be considered as a potential marker of BCI learning.

Characterization of MR Imaging-Visible Perivascular Spaces in the White Matter of Healthy Adolescents at 3T.

BACKGROUND AND PURPOSE: Perivascular spaces play a role in cerebral waste removal and neuroinflammation. Our aim was to provide data regarding the burden of MR imaging-visible perivascular spaces in white matter in healthy adolescents using an automated segmentation method and to establish relationships between common demographic characteristics and perivascular space burden. MATERIALS AND METHODS: One hundred eighteen 12- to 21-year-old subjects underwent T1- and T2-weighted 3T MR imaging as part of the National Consortium on Alcohol and Neurodevelopment in Adolescence. Perivascular spaces were identified in WM on T2-weighted imaging using a local heterogeneity approach coupled with morphologic constraints, and their spatial distribution and geometric characteristics were assessed. RESULTS: MR imaging-visible perivascular spaces were identified in all subjects (range, 16-287). Males had a significantly higher number of perivascular spaces than females: males, mean, 98.4 ± 50.5, versus females, 70.7 ± 36.1, (P < .01). Perivascular space burden was bilaterally symmetric (r > 0.4, P < .01), and perivascular spaces were more common in the frontal and parietal lobes than in the temporal and occipital lobes (P < .01). Age and pubertal status were not significantly associated with perivascular space burden. CONCLUSIONS: Despite a wide range of burden, perivascular spaces are present in all healthy adolescents. Perivascular space burden is higher in adolescent males than in females, regardless of age and pubertal status. In this population, perivascular spaces are highly symmetric. Although widely reported as a feature of the aging brain, awareness of the presence of perivascular spaces in a cohort of healthy adolescents provides the foundation for further research regarding the role of these structural variants in health and disease.

Distinguishing Extravascular from Intravascular Ferumoxytol Pools within the Brain: Proof of Concept in Patients with Treated Glioblastoma.

BACKGROUND AND PURPOSE: Glioblastoma-associated macrophages are a major constituent of the immune response to therapy and are known to engulf the iron-based MR imaging contrast agent, ferumoxytol. Current ferumoxytol MR imaging techniques for localizing macrophages are confounded by contaminating intravascular signal. The aim of this study was to assess the utility of a newly developed MR imaging technique, segregation and extravascular localization of ferumoxytol imaging, for differentiating extravascular-from-intravascular ferumoxytol contrast signal at a delayed 24-hour imaging time point. MATERIALS AND METHODS: Twenty-three patients with suspected post-chemoradiotherapy glioblastoma progression underwent ferumoxytol-enhanced SWI. Segregation and extravascular localization of ferumoxytol imaging maps were generated as the voxelwise difference of the delayed (24 hours) from the early (immediately after administration) time point SWI maps. Continuous segregation and extravascular localization of ferumoxytol imaging map values were separated into positive and negative components. Image-guided biologic correlation was performed. RESULTS: Negative segregation and extravascular localization of ferumoxytol imaging values correlated with early and delayed time point SWI values, demonstrating that intravascular signal detected in the early time point persists into the delayed time point. Positive segregation and extravascular localization of ferumoxytol imaging values correlated only with delayed time point SWI values, suggesting successful detection of the newly developed extravascular signal. CONCLUSIONS: Segregation and extravascular localization of ferumoxytol MR imaging improves on current techniques by eliminating intrinsic tissue and intravascular ferumoxytol signal and may inform glioblastoma outcomes by serving as a more specific metric of macrophage content compared with uncorrected T1 and SWI techniques.

Post-polypectomy surveillance colonoscopy: are we following the guidelines?

PURPOSE: Polyps are a common finding on colonoscopy procedures. After completing polypectomy, patients are to be followed up with endoscopy. The purpose of the study was to assess the adherence of gastroenterologists to international post-polypectomy guidelines. METHODS: Israeli gastroenterologists answered a questionnaire, consisting of 30 items, regarding the recommendation for post-polypectomy surveillance following colonoscopy. RESULTS: One hundred and twelve gastroenterologists, representing 23% of the total number of Israeli gastroenterologists, participated in this study, by responding to the web-based questionnaire (mean age is 47 ± 10 years, males, 74 (66%)). From the total responses, 57.4% were compatible with the updated European post-polypectomy guidelines. The recommendations appeared remarkably inappropriate when applied to polyps that were identified as having low-risk tubular adenoma, tubular adenoma with high-grade dysplasia, and small serrated adenoma. In 37.2% of questionnaires, the recommended time to follow-up colonoscopy was shorter than currently stated in the guidelines. The appropriate polypectomy technique was chosen by 62% of the responses. Gastroenterologists younger than 45 years of age adhered more strongly to the international guidelines, particularly in cases of piecemeal polypectomy or high-risk adenoma polypectomy. CONCLUSIONS: Gastroenterologists follow the clinical guidelines for post-polypectomy surveillance intervals partially. 57.4% of the recommendations were compatible with the guidelines, whereas 37% of the recommendations were for shorter interval.

Antibiotic decision making in surgical intensive care: a qualitative analysis.

BACKGROUND: Antibiotic use in hospitals is high, particularly in surgical specialty and intensive care units. Antimicrobial stewardship programmes (ASPs) are increasingly intervening in antibiotic use by surgeons and intensivists. However, there is limited information on the features which characterize antibiotic decision making in the surgical intensive care unit (SICU), an area in hospital practice where critically ill surgery patients can be kept under close observation. AIM: To explore the features which characterize antibiotic decision making in the SICU. METHODS: A total of 160 h of ethnographic observation and 10 semi-structured interviews were conducted at two teaching hospitals in the USA. Data were analysed using thematic coding. FINDINGS: Three key characteristics of SICU practice with regard to antibiotic use were identified: (1) physical proximity makes SICU clinicians acutely aware of changes in patient status; (2) communication of patient status relies on active involvement by SICU clinicians; (3) SICU clinicians have contested and variable autonomy over antibiotic decisions. CONCLUSIONS: Antibiotic decision making in the SICU is a complex process involving multiple clinician teams with varying levels of physical proximity to and autonomy over patient cases. This study found that the SICU clinician team has increased physical proximity to patient cases but little autonomy over antibiotic decisions. If these characteristics are not considered, antimicrobial stewardship (AMS) interventions may have diminished success in addressing high levels of the antibiotic use in the SICU.

Combining VITEK® 2 with colistin agar dilution screening assist timely reporting of colistin susceptibility.

OBJECTIVES: The rise in carbapenem resistance among Gram-negative bacteria has renewed interest in colistin. Recently, the EUCAST-CLSI Polymyxin Breakpoints Working Group declared that broth microdilution (BMD) is the only valid method for colistin susceptibility testing. BMD is not easily incorporated into the routine work of clinical laboratories, and usually this test is incorporated serially, resulting in delayed susceptibility reporting. We tested a strategy of combining VITEK® 2 with a 2 µg/mL colistin agar dilution (VITEK® 2/AD) screening plate to improve performance and time to reporting of colistin susceptibility. METHODS: Colistin susceptibility for 364 clinical isolates was determined by VITEK® 2/AD and compared with the reference standard BMD according to the ISO 20776-1:2007 and CLSI guidelines. The EUCAST colistin susceptibility breakpoint of ≤2 µg/mL was used. Escherichia coli NCTC 13846 served as quality control strain. Agreement, very major error (VME) and major error rates were determined using ISO 20776-2:2007. RESULTS: The VME rate for VITEK® 2 alone was 30.6% (15/49, 95% CI 18.3-45.4%), and was reduced to 10.2% (5/49, 95% CI 3.4-22.2%) using the VITEK® 2/AD combined testing. The combined testing had categorical agreement with BMD of 97% (354/364, 95% CI 95.0-98.7%), and a major error (ME) rate of 1.6% (5/315, 95% CI 0.5-3.7%). Using the combined testing, even against challenging strains, 349 (95.8%, 95% CI 93.3-97.7%) colistin susceptibility results could be reported, and only 15 isolates required further analysis by BMD. DISCUSSION: Our method is simple to apply and allows rapid reporting of colistin susceptibility.

Long-Term Effects of Pregnancy on Renal Graft Function in Women After Kidney Transplantation Compared With Matched Controls.

BACKGROUND: An important benefit associated with kidney transplantation in women of child-bearing age is increased fertility. We retrospectively evaluated the maternal and fetal complications and evolution of graft function associated with 22 pregnancies post-kidney and kidney-pancreas transplantation, compared with controls without pregnancy post-transplantation, who were matched for gender, year of transplantation, type of donor, age at transplantation, number of transplants, type of transplant (kidney vs kidney-pancreas), and cause of native kidney failure, as well as for renal parameters including serum creatinine and urine protein excretion 1 year before delivery. RESULTS: The mean age at time of transplantation was 22.32 (range, 19.45-33.1) years. The mean interval between transplantation and delivery was 75.7 (range, 34-147.8) months. Main maternal complications were pre-eclampsia in 27.3%. The main fetal complications included delayed intrauterine growth (18.2%), preterm deliveries (89.4%), and one death at 3 days postdelivery. The mean serum creatinine level pre-pregnancy was 1.17 (range, 0.7-3.1) mg/dL. Graft failure was higher in the pregnancy group (6 vs 3) but did not differ statistically from the control group, and was associated with creatinine pre-pregnancy (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.15-3.45; P = .04), age at transplantation (1.13 [1.03-1.21]; P = .032), and time of follow-up (2.14 [1.27-2.98]; P = .026). Delta serum creatinine was not different in both groups: 1.05 ± 0.51 versus 0.99 ± 0.92 mg/dL, study versus control group, respectively (P = .17). CONCLUSION: Pregnancy after kidney transplantation is associated with serious maternal and fetal complications. We did not observe a significantly increased risk of graft loss or reduced graft function in comparison with recipients with similar clinical characteristics.

Analytical validation of a new point-of-care assay for serum amyloid A in horses.

BACKGROUND: Serum amyloid A (SAA) is a major acute phase protein in horses. A new point-of-care (POC) test for SAA (Stablelab) is available, but studies evaluating its analytical accuracy are lacking. OBJECTIVES: To evaluate the analytical performance of the SAA POC test by 1) determining linearity and precision, 2) comparing results in whole blood with those in serum or plasma, and 3) comparing POC results with those obtained using a previously validated turbidimetric immunoassay (TIA). STUDY DESIGN: Assay validation. METHODS: Analytical validation of the POC test was done in accordance with American Society of Veterinary Clinical Pathology guidelines using residual equine serum/plasma and whole blood samples from the Clinical Pathology Laboratory at the University of California-Davis. A TIA was used as the reference method. We also evaluated the effect of haematocrit (HCT). RESULTS: The POC test was linear for SAA concentrations of up to at least 1000 µg/mL (r = 0.991). Intra-assay CVs were 13, 18 and 15% at high (782 µg/mL), intermediate (116 µg/mL) and low (64 µg/mL) concentrations. Inter-assay (inter-batch) CVs were 45, 14 and 15% at high (1372 µg/mL), intermediate (140 µg/mL) and low (56 µg/mL) concentrations. SAA results in whole blood were significantly lower than those in serum/plasma (P = 0.0002), but were positively correlated (r = 0.908) and not affected by HCT (P = 0.261); proportional negative bias was observed in samples with SAA>500 µg/mL. The difference between methods exceeded the 95% confidence interval of the combined imprecision of both methods (15%). MAIN LIMITATIONS: Analytical validation could not be performed in whole blood, the sample most likely to be used stall side. CONCLUSION: The POC test has acceptable accuracy and precision in equine serum/plasma with SAA concentrations of up to at least 1000 µg/mL. Low inter-batch precision at high concentrations may affect serial measurements, and the use of the same test batch and sample type (serum/plasma or whole blood) is recommended. Comparison of results between the POC test and the TIA is not recommended.

A randomized, controlled clinical trial to evaluate the immunogenicity of a PreS/S hepatitis B vaccine Sci-B-Vac™, as compared to Engerix B®, among vaccine naïve and vaccine non-responder dialysis patients.

BACKGROUND: Dialysis patients have a suboptimal response to hepatitis B (HBV) vaccination. This study aimed to compare the immunogenicity of two vaccines: the third-generation Sci-B-Vac™ vs. the second-generation Engerix B®. The cohort included two groups of dialysis patients: naïve and previously vaccinated non-responders. Primary endpoints were antibody titers ≥10 IU/L at 3 and 7 month post-vaccination. Secondary objectives were seroprotection rates in vaccine-naïve patients and in previously vaccinated non-responders. METHODS: Eighty-six patients were assigned to vaccine (Sci-B-Vac™ or Engerix B®) using computer-generated randomization, stratified by age, gender, diabetes, and previous HBV vaccination. Sci-B-Vac™ was administered in three doses, 10 µg, at 0, 1, and 6 months in naïve patients; or 20 µg in previously vaccinated non-responders. Engerix B® included four doses, 40 µg at 0, 1, 2, and 6 months. RESULTS: Each group had 43 patients. Seroconversion was 69.8% with Engerix B® vs. 73.2% with Sci-B-Vac™. Antibody titers at 7 months were higher with Sci-B-Vac™ (266.4 ± 383.9, median 53.4) than with Engerix® (193.2 ± 328.9, median 19). However, these differences were not significant, perhaps due to a suboptimal sample size. CONCLUSIONS: This study suggests comparable immunogenicity for both vaccines. Thus, we cannot reject the null hypothesis that there is no difference in seroconversion by vaccine type. It is noteworthy that naïve patients were vaccinated with a standard dose of Sci-B-Vac™, while Engerix B® was administered at a double dose. Similarly, although mean antibody titer levels in the Sci-B-Vac™ group were higher than in the Engerix® group, this difference did not reach significance. Consequently, a future clinical trial should recruit a larger cohort of patients, using a standard double-dose protocol in both groups.

Loss of brain inter-frequency hubs in Alzheimer's disease.

Alzheimer's disease (AD) causes alterations of brain network structure and function. The latter consists of connectivity changes between oscillatory processes at different frequency channels. We proposed a multi-layer network approach to analyze multiple-frequency brain networks inferred from magnetoencephalographic recordings during resting-states in AD subjects and age-matched controls. Main results showed that brain networks tend to facilitate information propagation across different frequencies, as measured by the multi-participation coefficient (MPC). However, regional connectivity in AD subjects was abnormally distributed across frequency bands as compared to controls, causing significant decreases of MPC. This effect was mainly localized in association areas and in the cingulate cortex, which acted, in the healthy group, as a true inter-frequency hub. MPC values significantly correlated with memory impairment of AD subjects, as measured by the total recall score. Most predictive regions belonged to components of the default-mode network that are typically affected by atrophy, metabolism disruption and amyloid-ß deposition. We evaluated the diagnostic power of the MPC and we showed that it led to increased classification accuracy (78.39%) and sensitivity (91.11%). These findings shed new light on the brain functional alterations underlying AD and provide analytical tools for identifying multi-frequency neural mechanisms of brain diseases.

Coping strategies, satisfaction with life, and quality of life in Crohn's disease: A gender perspective using structural equation modeling analysis.

OBJECTIVE: To identify coping strategies and socio-demographics impacting satisfaction with life and quality of life in Crohn's disease (CD). METHODS: 402 patients completed the Patient Harvey-Bradshaw Index, Brief COPE Inventory, Satisfaction with Life Scale (SWLS), Short Inflammatory Bowel Disease Questionnaire (SIBDQ). We performed structural equation modeling (SEM) of mediators of quality of life and satisfaction with life. RESULTS: The cohort comprised: men 39.3%, women 60.1%; P-HBI 4.75 and 5.74 (p = 0.01). In inactive CD (P-HBI≤4), both genders had SWLS score 23.8; men had SIBDQ score 57.4, women 52.6 (p = 0.001); women reported more use of emotion-focused, problem-focused and dysfunctional coping than men. In active CD, SWLS and SIBDQ scores were reduced, without gender differences; men and women used coping strategies equally. A SEM model (all patients) had a very good fit (X2(6) = 6.68, p = 0.351, X2/df = 1.114, SRMR = 0.045, RMSEA = 0.023, CFI = 0.965). In direct paths, economic status impacted SWLS (ß = 0.39) and SIBDQ (ß = 0.12), number of children impacted SWLS (ß = 0.10), emotion-focused coping impacted SWLS (ß = 0.11), dysfunctional coping impacted SWLS (ß = -0.25). In an indirect path, economic status impacted dysfunctional coping (ß = -0.26), dysfunctional coping impacted SIBDQ (ß = -0.36). A model split by gender and disease activity showed that in active CD economic status impacted SIBDQ in men (ß = 0.43) more than women (ß = 0.26); emotional coping impacted SWLS in women (ß = 0.36) more than men (ß = 0.14). CONCLUSIONS: Gender differences in coping and the impacts of economic status and emotion-focused coping vary with activity of CD. Psychological treatment in the clinic setting might improve satisfaction with life and quality of life in CD patients.

Patient-centered quality of life measures after alloplastic temporomandibular joint replacement surgery.

The purpose of this study was to evaluate patient-reported outcome measures of quality of life (QoL) for patients with end-stage temporomandibular joint (TMJ) disease who have undergone TMJ prosthetic replacement. The records of 36 patients who had undergone alloplastic total joint replacement procedures were analyzed. Patients were treated using either TMJ Concepts or Biomet/Lorenz prosthetics. Patients were asked to complete a 12-item TMJ-S-QoL survey, which encompassed questions pertaining to pain, speech, chewing function, and various aspects of social life and mental health. The questions were answered on a 5-point scale. Data were analyzed using the Wilcoxon signed-rank test. Among the 36 patients (six male and 30 female), 18 responded to the survey. Markers of QoL after surgery were compared to the preoperative period. Significant improvements were reported for pain (94.4% of patients), chewing (83.3% of patients), speech (55.6% of patients), anxiety (72.2% of patients), activity (66.7% of patients), recreation (61.1% of patients), and mood (66.7% of patients) (all P<0.05). TMJ prosthetic replacement significantly enhanced QoL among patients suffering from chronic pain, limited range of motion, anxiety, impaired speech, and chewing due to end-stage TMJ disease in this sample of surgical patients.

Evaluation of carriage and environmental contamination by carbapenem-resistant Acinetobacter baumannii.

We evaluated the sensitivity of surveillance cultures for carbapenem-resistant Acinetobacter baumannii (CRAB) in patients and in their environment. Patients with a CRAB-positive clinical culture were sampled within 7 days; the buccal mucosa and rectum were sampled using swabs, and skin was sampled using pre-moistened sterile sponges. Sponges were also used to sample the surrounding environment. Specimens were inoculated onto CHROMagar MDR Acinetobacter plates both directly and after overnight enrichment. CRAB load was scored semi-quantitatively and composite scores for patient colonization and environmental contamination were calculated. Thirty-four patients were included. Screening sensitivity was 28/34 (82%) for buccal mucosa, 30/34 (88%) for skin, and 25/34 (74%) for rectum. Combined sensitivity was 32/34 (94%). Among patients with CRAB-positive respiratory cultures, sensitivity for buccal mucosa was 20/20 (100%). Direct inoculation had excellent sensitivity: 25/28 (89%) for all three sites combined. In the subgroup of patients who did not have a respiratory source for CRAB, direct inoculation sensitivity was lower than among patients with CRAB-positive respiratory cultures: 5/8 (63%) versus 20/20 (100%). The environment of all patients was contaminated with CRAB. There was a positive correlation between the patient colonization score and the environmental contamination score (r = 0.63, p <0.001; r = 0.4, p 0.04 for buccal mucosa, r = 0.7, p <0.001 for skin, and r = 0.46, p 0.14 for rectum). In conclusion, screening for CRAB carriers can be performed by direct plating of skin and buccal mucosa samples. Environmental contamination is common and can be monitored. Implementing screening may facilitate infection control efforts to limit the spread of CRAB.

Time to Detection with BacT/Alert FA Plus Compared to BacT/Alert FA Blood Culture Media.

Rapid identification of the causative pathogen in patients with bacteremia allows adjustment of antibiotic therapy and improves patient outcomes. We compared in vitro and real-life time to detection (TTD) of two blood culture media, BacT/Alert FA (FA) and BacT/Alert FA Plus (FA Plus), for the nine most common species of bacterial pathogens recovered from blood samples. Experimental data from simulated cultures was compared with microbiology records of TTD for both culture media with growth of the species of interest in clinical blood cultures. In the experimental conditions, median TTD was 3.8 hours (23.9 %) shorter using FA Plus media. The magnitude of reduction differed between species. Similarly, in real life data, FA Plus had shorter TTD than FA media; however, the difference between culture media was smaller, and median TTD was only 1 hour (8.5 %) less. We found shorter TTD with BacT/Alert FA Plus culture media, both experimentally and in real-life conditions and unrelated to antibiotic neutralization, highlighting the importance of appropriate blood culture media selection.

Clinically relevant concentrations of lidocaine and ropivacaine inhibit TNFα-induced invasion of lung adenocarcinoma cells in vitro by blocking the activation of Akt and focal adhesion kinase.

BACKGROUND: Matrix-metalloproteinases (MMP) and cancer cell invasion are crucial for solid tumour metastasis. Important signalling events triggered by inflammatory cytokines, such as tumour necrosis factor α (TNFα), include Src-kinase-dependent activation of Akt and focal adhesion kinase (FAK) and phosphorylation of caveolin-1. Based on previous studies where we demonstrated amide-type local anaesthetics block TNFα-induced Src activation in malignant cells, we hypothesized that local anaesthetics might also inhibit the activation and/or phosphorylation of Akt, FAK and caveolin-1, thus attenuating MMP release and invasion of malignant cells. METHODS: NCI-H838 lung adenocarcinoma cells were incubated with ropivacaine or lidocaine (1 nM-100 µM) in absence/presence of TNFα (20 ng ml(-1)) for 20 min or 4 h, respectively. Activation/phosphorylation of Akt, FAK and caveolin-1 were evaluated by Western blot, and MMP-9 secretion was determined by enzyme-linked immunosorbent assay. Tumour cell migration (electrical wound-healing assay) and invasion were also assessed. RESULTS: Ropivacaine (1 nM-100 µM) and lidocaine (1-100 µM) significantly reduced TNFα-induced activation/phosphorylation of Akt, FAK and caveolin-1 in NCI-H838 cells. MMP-9 secretion triggered by TNFα was significantly attenuated by both lidocaine and ropivacaine (half-maximal inhibitory concentration [IC50]=3.29×10(-6) M for lidocaine; IC50=1.52×10(-10) M for ropivacaine). The TNFα-induced increase in invasion was completely blocked by both lidocaine (10 µM) and ropivacaine (1 µM). CONCLUSIONS: At clinically relevant concentrations both ropivacaine and lidocaine blocked tumour cell invasion and MMP-9 secretion by attenuating Src-dependent inflammatory signalling events. Although determined entirely in vitro, these findings provide significant insight into the potential mechanism by which local anaesthetics might diminish metastasis.

Clinical and demographic characteristics predictive of treatment outcomes for certolizumab pegol in moderate to severe Crohn's disease: analyses from the 7-year PRECiSE 3 study.

BACKGROUND: Clinical factors were previously identified as predictors of short-term treatment efficacy in Crohn's disease (CD). The PRECiSE 3 (P3) 7-year trial provides an opportunity to study predictors of short- and long-term clinical remission among CD patients treated with certolizumab pegol (CZP). AIM: To identify factors that influence long-term remission of CD with CZP treatment. METHODS: Patients who had completed placebo-controlled studies (PRECiSE 1/PRECiSE 2, P1/P2) enrolled in P3 and received open-label CZP 400 mg every 4 weeks up to 7 years. Baseline predictors included, but were not limited to, smoking status, disease duration, prior inflammatory bowel disease (IBD) surgery, Harvey-Bradshaw Index (HBI), albumin, haematocrit and CZP exposure; association with time to initial remission (HBI ≤4) was tested for patients who received CZP in P1/P2; time to loss of remission/frequency of maintenance of remission was also tested. Univariate analyses and multivariate Cox or logistic regression models were used. RESULTS: Predictors for initial remission (N = 377) included age, haematocrit, prior IBD surgery and entry HBI (P < 0.05 for all). Predictors for loss of remission (N = 437) included HBI, serum albumin concentration, haematocrit, smoking status and exposure. Predictors of maintenance of remission (N = 437) included haematocrit, IBD surgery, HBI, disease duration, serum albumin concentration and exposure. Significant predictors were confirmed with stepwise multivariate regression models. CONCLUSIONS: These analyses identified several influential parameters for short-and long-term remission of Crohn's disease with certolizumab pegol treatment. The data yield valuable hypotheses regarding factors that influence certolizumab pegol treatment. More investigation is needed. (ClinicalTrials.gov identifier NCT00552058).

Treatment Steps, Surgery, and Hospitalization Rates During the First Year of Follow-up in Patients with Inflammatory Bowel Diseases from the 2011 ECCO-Epicom Inception Cohort.

BACKGROUND AND AIMS: The ECCO-EpiCom study investigates the differences in the incidence and therapeutic management of inflammatory bowel diseases [IBD] between Eastern and Western Europe. The aim of this study was to analyse the differences in the disease phenotype, medical therapy, surgery, and hospitalization rates in the ECCO-EpiCom 2011 inception cohort during the first year after diagnosis. METHODS: Nine Western, five Eastern European centres and one Australian centre with 258 Crohn's disease [CD], 380 ulcerative colitis [UC] and 71 IBD unclassified [IBDU] patients [female/male: 326/383; mean age at diagnosis: 40.9 years, SD: 17.3 years] participated. Patients' data were registered and entered in the web-based ECCO-EpiCom database [www.epicom-ecco.eu]. RESULTS: In CD, 36 [19%] Western Europe/Australian and 6 [9%] Eastern European patients received biological therapy [p = 0.04], but the immunosuppressive [IS] use was equal and high in these regions [Eastern Europe vs Western Europe/Australia: 53% vs 45%; p = 0.27]. Surgery was performed in 17 [24%] CD patients in Eastern Europe and 13 [7%] in Western Europe/Australia [p < 0.001, pLogRank = 0.001]. Of CD patients from Eastern Europe, 24 [34%] were hospitalized, and 39 [21%] from Western Europe/Australia, [p = 0.02, pLogRank = 0.01]. In UC, exposure to biologicals and colectomy rates were low and hospitalization rates did not differ between these regions during the 1-year follow-up period [16% vs 16%; p = 0.93]. CONCLUSIONS: During the first year after diagnosis, surgery and hospitalization rates were significantly higher in CD patients in Eastern Europe compared with Western Europe/Australia, whereas significantly more CD patients were treated with biologicals in the Western Europe/Australian centres.