The effects of surface layer proteins isolated from Clostridium difficile on TLR4 signalling

Clostridium difficile (C. difficile) is a gram-positive, spore-forming, pathogenic bacterium that results in a range of gastrointestinal diseases. The incidence of C. difficile infection (CDI) has increased dramatically and has a significant impact on healthcare settings worldwide. The severity of disease may be dependent on the ribotype (RT) of C. difficile present. Previous research from our laboratory has shown that Surface Layer Proteins (SLPs) from RT 001 activate Toll-like receptor 4 (TLR4), with subsequent activation of downstream signalling pathways known to be important in the clearance of CDI. In this study we demonstrate that SLPs from RT 001 fail to activate IRF3 signalling, while SLPs from RT 027 activate both arms of the TLR4 pathway. Evidence from the literature suggests that microRNAs (miRNAs) tightly regulate TLR4 signalling and have a role in orchestrating the host’s immune response to infection. The profile of miRNAs regulated in response to SLPs from C. difficile has not been profiled before. Subsequently we identified novel miRNAs regulated in response to LPS, SLPs from RT 001 and RT 027 in vitro. We found 24 miRNAs were differentially regulated between SLPs in response to RT 001 and RT 027 and there was a global down regulation of miRNAs in response to SLPs from RT 027. These miRNAs may modulate TLR4 signalling. Data from colonic tissue, from an in vivo murine model show miR-146a, miR-145, miR-155 and let-7e may have a role in regulating the host’s immune response during early and late stage CDI. The absence of miRNAs regulated in response to RT 027 may correlate to less efficient clearance by the host’s immune response and more persistent infection. The miRNAs are predicted to target essential cell processes and the impact of the modulation of the immune response by these miRNAs may lead to biologically relevant changes at the cell level. Further work is needed to fully elucidate the complexities of these miRNAs in relation to the networks they modulate. The effectiveness of current treatments is limited by a lack of response in some patients and high recurrence rates. The data generated in this study may be used to develop miRNA based therapy for the treatment of persistent CDI, allowing bacterial clearance by the host’s immune system without the need for antibiotics

The Vehicle, Spring 1985

Vol. 26, No. 2 Table of Contents Beyond the FieldsKeila Tooleypage 3 Lonely Sculptor Accustomed to Living AloneMichelle Mitchellpage 4 Mona LisaBob Zordanipage 4 Poet Born in Pearl HarborAngelique Jenningspage 5 IntroductionsGraham Lewispage 6 Living InsideJennifer Soulepage 9 PictureKathy Greypage 10 Salvadore Dali in a Wheelchair on TVAngelique Jenningspage 11 Sonata in E FlatBecky Lawsonpage 12 Myopia and Wild KingdomMichelle Mitchellpage 12 On Becoming a GrandmotherKeila Tooleypage 13 A VisionJennifer D. Pringlepage 14 The Covered BridgeDebbie Woodleypage 14 Jacob\u27s LifeJoan Sebastianpage 15 ForgotGraham Lewispage 15 A Dozen and One TrainsongsAngelique Jenningspage 16 Women\u27s PlaceJennifer Soulepage 19 Night SailingKim Dumentatpage 20 She Isn\u27t There WhenMichelle Mitchellpage 20 A Case for the Common ColdMaggie Kennedypage 21 the cityTammy Batespage 22 The RattlesnakeEric S. McGeepage 22 New PictureKeila Tooleypage 23 Lewis and SinGraham Lewispage 24 Funny BarbecueBob Zordanipage 26 In a DreamF. Link Rapierpage 26 The Winter\u27s ColdJennifer Soulepage 27 Diary EntryTammy Batespage 27 Minor God and Patron Saint of Rabbits SpeaksAngelique Jenningspage 28 A MomentBrett Wilhelmpage 29 The Bishop SeatF. Link Rapierpage 30 The Thought of Being Rid of MyselfKeila Tooleypage 33 I Saw A ChildBea Cessnapage 33 Complacent gourmetGary Burrowspage 34 Night DreamsJennifer Soulepage 35 Changing ImagesAmy Callpage 35 Olsen Rug Co. Waterfall & ParkMaggie Kennedypage 36 Edge of the WildF. Link Rapierpage 37 DragonS. Hillpage 37 Harvests of CornBob Zordanipage 38 The Club JeromeGary Burrowspage 39 Tarzan And The CabPatrick Peterspage 39 The Rain That Never CameLynanne Feilenpage 40 Wonderment of the Far CrescentF. Link Rapierpage 40https://thekeep.eiu.edu/vehicle/1047/thumbnail.jp

The Vehicle, Fall 1983

Vol. 25, No. 1 Table of Contents Amish BoyDevon Flesorpage 3 SyllogismJ. Maura Davispage 3 Ten SecondsD.L. Lewispage 4 The Cedar ChestBridget M. Howepage 4 A Christmas With CarolSteve Longpage 5 TeethMichelle Mitchellpage 7 An I-Love-You PoemD.L. Lewispage 8 The Dragon SlayerSusan Gradypage 8 A DefinitionAmy J. Eadespage 9 FingernailsSuzanne Hornpage 10 The Liar\u27s TableBrook Wilsonpage 10 Fifi\u27s Last PartySteve Longpage 12 Absence/PresenceSuzanne Hornpage 13 From the Rantings of a Mad Astronomy StudentAmy J. Eadespage 13 In the Name of the Father, the Son, and MachiavelliF. Link Rapierpage 15 Errant LoverBecky Lawsonpage 16 DaddyKevin Lylespage 16 GhostsGary Ervinpage 17 TangoF. Link Rapierpage 17 Grandma\u27s SlippersBecky Lawsonpage 18 EdgesAmy J. Eadespage 19 Having ChildrenDevon Flesorpage 20 Young Black GirlKevin Lylespage 21 CatSuzanne Hornpage 22 Breakfast for OneMichelle Mitchellpage 22 A Modest ProposalBrooke Sanfordpage 23 Post MortemF. Link Rapierpage 26 Who Said I Forgot?Lynne Krausepage 27 The Corner Booth at StuckeysMaggie Kennedypage 28 The First DayDavis Brydenpage 29 DownLynne Krausepage 30 Fairie RingDevon Flesorpage 31 The LaundrymatKathy Fordpage 32 Sunday in OctoberBridget M. Howepage 32 The Kitchen WindowMaggie Kennedypage 33 UntitledChristina Maire Vitekpage 34 8th Grade Field Trip to SpringfieldMichelle Mitchellpage 34 Children of the FortiesF. Link Rapierpage 35 one winter and i was eightGary Ervinpage 35 Don\u27t we all know?Thomas B. Waltrippage 36 The TravelerMaggie Kennedypage 36 The VisitKathy Fordpage 40 CubismMaggie Kennedypage 40https://thekeep.eiu.edu/vehicle/1042/thumbnail.jp

The Vehicle, Fall 1983

Vol. 25, No. 1 Table of Contents Amish BoyDevon Flesorpage 3 SyllogismJ. Maura Davispage 3 Ten SecondsD.L. Lewispage 4 The Cedar ChestBridget M. Howepage 4 A Christmas With CarolSteve Longpage 5 TeethMichelle Mitchellpage 7 An I-Love-You PoemD.L. Lewispage 8 The Dragon SlayerSusan Gradypage 8 A DefinitionAmy J. Eadespage 9 FingernailsSuzanne Hornpage 10 The Liar\u27s TableBrook Wilsonpage 10 Fifi\u27s Last PartySteve Longpage 12 Absence/PresenceSuzanne Hornpage 13 From the Rantings of a Mad Astronomy StudentAmy J. Eadespage 13 In the Name of the Father, the Son, and MachiavelliF. Link Rapierpage 15 Errant LoverBecky Lawsonpage 16 DaddyKevin Lylespage 16 GhostsGary Ervinpage 17 TangoF. Link Rapierpage 17 Grandma\u27s SlippersBecky Lawsonpage 18 EdgesAmy J. Eadespage 19 Having ChildrenDevon Flesorpage 20 Young Black GirlKevin Lylespage 21 CatSuzanne Hornpage 22 Breakfast for OneMichelle Mitchellpage 22 A Modest ProposalBrooke Sanfordpage 23 Post MortemF. Link Rapierpage 26 Who Said I Forgot?Lynne Krausepage 27 The Corner Booth at StuckeysMaggie Kennedypage 28 The First DayDavis Brydenpage 29 DownLynne Krausepage 30 Fairie RingDevon Flesorpage 31 The LaundrymatKathy Fordpage 32 Sunday in OctoberBridget M. Howepage 32 The Kitchen WindowMaggie Kennedypage 33 UntitledChristina Maire Vitekpage 34 8th Grade Field Trip to SpringfieldMichelle Mitchellpage 34 Children of the FortiesF. Link Rapierpage 35 one winter and i was eightGary Ervinpage 35 Don\u27t we all know?Thomas B. Waltrippage 36 The TravelerMaggie Kennedypage 36 The VisitKathy Fordpage 40 CubismMaggie Kennedypage 40https://thekeep.eiu.edu/vehicle/1042/thumbnail.jp

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Impact of Optimized Breastfeeding on the Costs of Necrotizing Enterocolitis in Extremely Low Birthweight Infants

To estimate risk of NEC for ELBW infants as a function of preterm formula and maternal milk (MM) intake and calculate the impact of suboptimal feeding on NEC incidence and costs