text:
A stock photo of police tape (Scott Olson/Getty Images)
Police: Carjacker Beaten to Death After Stealing Car With Children Inside in Philadelphia
By Simon Veazey
Philadelphia police say bystanders beat a suspected carjacker to death after he drove off with 3 children in a car, and was chased down and pulled from the vehicle by the parents.
According to local reports, Philadelphia police say that a 25-year-old woman left her car running while she went inside the pizza shop where her boyfriend worked in the Strawberry Mansion part of the city, on the evening of July 11, leaving her three children inside.
A 54-year-old man jumped inside the Hyundai, driving off with the children still inside.
But he didn't get far.
The couple gave chase, and when the car got stuck in traffic about 3 blocks later, they caught up with the thief.
"They were able to pull this car thief out of the vehicle, " Chief Inspector Scott Small with the Philadelphia Police Department told WPVI.
"He fled on foot about a half a block. And the boyfriend caught up to him and there was some sort of a physical struggle that ensued. Then other males from the neighborhood intervened and began punching and kicking the male who took the vehicle."
The 54-year-old was rendered unconscious by the attack, reported CBS, which took place on 29th Street, near York Street.
BREAKING: Police say a man killed a suspect who carjacked his girlfriend outside of a North Philadelphia pizza shop with the couple's three young children inside the stolen vehicle.
CBS Philly စာစုတင်ရာတွင် အသုံးပြုမှု ၂၀၁၉၊ ဇူလိုင် ၁၁၊ ကြာသပတေးနေ့
He was taken to Temple University Hospital, where he died about an hour later from his injuries, which included severe head trauma.
The junction of 29th Street and York Street in Philadelphia (Screenshot/Google Maps)
Police say the three children are 5 years old, a year and a half, and 7 months old, CBS reported.
The boyfriend was the father of two of those children.
The parents remained at the scene of the incident, and were taken to be questioned by homicide detectives, the Philadelphia Inquirer reported. The children have been placed with family members.
According to WPVI, it is unclear whether charges will be filed.
Police say that they are continuing to investigate and are trying to track down the other males involved in the assault, reported CBS, which was captured by a nearby surveillance camera.
A father chased after a car thief who stole a vehicle with two of his three children inside and then beat him to death with help from bystanders, police said: https://t.co/OybBGDtX1v pic.twitter.com/st25FO2a1p
— NBC10 Philadelphia (@NBCPhiladelphia) July 12, 2019
Chief Inspector Small told NBC10 that both parents are cooperating with investigators and that both the homicide unit and the District Attorney's Office will work to determine if the father will be charged.
The names of the carjacker and the parents have not been released.
14-Year-Old Steals Car With Baby Inside
Last week, in North Carolina, a food delivery car with a 1-year-old baby inside was stolen as the mother made a delivery, leaving the engine running.
The suspected carjacker was a 14-year-old boy, who was charged with kidnapping.
The SUV was taken on the evening of July 5 while the mother made a delivery for "DoorDash," an online, on-demand food service, police said, according to local reports.
The incident occurred in Southern Pines, North Carolina at about 9 p.m.
The SUV was found abandoned over an hour later, with the infant still safely inside.
Four days later, on July 10, police announced that a 14-year-old had been arrested and charged with first-degree kidnapping and theft of a motor vehicle, according to the Sandhills Sentinel.
"This juvenile is a resident of Southern Pines, North Carolina and was located in Aberdeen, North Carolina by officers from the Southern Pines Police Department's Investigation Division," said the Southern Pines Police Department in the press release, as per the Sandhills Sentinel.
The suspect has not been named because he is a juvenile.
Follow Simon on Twitter: @SPVeazey
Carjacking Chase Ends With 1 Dead and 2 Injured in Washington State
By Henry Jom
On Sunday, June 17, a man who had attempted to carjack three vehicles was shot dead by an armed civilian in a Walmart parking lot, ending an ...
Video: 13-Year-Olds Charged With Carjacking Teacher at School
Two teenagers are accused of carjacking a teacher in Miami-Dade County, according to reports on Oct. 2. Miami-Dade police Detective Argemis Colome told Local10 that two 13-year-old ...
Texan Man Shoots Suspected Thief Trying to Steal Car Jack
By Zachary Stieber
A Texas homeowner who went outside on the morning of Dec. 11, found a man trying to steal his car jack and shot the suspect, police said. ...
Well-Known Georgia Businessman Shot Dead, Carjacking Suspect Sought
A well-known Georgia businessman and philanthropist was shot and killed in an apparent carjacking attempt, and police are searching for a suspect, according to officials. Jack Hough, ...
Recreational Fishing Boat Captain Catches a Great White Shark After 2 Mile Tug of War
A deep-sea fisherman has shared his spine-tingling experience of capturing a giant shark off the shore of Northern California on July 13. Golden State Sportfishing Captain Joey Gamez ...
Con Ed: Relay Protection System Failed, Leading to Blackout in New York City
NEW YORK—A relay protection system that should have isolated a faulty distribution cable, but didn't, led to the loss of power that darkened Manhattan for several hours, ...
NTD Evening News Full Broadcast (July 15)
By NTD Television
With Executive Order, Trump redefines 'Made in America'; ICE actions start, few specifics about arrests are known; Feds warn social media trolls not to visit area 51; ...
Abduction Suspected in Mysterious Disappearance of California Woman
Authorities are searching for a missing Huntington Beach woman who disappeared Friday while at a remote campsite in the Ancient Bristlecone Pine Forest located in central California. ...
IHOP Franchisee Says Minimum Wage Hikes That Force Layoffs, Reduced Hours Are 'Painful'
By Mark Tapscott
Tom Baber, who operates an IHOP restaurant and a Money Mailer shop in Mercer County, New Jersey, has to deal with "very personally painful" consequences of state-imposed ...
Cruz, Hawley Ask FTC to Examine Big Tech's Censoring of Content, Make Results Public
WASHINGTON—Sens. Ted Cruz (R-Texas) and Josh Hawley (R-Mo.) want the Federal Trade Commission (FTC) to investigate how major tech companies curate content, and make public what the ...
Mom Films Girls Dancing but Just Can't Stop Laughing When She Sees Their Horse
By Robert Jay Watson
For the Kessler family in San Antonio, Texas, horses aren't just pretty animals that they ride from time to time; they're a way of life. Kessler's daughters ...
Scared 5-Year-Old Throws Up Every Day Due to Bullying, Then 2 Football Players Show Up
By Li Yen, Epoch Times
One out of every five (20.8 percent) students reports being bullied, according to data published by the National Center for Educational Statistics in 2016. Bullying hurts, and it can ...
Couple Mocks Woman With 5 Kids Using Food Stamps, Then a Stranger Gets Back at Them
After a couple in a Walmart checkout line aired their spiteful views about a foster mother using food stamps to pay for her groceries, the lady in ...
Woman Falls Asleep on Flight, Wakes Up Alone in Total Darkness Trapped in Empty Plane
We've all done it before. Maybe it's a bus, a train, or a plane, but after getting settled in for a long journey, we're tired after a ...
Cow 'Cries' All Night After Calf Was Almost Sold Off. When They Reunite, She Loses It
As human beings, we often like to think of ourselves as being very special compared to other animals, especially where intelligence and emotions are concerned. But to ...
Hundreds of People Fought to Save This Dog From 'Hell'–Then Nobody Wanted Him
You have to wonder how "real" all those so-called acts of kindness on social media really are. Just ask Noah, the sorry K-9 who was discovered abandoned in ...
Owner Thinks Dog's Covered in Bug Bites, but Vet Calls the Police Upon a Closer Look
By Louise Bevan
No living creature deserves to be on the receiving end of unprovoked violence. But that's what happened to a 100-pound (approx. 181-kilogram) English Mastiff named Jackson who ...
Teen Builds Own House for $1,500. See What's Inside His 89 Sq Ft Architectural Gem
It's summertime, and that means summer vacations for kids across America. There's nothing better than the first few weeks. No classes, no alarm going off early in ...
Lady Thinks She Inherited Painting Worth $200. Upon Realizing Its True Value, She's in Tears
By Jocelyn Neo
Antiques passed down from generation to generation can sometimes fetch a hefty sum. The only thing is, some owners may not even know of the actual value ...
People Nowadays Have No Idea of These Auto Features in Old Cars. Do You Remember?
For lots of people today, the most important features in car aren't about driving at all—they're about technology. From bluetooth for phones and tablets, to augmented-reality navigation ...
10-Second Challenge: How Fast Can You Spot Which Cat Is Different in This Photo
Everybody loves a good brain teaser and there's nothing more fun than a "spot the difference picture." But did you know that scientists were able to identify ...
NEW By Reuters
NEW By The Associated Press
9hr By Charlotte Cuthbertson
9hr By Emel Akan


Getting crabby for Valentine's Day is never a bad thing at the All Saints Crab Feed!
All are welcome to the 46th Annual All Saints Crab Feed for all-you-can-eat salad, vegetarian pasta, bread and crab. Bring your friends and/or your sweetheart and join us for an evening of entertainment, a friendly get together and wonderful food!
Get Your Tickets Early! This event always sells out and ticket sales end February 10!
The evening begins at 5pm with a no host cocktail hour. Tickets include crab, vegetarian pasta, salad, and bread with a dessert. Beer, wine, and soft drinks will be available for purchase.
Entertainment this year will be Tonic, a Bay Area jazz trio that's been singing jazz standards in close harmony for over 12 years!
Take a chance on our raffle!
Due to limited seating space, children 8 and under will be under supervised care in our fireside room where they will enjoy a vegetarian pasta dinner along with activities, movies, games and fun!
Early ticket purchase guarantees a place at the crab feed, which sells out every year.
Buying tickets separately, but want to sit together? Register as a group and be sure you all buy your tickets under the same group name.


Simman Solicitors is one of UK's leading Law firms based in Croydon and established in 2001. We are a reputable and dedicated firm that prides ourselves in working with our clients to ensure the best possible outcomes for their matters. We understand the daunting experience of having to take on legal advice, but we as a team of professionals work alongside our clients catering to their individual needs.
Our ethos is to tailor our time to suit your needs.
The registered office address is 83 Southend, Croydon, CR0 9AD, England.


text:
Origin of agouPhylogenetic Characterizationti-melanistic polymorphism in wild black rats (Rattus rattus) inferred from Mc1r gene sequences
Yoshikazu Kambe, Tsutomu Tanikawa, Yasuharu Matsumoto, Morihiko Tomozawa, Ken P. Aplin, Hitoshi Suzuki
We examined nucleotide changes that underlie coat color variation in Black Rats (the Rattus rattus species complex), which show polymorphism in dorsal fur color, including either grayish brown (agouti) or black (melanistic) forms. We examined the full coding sequence of a gene known to produce melanism in other vertebrates melanocortin-1-receptor gene Mc1r (954 bp) using samples of both R. rattus (with 2n = 38) and its close relative Asian Black Rat (R. tanezumi; 2n = 42). We used 61 specimens from Japan with karyotype-known individuals and four samples from Pakistan. We found 11 allele sequences and constructed a network tree that shows two distinct clusters, with allelic segregation according to karyotype and by inference, representing the two species. We found that a nucleotide substitution from G to A at site 280, producing an amino acid change from glutamic acid to lysine, was associated with the dominant trait of the melanistic form of the coat color in R. rattus. Notably, the derived SNP 280A was found in a single allele, with the ancestral SNP 280G present in seven alleles. By contrast, all three alleles for R. tanezumi retain the ancestral SNP 280G. These results suggest a possible recent origin of melanism in R. rattus.
https://doi.org/10.2108/zsj.28.560
Mc1r
R. tanezumi
Rattus rattus
coat color variation
melanism
10.2108/zsj.28.560
Fingerprint Dive into the research topics of 'Origin of agouPhylogenetic Characterizationti-melanistic polymorphism in wild black rats (Rattus rattus) inferred from Mc1r gene sequences'. Together they form a unique fingerprint.
Rattus rattus Agriculture & Biology
genetic polymorphism Agriculture & Biology
nucleotide sequences Agriculture & Biology
melanosis Agriculture & Biology
alleles Agriculture & Biology
karyotyping Agriculture & Biology
color Agriculture & Biology
nucleotides Agriculture & Biology
Kambe, Y., Tanikawa, T., Matsumoto, Y., Tomozawa, M., Aplin, K. P., & Suzuki, H. (2011). Origin of agouPhylogenetic Characterizationti-melanistic polymorphism in wild black rats (Rattus rattus) inferred from Mc1r gene sequences. Zoological Science, 28(8), 560-567. https://doi.org/10.2108/zsj.28.560
Origin of agouPhylogenetic Characterizationti-melanistic polymorphism in wild black rats (Rattus rattus) inferred from Mc1r gene sequences. / Kambe, Yoshikazu; Tanikawa, Tsutomu; Matsumoto, Yasuharu; Tomozawa, Morihiko; Aplin, Ken P.; Suzuki, Hitoshi.
In: Zoological Science, Vol. 28, No. 8, 08.2011, p. 560-567.
Kambe, Y, Tanikawa, T, Matsumoto, Y, Tomozawa, M, Aplin, KP & Suzuki, H 2011, 'Origin of agouPhylogenetic Characterizationti-melanistic polymorphism in wild black rats (Rattus rattus) inferred from Mc1r gene sequences', Zoological Science, vol. 28, no. 8, pp. 560-567. https://doi.org/10.2108/zsj.28.560
Kambe Y, Tanikawa T, Matsumoto Y, Tomozawa M, Aplin KP, Suzuki H. Origin of agouPhylogenetic Characterizationti-melanistic polymorphism in wild black rats (Rattus rattus) inferred from Mc1r gene sequences. Zoological Science. 2011 Aug;28(8):560-567. https://doi.org/10.2108/zsj.28.560
Kambe, Yoshikazu ; Tanikawa, Tsutomu ; Matsumoto, Yasuharu ; Tomozawa, Morihiko ; Aplin, Ken P. ; Suzuki, Hitoshi. / Origin of agouPhylogenetic Characterizationti-melanistic polymorphism in wild black rats (Rattus rattus) inferred from Mc1r gene sequences. In: Zoological Science. 2011 ; Vol. 28, No. 8. pp. 560-567.
@article{4f14455fba3e4f27b90d675b136673d7,
title = "Origin of agouPhylogenetic Characterizationti-melanistic polymorphism in wild black rats (Rattus rattus) inferred from Mc1r gene sequences",
abstract = "We examined nucleotide changes that underlie coat color variation in Black Rats (the Rattus rattus species complex), which show polymorphism in dorsal fur color, including either grayish brown (agouti) or black (melanistic) forms. We examined the full coding sequence of a gene known to produce melanism in other vertebrates melanocortin-1-receptor gene Mc1r (954 bp) using samples of both R. rattus (with 2n = 38) and its close relative Asian Black Rat (R. tanezumi; 2n = 42). We used 61 specimens from Japan with karyotype-known individuals and four samples from Pakistan. We found 11 allele sequences and constructed a network tree that shows two distinct clusters, with allelic segregation according to karyotype and by inference, representing the two species. We found that a nucleotide substitution from G to A at site 280, producing an amino acid change from glutamic acid to lysine, was associated with the dominant trait of the melanistic form of the coat color in R. rattus. Notably, the derived SNP 280A was found in a single allele, with the ancestral SNP 280G present in seven alleles. By contrast, all three alleles for R. tanezumi retain the ancestral SNP 280G. These results suggest a possible recent origin of melanism in R. rattus.",
keywords = "Mc1r, R. tanezumi, Rattus rattus, coat color variation, melanism",
author = "Yoshikazu Kambe and Tsutomu Tanikawa and Yasuharu Matsumoto and Morihiko Tomozawa and Aplin, {Ken P.} and Hitoshi Suzuki",
doi = "10.2108/zsj.28.560",
journal = "Zoological Science",
publisher = "Zoological Society of Japan",
T1 - Origin of agouPhylogenetic Characterizationti-melanistic polymorphism in wild black rats (Rattus rattus) inferred from Mc1r gene sequences
AU - Kambe, Yoshikazu
AU - Tanikawa, Tsutomu
AU - Matsumoto, Yasuharu
AU - Tomozawa, Morihiko
AU - Aplin, Ken P.
AU - Suzuki, Hitoshi
N2 - We examined nucleotide changes that underlie coat color variation in Black Rats (the Rattus rattus species complex), which show polymorphism in dorsal fur color, including either grayish brown (agouti) or black (melanistic) forms. We examined the full coding sequence of a gene known to produce melanism in other vertebrates melanocortin-1-receptor gene Mc1r (954 bp) using samples of both R. rattus (with 2n = 38) and its close relative Asian Black Rat (R. tanezumi; 2n = 42). We used 61 specimens from Japan with karyotype-known individuals and four samples from Pakistan. We found 11 allele sequences and constructed a network tree that shows two distinct clusters, with allelic segregation according to karyotype and by inference, representing the two species. We found that a nucleotide substitution from G to A at site 280, producing an amino acid change from glutamic acid to lysine, was associated with the dominant trait of the melanistic form of the coat color in R. rattus. Notably, the derived SNP 280A was found in a single allele, with the ancestral SNP 280G present in seven alleles. By contrast, all three alleles for R. tanezumi retain the ancestral SNP 280G. These results suggest a possible recent origin of melanism in R. rattus.
AB - We examined nucleotide changes that underlie coat color variation in Black Rats (the Rattus rattus species complex), which show polymorphism in dorsal fur color, including either grayish brown (agouti) or black (melanistic) forms. We examined the full coding sequence of a gene known to produce melanism in other vertebrates melanocortin-1-receptor gene Mc1r (954 bp) using samples of both R. rattus (with 2n = 38) and its close relative Asian Black Rat (R. tanezumi; 2n = 42). We used 61 specimens from Japan with karyotype-known individuals and four samples from Pakistan. We found 11 allele sequences and constructed a network tree that shows two distinct clusters, with allelic segregation according to karyotype and by inference, representing the two species. We found that a nucleotide substitution from G to A at site 280, producing an amino acid change from glutamic acid to lysine, was associated with the dominant trait of the melanistic form of the coat color in R. rattus. Notably, the derived SNP 280A was found in a single allele, with the ancestral SNP 280G present in seven alleles. By contrast, all three alleles for R. tanezumi retain the ancestral SNP 280G. These results suggest a possible recent origin of melanism in R. rattus.
KW - Mc1r
KW - R. tanezumi
KW - Rattus rattus
KW - coat color variation
KW - melanism
U2 - 10.2108/zsj.28.560
DO - 10.2108/zsj.28.560
JO - Zoological Science
JF - Zoological Science

redpajama_set_name: RedPajamaCommonCrawl


text:
Research | Open | Published: 20 January 2016
T cells from patients with Candida sepsis display a suppressive immunophenotype
Andrej Spec1,
Yuichiro Shindo2,
Carey-Ann D. Burnham3,
Strother Wilson2,
Enyo A. Ablordeppey2,
Evan R. Beiter2,
Katherine Chang2,
Anne M. Drewry2 &
Richard S. Hotchkiss1,2,4
Critical Carevolume 20, Article number: 15 (2016) | Download Citation
The Letter to this article has been published in Critical Care 2016 20:191
Despite appropriate therapy, Candida bloodstream infections are associated with a mortality rate of approximately 40 %. In animal models, impaired immunity due to T cell exhaustion has been implicated in fungal sepsis mortality. The purpose of this study was to determine potential mechanisms of fungal-induced immunosuppression via immunophenotyping of circulating T lymphocytes from patients with microbiologically documented Candida bloodstream infections.
Patients with blood cultures positive for any Candida species were studied. Non-septic critically ill patients with no evidence of bacterial or fungal infection were controls. T cells were analyzed via flow cytometry for cellular activation and for expression of positive and negative co-stimulatory molecules. Both the percentages of cells expressing particular immunophenotypic markers as well as the geometric mean fluorescence intensity (GMFI), a measure of expression of the number of receptors or ligands per cell, were quantitated.
Twenty-seven patients with Candida bloodstream infections and 16 control patients were studied. Compared to control patients, CD8 T cells from patients with Candidemia had evidence of cellular activation as indicated by increased CD69 expression while CD4 T cells had decreased expression of the major positive co-stimulatory molecule CD28. CD4 and CD8 T cells from patients with Candidemia expressed markers typical of T cell exhaustion as indicated by either increased percentages of or increased MFI for programmed cell death 1 (PD-1) or its ligand (PD-L1).
Circulating immune effector cells from patients with Candidemia display an immunophenotype consistent with immunosuppression as evidenced by T cell exhaustion and concomitant downregulation of positive co-stimulatory molecules. These findings may help explain why patients with fungal sepsis have a high mortality despite appropriate antifungal therapy. Development of immunoadjuvants that reverse T cell exhaustion and boost host immunity may offer one way to improve outcome in this highly lethal disorder.
Many Candida spp. are saprophytic fungi that occupy ecologic niches on human skin and gastrointestinal tract. In an immunocompromised host, this can lead to an opportunistic invasive infection of the skin and mucosa, or life-threatening infections of the bloodstream [1–3]. Candida ranges from the most common to third most common genus causing nosocomial bloodstream infections in the United States [4, 5]. Despite highly active antifungal medications, mortality remains high [6]. The mortality in Candida bloodstream infections approaches 40 %, higher than mortality occurring in sepsis due to most bacterial pathogens [4]. Estimates suggest that there are between 7,000 and 28,000 nosocomial Candida bloodstream infections per year, leading to 2,800 and 11,200 deaths per year in the United States [4, 6, 7]. A large-scale prophylaxis trial was not effective at decreasing the incidence of Candida bloodstream infections or improving outcome [8]. The fact that mortality from invasive fungal infections remains elevated despite the use of antimicrobial agents that are highly active against fungal pathogens, implies that defective host immunity may contribute to the persistent high mortality. Therefore, measures that augment host immunity may be fundamental to improving survival. This theory is supported by recent animal studies and a small clinical trial of patients with fungal sepsis, which demonstrated that therapies that enhance host immunity can restore immune function and, in the case of the animal studies, improve outcome [9–11].
T cell activation is carefully regulated by expression of positive and negative co-stimulatory molecules that prevent unbridled T cell function. CD28 is the classic positive co-stimulatory receptor that, acting in conjunction with the T cell receptor (TCR), induces T cells to undergo proliferation and to produce cytokines such as interferon gamma (IFN-γ) and interleukin-2 (IL-2) that are critical in controlling infection [12]. To prevent excessive T cell activation, lymphocytes also express negative co-stimulatory molecules that suppress and downregulate their function [13–16]. Programmed cell death 1 (PD-1) is a member of the B7-CD28 superfamily that functions in an inhibitory role [14–16]. During T cell activation, PD-1 is rapidly induced and expressed on the surface of CD4 and CD8 T cells where it interacts with its ligands PD-L1 and PD-L2 [13–17]. PD-L1 is expressed on both hematopoietic and non-hematopoietic cells and its expression is highly upregulated during inflammatory states [16, 18]. Activation of PD-1 by its ligands causes inhibition of many T cell functions including cytokine production and cytotoxic activity. The critical role of PD-1 in immune regulation is demonstrated by studies which showed that PD-1-null mice develop autoimmune diseases including cardiomyopathy and a lupus-like syndrome [14–16].
Increased T cell PD-1 expression occurs under conditions of chronic antigenic stimulation, such as persistent viral infections, and leads to T cell exhaustion [14–16]. These exhausted T cells are poorly functional, likely to undergo apoptosis, and ineffective thereby contributing to the chronic viral infections [14–16]. Antibodies that block PD-1 restore T cell function, increase antiviral T cell responses, and decrease viral load in certain viral infections [15, 16]. Blockade of the PD-1 pathway has also improved survival in bacterial infections. Three independent investigative teams have demonstrated that blockade of the PD-1 pathway improves survival in clinically relevant animal models of bacterial sepsis [18–20]. The potential clinical relevance of these animal studies is highlighted by recent studies showing that PD-1 overexpression on circulating T cells from patients with sepsis correlated with decreased T cell proliferative capacity, increased secondary nosocomial infections, and mortality [21, 22].
Although several studies have shown that PD-1 and PD-L1 expression is increased on T cells and antigen-presenting cells from patients with bacterial sepsis, there are no studies to date that have examined expression of PD-1 or PD-L1 on immune cells from patients with Candida bloodstream infections. Thus, the objective of the present study was to assess this expression. In addition to PD1 and PD-L1, we also examined immune cell expression of other important receptor/ligands that have been implicated in regulating T cell function during infection. These molecules included CD69, an early activation marker, CD28, a key positive co-stimulatory molecule, IL-7 receptor (IL-7R), which is decreased in exhausted T cells, the negative co-stimulatory molecules T cell immunoglobulin domain and mucin domain 3 (TIM-3) and B and T lymphocyte attenuator (BTLA), and CD57 which has been reported to identify poorly functional "immunosenescent" lymphocytes [23–29].
This was a prospective observational study conducted between 2013 and 2015 and approved by the Washington University Human Research Protection Office.
Patients were included if they were 18 years old or older and had a blood culture positive for any Candida species. Potential study participants were identified by the microbiology laboratory, which notified investigators of blood cultures positive for a Candida spp. The control group of patients was composed of critically ill, non-septic patients (controls) who were cared for in the intensive care unit (ICU) following trauma or major surgery, but did not have fungal or bacterial sepsis.
The exclusion criteria were identical for the Candida bloodstream infections and control patients. In order to eliminate potential confounding effects of immunosuppressive medications or underlying disease on the immunophenotype of patient lymphocytes, patients with the following criteria were excluded from study: patients with human immunodeficiency virus (HIV), patients who had undergone organ or bone marrow transplantation, patients on high-dose corticosteroids (≥300 mgs/day of hydrocortisone equivalent) or other immunosuppressive medications, patients with viral hepatitis and autoimmune diseases.
Data and sample collection
Analyses were performed on residual blood remaining after clinical hematologic testing. Because the tests were conducted on residual blood remaining in the laboratory samples (no patients had venous or arterial blood puncture) the study was granted a waiver of informed consent and approved by the Washington University Human Research Protection Office. In general, most blood samples for patients with Candida bloodstream infections were obtained within 24–48 hours of cultures returning positive for Candida. Clinical and demographic data was collected at enrollment. Patient survival versus mortality was followed for 90 days after entry into the study or until hospital discharge.
Flow cytometric data included both the percentage of cells positive for a particular immunophenotypic marker as well as the geometric mean fluorescence intensity (GMFI), a quantitative measure of the expression of receptors or ligands expressed on a per cell basis. Antibodies for flow cytometric determinations were purchased from Biolegend (San Diego, CA, USA), BD Biosciences (San Diego, CA, USA), or eBiosciences (San Diego, CA, USA). Studies were performed on cells remaining after red blood cell lysis of diluted whole blood that had undergone antibody immunostaining as previously described [3]. Lymphocytes were identified by forward scatter (FSC) and side scatter (SSC) properties. T lymphocyte subsets were further identified by CD3+, CD4+, or CD8+ immunostaining. Additional immunostaining was performed on CD4 and CD8 T cells to identify the following:
CD69, a marker of cell activation [9]
CD28, a key positive co-stimulatory molecule [12],
programmed cell death- 1 (PD-1, CD279), a negative co-stimulatory molecule that is considered a marker of cell exhaustion [10]
programmed cell death ligand 1 (PD-L1, CD274), the ligand for PD-1 that is expressed on T cells and monocyte/macrophages, dendritic cells [10]
BTLA, a negative co-stimulatory molecule [11]
TIM-3, a negative co-stimulatory molecule [17]
interleukin-7 receptor (IL-7R), signaling through IL-7 is essential for lymphocyte survival and proliferation. Decreased IL-7R expression is used to identify "exhausted" T cells [13, 14].
CD57, a marker used to identify poorly functional "senescent" T cells [15]
2B4, a multifunctional receptor that may have either inhibitory or stimulatory effects on T cells [16].
The data were analyzed using SPSS version 23 (IBM Corp., Armonk, NY, USA). Scatter plots were made using Prism (GraphPad Software Inc., San Diego, CA, USA). All continuous data were analyzed for normality using a Kolmogorov–Smirnov test with an alpha cutoff of 0.05. Normally distributed data were reported with means and standard deviations and analyzed using independent samples t tests. Non-normally distributed data were reported with medians and interquartile ranges and were analyzed with a Mann–Whitney U test. Categorical clinical data were compared using chi-square tests, or Fisher's exact test, as appropriate. p ≤0.05 was considered statistically significant.
Clinical and laboratory characteristics
During the study, 27 (62.8 %) eligible patients with Candida bloodstream infections that met inclusion and exclusion criteria were included. Sixteen (37.2 %) critically ill non-septic patients were recruited as controls. Baseline demographic data were similar between the two groups (Tables S1A and S1B in Additional file 1). No statistically significant differences were found between the mean age, gender, race, acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure assessment (SOFA) scores, white blood cell counts, respiratory rate, heart rate, and baseline creatinine. Both of the groups had a 90-day mortality of approximately 20 %. The absolute neutrophil count was similar between patient groups, 7.23 × 103 versus 6.43 × 103 cells/mm3, respectively. The mean absolute lymphocyte count was significantly higher in patients with Candidemia versus control patients, i.e., 1.13 × 103 cells/mm3 versus 0.61 × 103 cells/mm3, respectively, ( p = 0.02). Both the mean absolute lymphocyte count for patients with Candidemia and for control, critically ill patients were below the lower limit of normal for Barnes Jewish Hospital, i.e., 1.20 × 103 cells/mm3 (Table 1).
Table 1 Baseline characteristics of patients with Candida bloodstream infections and critically ill control patients
Flow cytometry findings
Although there was no difference in the percentage of CD8 T cells that were positive for PD-1 in patients with Candidemia versus control patients, patients with Candidemia did have an increase in the geometric mean fluorescence intensity (GMFI), indicating that the cells which were positive for PD-1 had an increase in the number of PD-1 molecules on a per cell basis; (p <0.05), (Fig. 1). For some signaling molecules or hormones, the number of cell receptors (indicated by the MFI) is an important determinant of the cell response. There were no differences in either the percentage of cells positive for PD-1 or the MFI for PD-1 from CD4 T cells of patients with Candidemia versus control patients. For PD-L1, both the percentage of CD8 T cells positive for PD-L1 as well as the MFI of the cells that were positive for PD-L1 was increased in patients with Candidemia versus control patients; p <0.01, (Figs. 1 and 2). Compared to control patients, the MFI for PD-L1 was increased in CD4 T cells from patients with Candidemia; p <0.05. There was no difference in the percentage of CD4 T cells that were positive for PD-L1 in patients with Candidemia versus control patients, (Fig. 1). These results, showing a more prominent effect of fungal sepsis on expression of PD-1 and PD-L1 on CD8 T cells compared to CD4 T cells, have been observed in previous studies of patients with bacterial sepsis [30].
Co-inhibitory molecule expression on CD4 and CD8 T cells. PD-1, PD-L1, and BTLA are co-inhibitory molecules. The percentage of PD-L1 expression on CD8 T cells and the GMFIs of CD4 and CD8 T cells were significantly increased in patients with CBSI compared to CINS (p ≤0.01). Several patients with CBSI had higher percentage of PD-L1 expression on CD4 T cells than those with CINS, although there was no statistical significance between the groups (p = 0.161). Horizontal lines indicate mean or median values. Asterisks indicate significant differences between CINS and CBSI (* p ≤0.05 and ** p ≤0.01). BTLA B and T lymphocyte attenuator, CBSI Candida bloodstream infection, CINS critically ill non-sepsis, GMFI geometric mean fluorescence intensity, PD-1 programmed cell death 1, PD-L1 programmed cell death ligand 1
PD-L1 expression on CD8 T cells in CINS and CBSI. Representative flow cytometric findings in patients with CINS and CBSI are shown. The percentage of PD-L1-positive CD8 T cells was higher in CBSI than in CINS. CBSI Candida bloodstream infection, CINS critically ill non-sepsis, PD-1 programmed cell death 1, PD-L1 programmed cell death ligand 1
The percentage of CD8 T cells positive for the early activation marker CD69 was increased in patients with Candidemia versus control patients, 13.36 % versus 4.85 %, respectively, (Fig. 3), (p <0.01). Similarly, the MFI of CD69 in CD8 T cells from patients with Candidemia was also increased compared to control patients; p <0.01. No differences in CD69 expression were observed in patients with Candidemia versus control patients for CD4 T cells.
Co-stimulatory molecule expression and markers related to cell activation on CD4 and CD8 T cells. CD28 is a co-stimulatory molecule that is necessary for optimal T cell activation. CD69 is marker of cellular activation. IL-7R activation leads to T cell activation and proliferation. CD28 expression on CD4 T cells was significantly decreased in patients with CBSI, compared to those with CINS. In CD8 T cells, both the percentage and GMFI for CD69 were increased in CBSI compared to CINS. On the other hand, the percentage and GMFI of the IL-7R tended to be lower in CD4 T cells from CBSI versus CINS patients. However, this difference did not reach statistical significance, p = 0.07 and p = 0.08 respectively. Horizontal lines indicate mean or median values. Asterisks indicate significant differences between CINS and CBSI (* p ≤0.05 and ** p ≤0.01). CBSI Candida bloodstream infection, CINS critically ill non-sepsis, GMFI geometric mean fluorescence intensity, IL-7R interleukin-7 receptor
In contrast to the increase in inhibitory receptor/ligands noted in CD8 T cells, there was a significant decrease in the percentage of CD4 T cells expressing CD28, a major positive co-stimulatory molecule, in patients with Candidemia compared to controls, 79.8 % versus 92.6 %, respectively; p <0.05, (Fig. 3). There were no statistical differences for either the percentage of cells positive for CD28 or the MFI for CD28 in CD8 T cells from the two groups of patients.
Decreased expression of IL-7 receptor (IL-7R) is characteristic of poorly functional CD4 and CD8 T cells that result from chronic antigenic stimulation [18, 19]. Although the difference did not quite reach statistical significance, there was a trend toward a decreased percentage of CD4 T cells positive for the IL-7R and decreased MFI in patients with Candidemia compared to controls, p = 0.08 and p = 0.07 respectively (Figs. 3 and 4). There were no statistical differences in either the percent positivity or the MFI for other markers of T cell exhaustion, i.e., BTLA, CD57, TIM-3, or 2B4 for either CD4 or CD8 T cells in the two groups of patients, (Figs. 1 and 5).
Interleukin 7 receptor expression on CD4 and CD8 T cells - differences between CINS and CBSI. Representative flow cytometric findings in patients with CINS and CBSI are shown. The percentages of IL-7R-positive CD4 and CD8 T cells were lower in CBSI than in CINS. CBSI Candida bloodstream infection, CINS critically ill non-sepsis, IL-7R interleukin- 7 receptor
CD marker expression on CD4 and CD8 T cells related to senescence and inhibitory or stimulatory effects. CD57 is a marker that is used to identify senescent, poorly functional T cells. TIM-3 is a co-inhibitory molecule that impairs T cell function. 2B4 (CD244) is a dual-functional receptor that may have either inhibitory or stimulatory effects on T cells depending upon other stimuli and environmental settings. Horizontal lines indicate mean or median values. Asterisks indicate significant differences between CINS and CBSI (* p ≤0.05 and ** p ≤0.01). CBSI Candida bloodstream infection, CINS critically ill non-sepsis, TIM-3T cell immunoglobulin domain and mucin domain 3
The incidence of Candida bloodstream infection is increasing and Candida is currently one of the most common nosocomial bloodstream infections in many intensive care units (ICUs) [1, 2, 4, 5, 20, 21]. The ability of the host to survive a Candida bloodstream infection requires a well-coordinated response by the innate and adaptive immune system, both of which are frequently impaired in patients with fungal sepsis [22–24]. Many of the patients acquiring fungal sepsis are immunosuppressed due to underlying malignancies and treatment with chemo or radiation therapy. Patients undergoing bone marrow or solid organ transplantation are also immunosuppressed and have a high incidence of fungal infection. There is increasing recognition that many ICU patients who are presumed to be immunocompetent also acquire invasive fungal infections. Many of these patients are elderly individuals whose immune system is impaired due to "immunosenescence" [31]. Additionally, ICU patients with bacterial sepsis have impaired immunity due to a variety of factors including: loss of immune effector cells, increased immunosuppressive cells including T regulatory cells and myeloid-derived suppressor cells, and T cell exhaustion [22]. Patients in the ICU also may require central venous lines, arterial lines, and Foley catheters, which compromise the body's protective barrier. In this regard, the majority of the fungal infections in the present study were felt to be related to invasive lines (Additional file 1: Table S1A) rather than to parenchymal infections. Also, the present study excluded patients who had undergone bone marrow or stem cell transplantation, HIV patients, and patients on high-dose immunosuppressive medication. These factors may explain the relatively low mortality in the present study (22 %) compared to higher mortality figures reported in other studies [4].
The fact that many patients with fungal sepsis die despite being treated with drugs to which the fungal pathogens are sensitive suggests that impaired host immunity is a factor in the poor survival seen in fungal sepsis. Thus, enhancing host immunity may improve outcome. This hypothesis is supported by studies of interleukin-7 (IL-7), a pleiotropic cytokine that enhances T cell function [10, 32–35]. Using a mouse model of fungal sepsis, our group demonstrated that IL-7 improved IFN-γ production, decreased apoptosis, and increased survival in mice with Candida sepsis [14]. Furthermore, a report in which investigators treated patients with invasive fungal infections and decreased HLA-DR expression, a measure of impaired immunity, with IFN-γ immunotherapy demonstrated an improvement in patient immune function [9]. Thus, immunoadjuvant therapy is moving forward in fungal sepsis and the ability to identify those patients who are good candidates for immunotherapy is needed.
To our knowledge, this is the first study to investigate the immunophenotype of lymphocytes of patients with Candida bloodstream infection. The present results are consistent with T cell exhaustion, a condition that occurs following chronic antigenic stimulation in which T cells become poorly functional with reduced cytokine production, decreased proliferative capacity, and are prone to undergo apoptotic cell death. An increase in T cell expression of the inhibitor receptor PD-1 and its ligand, PD-L1 are essential for mediating T cell exhaustion [16, 17, 19, 25, 26]. In this study, CD8 T cells from patients with Candida bloodstream infection had an increase in both the percentage of cells positive for PD-L1 and in the MFI (a measure of the number of receptors or ligands on a per cell basis) for PD-L1 compared to controls (Figs. 1 and 2). Similarly, CD4 T cells from patients with Candida bloodstream infection had an increase in the MFI for PD-1 expression compared to controls.
Another cell phenotypic marker that is consistent with exhausted T cells is decreased T cell IL-7R expression [24]. Decreased IL-7R results in decreased concentrations of Bcl-2, an anti-apoptotic protein that is essential for T cell survival. The present results showed a non-statistically significant trend toward a decrease in the percentage of CD4 T cells positive for IL-7R (p = 0.08) and in the MFI (p = 0.07) in patients with Candida bloodstream infection compared to controls. Although there were no differences in BTLA, TIM-3, or 2B4, other markers of T cell exhaustion, in patients with Candida bloodstream infection versus controls, cellular expression of these markers is not as frequently abnormal as expression of PD-1 or PD-L1 in T cell exhaustion [14].
In addition to markers of T cell exhaustion, patients with Candida bloodstream infection also had another potentially important finding consistent with an impaired T cell response to pathogens, i.e., a decrease in the percentage of CD4 T cells expressing CD28. CD28 is a key co-stimulatory molecule that is essential for T cell activation and survival [17]. Stimulation through CD28 activates signaling pathways that result in production of various cytokines that help to combat infectious pathogens. Previous work from our group has shown that expression of CD28 is decreased in both animals and patients with sepsis [10, 22]. In this regard, CD4 T cells from animals with sepsis that were treated with IL-7 had an increase in CD28 expression and improvement in T cell function.
In contrast to the high mortality, often approaching 40 %, which typically is associated with invasive fungal infections, the mortality in the present study was only 22 %. There are several reasons for the relatively low mortality in the present study. First, the present study excluded patients who underwent organ or bone marrow transplantation. These patients have a high incidence of fatal fungal infections because of their severely impaired immune systems. Second, we also excluded acquired immunosuppressive deficiency syndrome (AIDS) patients and patients who were taking high-dose corticosteroids ((≥300 mgs/day of hydrocortisone equivalent) or other immunosuppressive medications. These patients are also more likely to succumb to fungal infections because of their inability to mount an effective immune response.
This study has a number of limitations. First, although this study showed that lymphocytes from patients with fungal bloodstream infections have phenotypic markers consistent with immunosuppression and T cell exhaustion, no cell functional studies were performed. Thus, we do not know the degree or intensity of T cell impairment. Second, these findings do not establish a causal link between markers of T cell exhaustion and increased morbidity or mortality in patients with fungal sepsis. Although studies do demonstrate a correlation of increased T cell exhaustion and decreased outcomes in sepsis, no such studies exist for patients with fungal sepsis. It is important to note, however, that previous studies from our group showed that therapy with anti-PD-1 and anti-PD-L1 antibodies reversed T cell dysfunction and improved survival in both primary candidiasis and in a two-hit model of fungal infection [11]. These studies do provide support for the hypothesis that dysfunctional T cells are a key pathologic factor in lethal fungal infections.
A second limitation of the study is that we are not able to determine a reason for the difference in the phenotypic response of CD4 and CD8 T cells during fungal infection. The present findings show a greater effect of fungal sepsis to increase PD-1 and PD-L1 expression (either on the percentage positive and/or MFI for PD-1 or PD-L1) on CD8 T versus CD4 T cells. We have previously reported differential effects of bacterial sepsis on PD-1 and PD-L1 in CD8 versus CD4 T cells [11, 22, 30]. Although there is no clear explanation for this different cellular effect, it may be related to the unique functions of CD4 versus CD8 T cells, i.e., CD4 T cells having a "helper" function to activate other immune cells while CD8 T cells act to eliminate pathogens by cell killing.
In conclusion, the present results demonstrate that T cells from patients with Candida bloodstream infection have a phenotype consistent with an immunosuppressive "exhaustive" state. In the future, examination of these flow cytometric markers may be useful in identifying patients with fungal sepsis who have impaired immunity and thus are candidates for trials of agents which boost host immunity.
Patients with Candida bloodstream infections exhibit an immunosuppressed phenotype.
This phenotype appears to be mediated through the PD-1 axis.
BTLA:
B and T lymphocyte attenuator
(G)MFI:
(Geometric) mean fluorescence intensity
ICU:
IFN-γ:
Interferon gamma
IL-2:
Interleuken-2
IL-7R:
IL-7 receptor
PD-1:
Programmed cell death 1
PD-L1:
Programmed cell death ligand 1
T cell receptor
TIM-3:
T cell immunoglobulin domain and mucin domain 3
Arendrup MC. Epidemiology of invasive candidiasis. Curr Opin Crit Care. 2010;16:445–52.
Lepak A, Andes D. Fungal sepsis: optimizing antifungal therapy in the critical care setting. Crit Care Clin. 2011;27:123–47.
Lipsett PA. Surgical critical care: fungal infections in surgical patients. Crit Care Med. 2006;34:S215–24.
Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39:309–17.
Magill SS, Edwards JR, Bamberg W, Beldavs ZG, Dumyati G, Kainer MA, et al. Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 2014;370:1198–208.
Pappas PG, Kauffman CA, Andes D, Benjamin Jr DK, Calandra TF, Edwards Jr JE, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503–35.
Wenzel RP, Edmond MB. The impact of hospital-acquired bloodstream infections. Emerg Infect Dis. 2001;7:174–7.
Wenzel RP, Gennings C. Bloodstream infections due to Candida species in the intensive care unit: identifying especially high-risk patients to determine prevention strategies. Clin Infect Dis. 2005;41 Suppl 6:S389–93.
Delsing CE, Gresnigt MS, Leentjens J, Preijers F, Frager FA, Kox M, et al. Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: a case series. BMC Infect Dis. 2014;14:166.
Unsinger J, Burnham CA, McDonough J, Morre M, Prakash PS, Caldwell CC, et al. Interleukin-7 ameliorates immune dysfunction and improves survival in a 2-hit model of fungal sepsis. J Infect Dis. 2012;206:606–16.
Chang KC, Burnham CA, Compton SM, Rasche DP, Mazuski RJ, McDonough JS, et al. Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis. Crit Care. 2013;17:R85.
Ostrosky-Zeichner L, Shoham S, Vazquez J, Reboli A, Betts R, Barron MA, et al. MSG-01: a randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk adults in the critical care setting. Clin Infect Dis. 2014;58:1219–26.
Crawford A, Wherry EJ. The diversity of costimulatory and inhibitory receptor pathways and the regulation of antiviral T cell responses. Curr Opin Immunol. 2009;21:179–86.
Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–9.
Brown KE, Freeman GJ, Wherry EJ, Sharpe AH. Role of PD-1 in regulating acute infections. Curr Opin Immunol. 2010;22:397–401.
Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8:239–45.
Greenfield EA, Nguyen KA, Kuchroo VK. CD28/B7 costimulation: a review. Crit Rev Immunol. 1998;18:389–418.
Huang X, Venet F, Wang YL, Lepape A, Yuan Z, Chen Y, et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci U S A. 2009;106:6303–8.
Brahmamdam P, Inoue S, Unsinger J, Chang KC, McDunn JE, Hotchkiss RS. Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukoc Biol. 2010;88:233–40.
Zhang Y, Zhou Y, Lou J, Li J, Bo L, Zhu K, et al. PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Crit Care. 2010;14:R220.
Guignant C, Lepape A, Huang X, Kherouf H, Denis L, Poitevin F, et al. Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit Care. 2011;15:R99.
Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306:2594–605.
Radulovic K, Niess JH. CD69 is the crucial regulator of intestinal inflammation: a new target molecule for IBD treatment? J Immunol Res. 2015;2015:497056.
Lang KS, Recher M, Navarini AA, Harris NL, Lohning M, Junt T, et al. Inverse correlation between IL-7 receptor expression and CD8 T cell exhaustion during persistent antigen stimulation. Eur J Immunol. 2005;35:738–45.
Ngiow SF, Teng MW, Smyth MJ. Prospects for TIM3-targeted antitumor immunotherapy. Cancer Res. 2011;71:6567–71.
Morou A, Palmer BE, Kaufmann DE. Distinctive features of CD4+ T cell dysfunction in chronic viral infections. Curr Opin HIV AIDS. 2014;9:446–51.
Cannons JL, Tangye SG, Schwartzberg PL. SLAM family receptors and SAP adaptors in immunity. Annu Rev Immunol. 2011;29:665–705.
Shubin NJ, Chung CS, Heffernan DS, Irwin LR, Monaghan SF, Ayala A. BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction. J Leukoc Biol. 2012;92:593–603.
Zhu X, Niedermann G. Rapid and efficient transfer of the T cell aging marker CD57 from glioblastoma stem cells to CAR T cells. Oncoscience. 2015;2:476–82.
Chang K, Svabek C, Vazquez-Guillamet C, Sato B, Rasche D, Wilson S, et al. Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis. Crit Care. 2014;18:R3.
Nikolich-Zugich J. Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories. J Immunol. 2014;193:2622–9.
Kasten KR, Prakash PS, Unsinger J, Goetzman HS, England LG, Cave CM, et al. Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through gamma delta T-cell IL-17 production in a murine model of sepsis. Infect Immun. 2010;78:4714–22.
Kasten KR, Tschop J, Goetzman HS, England LG, Dattilo JR, Cave CM, et al. T-cell activation differentially mediates the host response to sepsis. Shock. 2010;34:377–83.
Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13:862–74.
Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol. 2011;11:330–42.
The investigators would like to acknowledge the nurses and staff of the 4400 Surgical ICU at Barnes Jewish Hospital, St Louis, MO, USA.
Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA
Andrej Spec
& Richard S. Hotchkiss
Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA
Yuichiro Shindo
, Strother Wilson
, Enyo A. Ablordeppey
, Evan R. Beiter
, Katherine Chang
, Anne M. Drewry
Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA
Carey-Ann D. Burnham
Department of Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA
Richard S. Hotchkiss
Search for Andrej Spec in:
Search for Yuichiro Shindo in:
Search for Carey-Ann D. Burnham in:
Search for Strother Wilson in:
Search for Enyo A. Ablordeppey in:
Search for Evan R. Beiter in:
Search for Katherine Chang in:
Search for Anne M. Drewry in:
Search for Richard S. Hotchkiss in:
Correspondence to Richard S. Hotchkiss.
AS co-conceived and co-designed the study, assisted with recruitment, performed statistical analysis and wrote the first draft of the manuscript. YS performed the majority of the flow cytometry, helped design the experiments, did data analysis, helped write the manuscript, and created the figures. CAB assisted with experimental design, patient recruitment, assisted with statistical analysis, and helped write the manuscript. SW assisted with study design, assisted in performing flow cytometry, and helped write the manuscript. EAA assisted in study design, performed patient recruitment, assisted in obtaining blood samples, and helped in manuscript preparation. ERB assisted in performing the flow cytometry, helped in study design, helped in data analysis, and helped revise the manuscript. KC helped in study design, data analysis, assisted with the flow cytometry, and helped revise the manuscript. AMD helped in study design, patient recruitment, statistical analysis, and assisted in writing up the manuscript. RSH co-conceived, co-designed and coordinated the study as well as helped draft the manuscript. All authors read and approved the final manuscript.
Andrej Spec and Yuichiro Shindo contributed equally to this work.
Additional file
Additional file 1: Table S1A.
Characteristics of patients with Candida infection (n = 27). Table S1B. Characteristics of critically ill control patients (n = 16). (DOC 41 kb)
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
https://doi.org/10.1186/s13054-016-1182-z
Bloodstream infection


text:
Chris Pratt jokes about his 'Avengers 4' role, new 'Guardian of Galaxy Vol. 3' cast
Actor Chris Pratt accepted the Generation Award at the recent "MTV: Movie Awards 2018" event. [Image via MTV/YouTube]
The man known as 'Star-Lord' in the Marvel Cinematic Universe teased the fans a bit about the new movies.
June 20, 2018 at 2:49 PM June 20, 2018 at 2:49 PM
Chris Pratt is well known by many fans now as the actor who plays Peter Quill aka "Star-Lord" in the Marvel Movies. Pratt first debuted in the "Guardians of the Galaxy Vol. 1" film and then continued through the sequel and "Avengers: Infinity War." In the latter of these films, Pratt's Star-Lord drew some angry reactions from fans based on what he did in a key moment of the film.
However, fans seem ready to move on, as is Pratt. He'll not only appear in the upcoming "Jurassic World" sequel but will be back in theaters in "Avengers 4" and "Guardians of the Galaxy Vol. 3" next year. Pratt, who is known as a jokester decided to have some fun with recent questions he received about those upcoming films.
Keep in mind that spoilers may follow for those who have yet to see the 2018 film, "Avengers: Infinity War."
Pratt on his role in 'Avengers 4'
"Avengers 4" will be the concluding chapter in the grand scheme of things for Marvel. It will be the sequel to "Avengers: Infinity War," a film which ended sort of abruptly for moviegoers. Towards the end of the film, the villainous Thanos was able to use all of the Infinity Stones he'd gathered along with the Gauntlet to snap his fingers and wipe out half of the world's population. Unfortunately (spoiler alert), that included some of the superheroes including Star-Lord.
Despite his demise towards the end of the film, most fans weren't buying it. Many viewers believe that Peter Quill will be returning in some way for the fourth "Avengers" movie.
Pratt was part of the recent "MTV: Movie Awards" show where he received the Generations Award for his overall movie resume. While there, he had some fun at the expense of the fans, as he answered questions about his role for "Avengers 4" and "Guardians 3."
Chris Pratt Teases 'Avengers 4' Events, 'Guardians Of The Galaxy Vol. 3' Cast https://t.co/VgmCKNTQ1d pic.twitter.com/3QY5kvwyKu
— Heroic Hollywood (@heroichollywood) June 20, 2018
When asked about the next "Avengers" movie, Pratt joked about not spoiling the possible surprises that are in store for fans.
We selected the best for you. From our partner Music Crowns
Aiden Myers And ELPORT Join Forces For 'The Song 2.0'
"My call time? Don't have one, so pretty cool. You don't want to ask too much because you don't want to poke inside the gift that's under the tree. Just wait, you'll see. Just wait, you'll see. We got your back, baby."
Clearly, Chris Pratt is being as secretive as can be about his appearance and role in the "Avengers 4" film.
However, fans expect he'll be in the film for at least part of it, even if his role isn't quite as big as it was in "Infinity: War."
Pratt on the 'Guardians Vol. 3' cast
One of the biggest clues that seem to indicate Pratt will be back for "Avengers 4" is that the new "Guardians of the Galaxy" film coming out in 2020. While the "Vol. 3" movie page at IMDb only includes two characters, Mantis and Ayesha, most fans think it would be strange to have a third "Guardians" movie without Star-Lord. Pratt has been one of the core members of the group since the first film in 2014.
However, Pratt decided to once again have some fun with the fans at the "MTV: Movie Awards," giving them a fake spoiler about who the third "Guardians" cast will include.
"They've cast the Blue Man Group.
It's gonna be all Blue Man Group! Oh, I'm not supposed to say anything! Everyone's gonna be mad! It's the Blue Man Group. It's an Andy Griffith hologram. They're the new Guardians. It's gonna be amazing."
Pratt also gave a speech about his life rules for the future generations, which included some jokes, and also some wise advice regarding doing good in the world.
Pratt is an actor who will have plenty of movies to come including "Jurassic World: Fallen Kingdom" and "The Lego Movie 2." Most fans are also expecting the core "Guardians of the Galaxy" cast to return for the 2020 film. So far, Mantis is listed which seems to be a clue that other "deceased" members of the group will return for the third installment. With that said, it's clear that Chris Pratt is fully aware of how important it is to keep these upcoming films as secret and spoiler-free as he can!
'90 Day Fiancé': Molly Hopkins health in stable condition after alleged assault by Olivia
'90 Day Fiancé': Jenny opens up to TLC producer after learning about Sumit's arranged marriage
'The Good Doctor' Season 4 Episode 7: Shaun fears the same fate as Lea's ex-husband
Blasting News recommends Ohio State Buckeyes target Malachi Nelson to replace Justin Fields '90 Day Fiancé': Fans outraged after discovering TLC's Pillow Talk might get canceled '90 Day Fiancé': Elizabeth gives fans hint that she might be pregnant with second child '90 Day Fiancé': Yara's pregnancy result could be released in the next episode 'Avengers 4' Rumors: Hulk joins SHIELD, official title teased in 'Infinity War' Blu-ray 'Teen Mom 2': Jenelle Evans compares David Eason's firing to that of Farrah Abraham '90 Day Fiance: The Other Way': Kenneth says his relationship is not acted Video '90 Day Fiance: The Other Way:' Sumit is facing backlash for choosing Jenny Video


text:
Facebook Dating service launches across the UK (and works in a similar way to Tinder)
Facebook Dating service launches in the UK (and works in a similar way to Tinder)
By Kris Tatum @KrisTatumNews Trending Today editor
Facebook Dating service launches across the UK (and works in a similar way to Tinder). Picture: Newsquest
Facebook's new dating service has launched across the UK and Europe for users to find relationships on the social network.
We've put together everything you need to know about the new service.
What is Facebook Dating?
The service was first tested in 2018 and introduced in the US last year. Facebook Dating is an opt-in service where users create a separate profile and interact with others away from their main Facebook page.
The social media giant hopes to emulate the success of apps such as Tinder, Hinge and Bumble, which have millions of users across their platforms.
The feature was initially due to be released in the UK earlier this year, but was delayed after a documentation timing issue with its lead EU regulator, the Irish Data Protection Commission (DPC).
The social media giant said that since its launch in other parts of the world, more than 1.5 billion matches had been made in the 20 countries where the feature is available.
What have Facebook said about the new Dating service?
Facebook said Dating had been built with "safety, security and privacy at the forefront".
"We worked with experts in these areas to provide easy access to safety tips and build protections into Facebook Dating, including the ability to report and block anyone, as well as stopping people from sending photos, links, payments or videos in messages," the company said.
"We won't suggest current Facebook friends as potential matches or notify them that you've joined Dating. For example, your Dating profile, Dating messages, and who you like or match within Dating won't appear on your Facebook News Feed.
"We're committed to making Facebook Dating a place where people feel comfortable looking for a date and starting meaningful relationships."
How will the Dating feature work?
The Dating feature also allows users to share Stories from Facebook or Instagram onto their dating profile and includes the Secret Crush tool, which lets users select up to nine of their existing friends from the network that they're interested in.
If that person adds you to their own Secret Crush list, they will be matched, but if they don't create a list or add the first user to it, that information will not be shared.
Once matched, users can go on virtual dates via the platform, using video calls built into the Dating feature.


text:
Q: Exportar configurações da base de dados MySQL Recentemente exportei uma base de dados mysql no formato .sql, entretanto algumas configurações não estão presentes, como por exemplo a configuração para FULLTEXT index.
Qual o procedimento correto para exportar esses tipos de configuração?

redpajama_set_name: RedPajamaStackExchange


text:
Pacifica to demolish another clifftop apartment…
Pacifica to demolish another clifftop apartment building
Waves and rain batter the coast where the condemned apartment building at 310 Esplanade Ave. sits perched on a crumbling cliff Thursday in Pacifica. A trail to the beach next to the building has also eroded. – Jim Gensheimer/Bay Area News Group
By Aaron Kinney and Bay Area News Group |
PUBLISHED: December 15, 2016 at 12:00 am | UPDATED: September 11, 2018 at 12:00 am
Pacifica >> Warning of an imminent disaster, city officials on Thursday said they intend to demolish a privately owned apartment building atop a cliff that has been weakened by years of coastal erosion.
The city evacuated the building at 310 Esplanade Ave. in January during last winter's El Niño storms. The bluff beneath the 20-unit structure has weakened since then, said City Manager Lorie Tinfow.
"The concern is that a substantial portion of the building could fall onto the beach," she said.
The city is trying to gain access to the building to begin demolition as soon as possible and has been in contact with an attorney for the owner, Millard Tong, she said. Tong did not immediately respond Thursday to a call seeking comment.
The building poses public health and safety risks, Tinfow said. There are also environmental concerns. The structure contains asbestos that could spill into the ocean if the bluff collapses.
Two apartment buildings directly south of 310 Esplanade were demolished in February and March, having been evacuated during the winter of 2009-10.
Tinfow addressed reporters Thursday morning as a major storm arrived on the coast, hurling waves into Pacifica's vulnerable shoreline.
Last winter's storms caused widespread damage to city infrastructure, including Pacifica Pier. The city has secured $3.6 million for repairs and is more than halfway done with those projects, but a new problem has arisen. Officials have determined Pacifica will have to fully replace about five blocks of the sea wall north of the pier, an undertaking that Van Ocampo, the city's director of public works, estimated at more than $10 million.
As if those problems weren't enough, last weekend a massive sinkhole opened up on a pathway that zigzags down to the beach just north of 310 Esplanade. The trail has been fenced off, denying access to the beach for annoyed neighborhood residents.
Responsibility for fixing the trail lies with the adjacent property owner, Oceanaire Apartment Homes, according to Tinfow. Oceanaire management has begun repairs, she said, but it's unclear how long they will take. A representative of the company did not immediately respond to a call seeking comment.
Four friends from the North Bay peered down at the damage Thursday, shielding their faces from the rain. They asked what had happened to the residents of 310 Esplanade.
"It's terrible," said Janice Pollock, of Napa. "I feel sorry for those people."
With the help of the Pacifica Resource Center, most displaced residents found other places in the area to live. But the loss of the three apartment buildings over the past six years has taken 52 affordable housing units out of circulation.
Aaron Kinney


text:
Q: VBA How to Delete Table Rows I have a table which can vary in range (rows only) depending on the numbers of inputs (rows).
I've written a code to transfer the data from the table to my data base. That's working fine.
But, at the end of this script, I'd like to delete the table rows, expect the first and the second rows, where respectively, my headers, and my formula lives.
Bearing in mind that the total number of rows can vary, how can I delete all the table rows but the 2 first one?
FYI
The table range (headres and first row) is A18:D19
    Dim Cl As Range
For Each Cl In Sheets("Data Entry").Range("A19:A1000")
    If Cl.Value = "" Then Exit For 'Exits on first empty cell
    Sheets("Source Ingredients").Range(Cl.Value).Value = Cl.Offset(, 2).Value

Thanks in advance
Greg

A: This works, where Table1 is the name of the table. If you aren't sure how to find this, click in the table, then select Table Design in the banner at the top, and the table name is on the top left under Properties.
Application.Range("Table1").ListObject.DataBodyRange.Offset(1, 0).Resize(Application.Range("Table1").ListObject.DataBodyRange.Rows.Count - 1, _
    Application.Range("Table1").ListObject.DataBodyRange.Columns.Count).Rows.Delete

With the address abbreviated using a With statement:
With Application.Range("Table1").ListObject.DataBodyRange
    .Offset(1, 0).Resize(.Rows.Count - 1, .Columns.Count).Rows.Delete
End With


text:
Game #12 – Hawks vs. Kings Spotlight: Sentimentality Is Dead, But No One Seems To Realize
By Sam Fels November 2, 2019 874 0
We, of course, don't think anyone should ever be sentimental toward Drew Doughty. He looks like when Butthead glued his hair to his face to look older, talks like that as well, and might just be a rapist. We have to accept that Kings fans will forever love him, as that's just how these things go, as he's the best d-man in team history since…good lord, Rob Blake? Really? That's it? So basically he's the best defenseman the team has ever had. Well there you go.
What the NHL's CBA has never really allowed for is for teams to be able to treat their current legends like that. But teams can't help themselves. And probably for good cause. No fan wants to see their most important players leave before they retire and play for someone else. It's weird, and at the base of it, not really why we got into sports in the first place. You're seeing it in baseball now, where all the efficiency bros have decided they're not going to pay players like Mookie Betts or maybe Kris Bryant and players like Bryce Harper and Manny Machado can't seem to find the list of suitors they should. Baseball's popularity is at best stagnating. It would be hard to reason these two aren't connected.
The perfectly run NHL team would be callous, because it has to be. There's a hard cap. It's not like baseball where you can spend over it if you're willing to part with some of your ungodly profits. Draftees don't immediately come through like football, and also you can immediately discard anything that's not working out like the NFL. Your contracts live to their fruition, for good or bad. It's almost always bad.
In a vacuum, as soon as your players, no matter how prominent, began to age, you'd move them along for younger models. Or you would just let them walk and use the cap space to find cheaper and younger alternatives. You would never let emotion get into it. But is that even possible?
What would Kings fans feel if Anze Kopitar and Drew Doughty were allowed to just walk away? These are the two linchpins of their only two Cup teams. Maybe they would all eventually learn to love the next crop the same way. But it's impossible to think that something wouldn't be lost in that sense. Surely something about being a fan of a team is its history, and poignantly its recent history. Can you really just discard that?
But by not discarding that, you're actively hurt the current team. The minute Drew Doughty signed his eight-year extension that pays him $11M a year, he basically turned into a grossly hairy tomato can that looks like the personification of a Mac's rainbow wheel. He's been especially horrific this year. All of Doughty's metrics have ballooned the wrong way. He's behind the team in everything, and looks like a toddler with a Zippo in his own end. Here's a list of relative numbers to the rest of the team for you so far this year, all per 60 minutes at evens:
Attempts-for: -11.72
Attempts against – +8.55
xGF – -0.57
xGA – -0.57
Shots for – -4.13
Shots against – +6.56
(JUST HOOK IT TO MY VEINS)
Doughty's individual rates have plummeted as well, as he's creating next to no offense, struggling to haul his bloated carcass around the ice and into the offensive zone. Only seven more years to go!
Perhaps the Kings are counting on a new CBA in a couple years to save them. Perhaps they thought they would get one after this year and got caught cold by the NHLPA's decision to not re-open it this year. Or maybe they were just too blinded by what Doughty has meant to the Kings, which they probably couldn't help.
No matter when the Kings feel they'll matter again, Doughty's contract is going to be cement shoes made by Dwarven blacksmiths. And much like Brent Seabrook, he'll become an object of ire for a section of the fanbase, if not a large swath of it. Some of it will be earned, as Doughty clearly has let his game and condition sink. But most of it will be due to signing a contract he was offered.
The Kings will mostly be to blame. But it's the players who linger long enough to go from hero to villain.
Game #65 – Hawks vs. Kings Preview, Demo Ski Rental – Modern Day Catastrophists
By Matt McClure March 2, 2019 1250 0
RECORDS: Hawks 27-28-9 Kings 23-33-8
PUCK DROP: 3:00PM CST
TV/RADIO: NBC Sports Chicago, NHL Network, WGN-AM 720
PLEASE NO MORE CALIFORNIA SONGS: JFTC
How the mighty have fallen. It's a cliche, but given the matchup between these two former titans, it's applicable. And while the Hawks are threatening to make a useless playoff appearance this year as the Kings did the previous season, the opponent they find for themselves today has no such delusions of grandeur.
At the start of today's games, the Kings find themselves with the second worst point total in the league, and dead last in the Western Conference, with only the fetid corpse of the Ottawa Senators providing the buffer between them and the dirt. The problems for this team has remained constant even coming from the salad days, where their team offense is 30th in the league, but only this time there hasn't been any defense and goaltending to bail them out. Age and workload and everything else has caught up with Jonathan Quick, whose .891 overall save percentage (.905 at evens) wouldn't even be good enough on a team that boasted some high octane offense on occasion, and he need look no further than the squad in white today as proof of that. Quick is now 33, and his contract will take him until he's 37, so if this is the rate of decline that Rob Blake and the Kings are going to have to live with, it's not going to get any better anytime soon. But rest assured, despite Rob Blake not being able to make a solid transaction to save his life, much like he couldn't ably perform any of his other post playing career duties, he'll somehow manage to get promoted to executive VP or some shit, because that's just what happens to Rob Blake.
In front of Quick the Kings' blue line is still anchored by accused rapist Drew Doughty, whose play has also completely fallen off the table. While he's still taking assignments in any and every situation as a true #1, he has not been able to flip the ice this season as in years past, and only has one goal all year for his troubles. The latter is a bit of bad luck, and now with longtime partner Jake Muzzin gone he's dragging around Derek Forbort, but if this is the new standard with his new contract kicking in at $11 mildo per NEXT year for the maximum 8 year term, the Kings are going to have to hope he rebounds at 30, and again, ask the guy wearing the XXXXXXL #7 sweater on the other bench how well that works out. With this season lost, the Kings are not at least trying to get a look at whatever they've got in their barren prospect cupboard, particularly with Alec Martinez hurt, so people named Kurtis MacDermid, Sean Walker, and Matt Roy are rounding out the bottom two pairings along with the overrated corpse of Dion Phaneuf.
Up front, Anze Kopitar hasn't been able to repeat his career year which saw him gain a Hart Trophy finalist nod primarily because no one else on the Kings was scoring last year. Well now Kopitar has backslid to what his usual numbers had been, but no one else on the Kings has picked up any of the slack. Yes, it's completely shocking that a 36 year old Ilya Kovalchuk has been a giant floaty turd on a team going nowhere, and he also has four more years left on his deal. No one on the Kings has more than 20 goals, which is probably most shocking from Jeff Carter, but again, the miles have more than likely caught up with him. Kyle Clifford and Trevor Lewis are still here, and it'd be easy to point and laugh about being permanently attached to 4th liners, but Marcus Kruger is still getting paid fairly nicely on the other side.
As for the Men of Four Feathers, this is an absolute must-have game in regulation if they're going to continue to delude themselves and everyone else that they're still vying for a playoff spot. The Nuclear Option of Saad, Toews, and Garbage Dick returns with The Drake now concussed, making the Hawks' forward group even more top heavy. But again, if they're going to do this, it's not going to be because John Hayden and Wide Dick Artie are going to start dominating from the third line. And given that there's no fathomable combination of defensive pairings that are going to slow anyone down, even this Nerf gun Kings offense, there's no reason not to lean on the proven weapons they've got. Any run is also going to require solid goaltending from the likely still dizzy Corey Crawford, who in all likelihood will go tomorrow night in Silicon Valley, leaving Cam Ward to hopefully not shit his pants this afternoon. It's a big ask, but he provides veteran leadership and and big game experience so hopefully he's up for it.
When these two played at the UC back in November the Hawks were just getting acclimated to Coach Rod Belding and the game was an unwatchable slog. According to Stan Bowman, the team is still learning his system, which apparently must be like learning Sanskrit given the on ice results in the defensive zone. While the Hawks have at least become some form of black comedic fun since then, the vultures have continued to pick at the Kings, but afternoon hockey is the great equalizer and almost always results in shitty play and shitty ice conditions, so expect the same this afternoon. Regardless of that, if this team wants to convince itself it should be playing past game 82, beating the worst team in the West is nothing short of mandatory. Let's go Hawks.
Game #65 Preview Suite
Douchebag Du Jour
I Make A Lot Of Graphs
Lineups & How Teams Were Built
Game #20 – Kings vs. Hawks Q&A: Out Of The Darkness…More Darkness
By Sam Fels November 16, 2018 1166 0
We really have to reach into the depths for our Kings Q&A. It's best if you don't know. Just know that he's truly warped.
Boy, your lot really sucks, huh?
Last Saturday, Sportsnet flashed a graphic that the five leading scorers on the Flames had more goals than the Kings have scored all season. In the two games since, the Kings have added one goal to their total of 34, which is also the season total of the quartet of Kane, DeBrincat, Toews, and Saad combined.
You mean Ilya Kovalchuk and his five goals weren't the answer?
Where would this team be without its leading scorer, Ilya Kovalchuk? The answer is in exactly the same spot standings-wise, and possibly the same place points-wise, depending on how a theoretical Knifey Spoony against Lundqvist and three friends turned out. If you pretend the Kings have two additional Kovalchuks? Well, they would break the salary cap by over $12 million, but also finally pull into a tie for 30th in goals with Anaheim. The only unrealistic part of this scenario is imagining the Kings bringing in multiple players in one offseason.
Anze Kopitar has six points. What's the deal there?
And only three of those six points were at evens, where his most common wingers are Alex Iafallo, and since his return from injury, Dustin Brown. Playing around with sortable categories on Natural Stat Trick, one notices that his current numbers are still above 50% (hovering around 52-53% for Corsi and Fenwick). However, they are mostly below either his rookie 2007-2008 season or his broken wrist 2016-2017 season. He's 31 and it has become easier and easier to concentrate on just shutting his line down. But I bet if Eastern Conference writers stayed up to watch him play more often, he would have at least eight or nine points by now.
Does Rob Blake have any idea what he's doing?
He knows exactly what he is doing: firing everyone under him before people realize this team is going nowhere. Was it really John Stevens' fault after just 95 games?
What does the immediate future hold? What should it hold?
The immediate future holds rooting against any hot streaks that pull them ahead of other bottom-feeding teams, or convince upper management not to make more drastic changes. Everything with a pulse should be traded, but the team's most liquid asset is Carl Hagelin, whose best case scenario is being flipped for a fifth-rounder to a team looking for #SPEED. Their youngest defenseman, Paul LaDue, is 26. Dion Phaneuf is still signed until 2021. The immediate future does not look great, even with a big lottery win, so maybe it is time to revert to planting drugs on albatross contracts.
Game #60 – Kings vs. Hawks Douchebag Du Jour: Rob Blake Might Be An Idiot
By Sam Fels February 19, 2018 1686 0
It's only his first year in the GM's chair on Figueroa, but Blake's deadline push-in for Dion Phaneuf doesn't bode well for Kings fans.
Dion Phaneuf has always been massively overrated. Hockey GMs and media have always been distracted by the noisy things he does. He makes big hits, he takes big slappers, he yells at his teammates a lot convincing them he's a leader. It's the kind of thing you always hear about in the sport.
But Phaneuf has never driven play. He's never helped his team create more chances than they give up. It's been six years since he scored more than 31 points, or more than 10 goals. He's not really an offensive weapon, and he's never been all that good defensively. You think you hate Brent Seabrook…
And the Kings problem has always been they're slow. They used to play slow under Sutter, they want to play faster under John Stevens, but only Doughty and Martinez can really go anywhere. How does Phaneuf help the Kings keep up with Vegas or Nashville or Winnipeg in the first round, all possible opponents who can really move? He's just going to have that same confused gape on his face he had in Calgary, Toronto, and Ottawa when none of those teams really went anywhere.
In addition, Blake has now taken on his ridiculous contract. He's signed until 2021 when he'll be 36. That's a boat anchor.
Lastly, Phaneuf is the kind of player that quite simply is being phased out of the game. All d-men have to be able to move and get up and join the play now. Even if you're a "stay-at-home" guy, you have to be able to win races and open yourself up to pass out of the zone. Phaneuf can't do that at 32. How's that going to look at 34?
Whatever, not our problem.
Game #60 Preview


One of the comments I hear from teachers all the time, particularly if they are new to social media, is how they feel overwhelmed by the sheer amounts of information that can flood your news feed every day. I've often heard it described as trying to take a drink from a fire hose. I'd say that expression is generally pretty accurate.
The best way to get connected and really learn from others is to follow a lot of people. When you don't follow many people, you don't see as much in your news feed. On the other hand, once you start down that road, it can become impossible to read everything that comes into your feed.
Some Twitter fans use other sites or apps like Tweetdeck or Hootsuite to organize their feed into different lists or groups, but I've never really had much success with that. I know I won't be able to see and read everything, but I've always felt like I have been missing good information that could really benefit me as an educator.
Enter Nuzzel! One of my fabulous #TOSAchat colleagues introduced it to me last week and it has CHANGED the way I do social media, particularly Twitter. Available for both iOS and Android, Nuzzel is an app that shows you the most relevant tweets from a given time period, such as the past 24 hours.
Not only that, but it tell you how many of your social media friends have shared it. Now you can know exactly what everyone is talking about (or tweeting about) because it shows up first on the list. You can view the tweet (or connected blog post), share it out again on social media, or export it anywhere (like Evernote where I personally like to store info for later reference – see blog post about Evernote). There's also a "friends of friends" screen so I can expand my search out to beyond just my own Twitter circle.
I can still go back to Twitter any time I want and take a sip from the firehose, but Nuzzel allows me to focus my searching and see the best of what's out there with just a few taps on my phone! Almost everything I've read through Nuzzel has been worth retweeting because it has been just that good. If you tweet, you MUST use Nuzzel!
Previous Previous post: Classroom = No Phone Zone?
Next Next post: Give Screencasting a Try!
Great article! If you want a way to slow down the firehose check out purrchr.com.


text:
High class outdoor tourism is a way forward for North Wales economy, says financial guru
Former Goldman Sachs chief economist says region must find its niche in the global marketplace
Owen HughesBusiness correspondent
Jim O'Neill, former chairman of Goldman Sachs
Economic 'rock star' Jim O'Neill, the man who coined the term BRIC for emerging economies, says North Wales must find its niche and get connected to punch above its weight in the global economy. O'Neill, a renowned economic commentator who recently stepped down as chairman of Goldman Sachs Asset Management, was in the region as a keynote speaker at an event organised by the North Wales Business Club.
The Daily Post took the opportunity to meet O'Neill at the Bodysgallen Hotel, near Llandudno, where he talked about how Wales could compete in a globalised marketplace.
Casting his eye on North Wales he said the region had to put itself at the forefront of communications technology, play on the proximity of the cities of Manchester and Liverpool and aim for well-off tourists seeking outdoor activities.
He said: "On a global perspective, North Wales is small.
"Coming to visit my parents in Rhos-on-Sea (where they retired), from big parts of the world, from London, it is a long way, so it is a natural disadvantage because it is not close.
"You guys are an hour and a half from Manchester.
"In my view, unless there is some new great natural commodity or energy resource found, North Wales has to somehow try and play on linkages to Manchester and Liverpool, because otherwise I am not sure what is the thing in a very globalised world that North Wales has to offer.
"Tourism is obviously a big thing but you can't guarantee the weather and you are not near the wealthy people of London so it is hard."
O'Neill grew up in Gatley in Manchester, where he fell in love with football, in particular Manchester United, where he went on to sit on the board.
He attended Burnage Comprehensive, whose alumni include Noel and Liam Gallagher before going to Sheffield University to study geography and economics before pursuing a career in the world of finance.
O'Neill went on to become chief economist of Wall Street banking powerhouse Goldman Sachs where he gained a reputation that made him one of the world's most sought-after economic commentators.
It was in that role that he coined the term 'BRIC' in 2001 to describe how the emerging markets of Brazil, Russia, India and China would challenge the West's economic dominance. It boosted him to celebrity status and earned him the the title "rock star" of economics and he was tipped as a future Governor of the Bank of England.
One of the trends he has witnessed during his high-flying career has been the march of the mega-cities.
He said: "If I look at what's happened to the global economy and football since I left university 38 years ago then I see big urban areas are the winners, look at the top league of football, in those days you had Derby, Nottingham Forest, Sheffield United, these days it is Manchester and London and maybe Liverpool.
"That is true globally as well, you have these big cities all over the globe. Areas that are not close to these big sprawling urban things, they are going to have to really work on 'what is your edge'. I think North Wales' edge is its beauty and with it tourism but then you have the disadvantage that you're in Britain and you don't have the weather.
"If it were me, particularly with the pound having fallen so much and the UK is cheap for people from overseas, they should be concentrating on high class outdoor tourism.
"That is an area I would really put a lot of effort into, it is something that very few other areas in the UK can match. With it they need more of these(referring to Bodysgallen Hotel), but they must be linked with doing something, like activities.
"People will also do these activities in most weathers, they will do that.
"But beyond tourism what else is North Wales going to attract people with?"
Looking forward he said Wales must ensure it invests in technology.
He added: "Broadband is vital now, and just technology generally.
"Reflecting back on my professional life I found myself thinking that South Korea is the country that is arguably the most interesting of my professional life because when I was young South Korea's wealth was about the same as an African country.
"Today it is more wealthy than North Wales, if you really look at how South Korea has done well, why is it?
"The answer is threefold, education, strong governance, in terms of helping direct business, and thirdly on use of technology for all its people.
"They are the best in the world, better than the US. In a modern global economy if you are not connected, mobile, computers, internet, you are just out of it.
"That is a way around it (natural infrastructure limits).
"If you are connected with wi-fi and everything you can run a business from anywhere and then you've got that beauty(pointing outside) as a place to live.
"So the Welsh Government has to make sure Wales is technologically connected, given the other disadvantages.
"When it comes to technology, going back to South Korea, I don't think it is a coincidence that South Korea has become so wealthy, it is because they allowed all their people to be plugged into technology.
"They were a bit more like 'Vince Cable' they believed the Government could do something to help its people.
"If Wales had an investment bank, an 'RBS Wales' owned by the Government, they could say 'right here is how you are going to help the economy more, you are going to make sure there is technology available to every citizen of North Wales, internet and all that'. And if we are really into alternative energy, then we are going to do it and invest in that too.
"Many Governments have investment banks, Germany has one and Wales could have one."
North Wales Weather
RhylDoctor's surgery targeted with anti-vaccination graffiti as patients waited for boostersGraffiti has been daubed on several areas outside the building
Gallery: New Year's celebrations across the UK in 2022
Essential Wales
Gallery: 2021 in pictures by Haydn Iball
Kiosks up for grabs for independent businesses on newly refurbished Colwyn Bay Pier
Colwyn BayConwy Council is looking to attract new vendors to offer food, drink, retail, arts and crafts
BBCReaders have their say on the BBC and agree with plans to ditch licence feeThe BBC has been under the scope recently due to critics and supporters arguing for and against the organisation. But what did you think?


You have glanced through the rules governing registration of home stays in Sikkim. Let's do an activity to test your understanding.
How Many Sikkim Home Stay Registration Prerequisites Do You Know?
Sikkim Registration of Home Stay Establishment Rules 2013 workbook. Bookmark.


text:
Oncidium hieroglyphicum är en orkidéart som beskrevs av Heinrich Gustav Reichenbach och Josef Ritter von Rawicz Warszewicz. Oncidium hieroglyphicum ingår i släktet Oncidium och familjen orkidéer. Inga underarter finns listade i Catalogue of Life.

Källor

Orkidéer
hieroglyphicum

redpajama_set_name: RedPajamaWikipedia


The successful candidate will be responsible for the local authority commissioned Advocacy and Independent Visitor services for various services in South of England, as well as some independent services to other providers and for the management and support of staff delivering these services, having experience in this area. The successful candidate will also be expected to support new services in the surrounding areas.
The successful candidate must live in the South of England and have a relevant professional qualification and have substantial proven practice experience in delivering direct work to children, young people and vulnerable adults in a social care setting. You must also have considerable experience of the supervision of staff/volunteers.
For an informal chat please contact Kevin Roberts on 07787105413.
NYAS operates robust safe procedures to ensure the protection of the children, young people and adults at risk we work with. To comply with NYAS's Safeguarding and Child Protection Policy candidates will be subject to an enhanced DBS check.