text:
The Pride Flag flies majestically over the San Francisco Gay Pride parade on June 30, 2019 in San Francisco, California. (Photo by Meera Fox/Getty Images)
Ohio Board of Education approves anti-LGBTQ+ resolution
by: David Rees, Karina Cheung
COLUMBUS, Ohio (WCMH) — The Ohio Board of Education has voted in support of a resolution that will reject proposed federal protections for LGBTQ+ students.
Ohio's top school board voted 10 to 7 to approve an amended resolution on Tuesday that opponents said will harm LGBTQ+ youth in the state. Board member Brendon Shea wrote the resolution after changes were proposed in June to Title IX, a federal program protecting people from discrimination based on sex. The changes include protections against discrimination based on sexual orientation and gender identity.
The vote comes after several meetings and hours of public testimony over the course of four months.
What does the resolution say?
Shea, of London, introduced the resolution in September, now titled the "Resolution to oppose the proposed changes to Title IX and to affirm parental rights and local control of Ohio K-12 education."
The resolution's newest version states the proposed Title IX changes "contradict the plain language of the original law," and requires school "sports teams to be based on gender identity rather than biological sex" while granting "access to sex-separate facilities based on gender identity rather than on biological sex."
Further, the resolution states the proposed regulations "require that K-12 schools to socially transition minor children to a different gender without requiring parental consent." Shea also states the regulations deprive students of their First Amendment right to speech.
Ohio school board votes on amended LGBTQ+ resolution
The amended resolution asks that the board call upon Ohio's legislature to "resist federal executive branch attempts to undermine the original intent of Title IX." It then directs the acting Superintendent of Public Instruction to issue, within 21 days, a copy of the resolution to every Ohio public school indicating that the board opposes the proposed changes, and considers the guidance "unenforceable" and does not compel them to take a particular course of action.
Regardless, the changes to Title IX remain unenforceable until the U.S. Department of Education reviews the more than 200,000 comments submitted during a public comment period this past summer. The process to finalize the regulations could take months or even years.
Still, a lawsuit filed by Ohio Attorney General David Yost and 21 other attorneys general claim the proposed policies are illegal. In July, a federal judge in Tennessee ruled in their favor, temporarily blocking parts of the new Title IX protections. A final ruling is still pending.
The resolution states the board supports the efforts of the Ohio Attorney General.
Strong reactions on both sides
Rejecting the proposed protections has drawn strong reactions throughout the past four months. Earlier this fall, the Columbus City School Board passed its own resolution in opposition to Shea's proposal.
"This legislation is absolutely disgusting," said Columbus City School Board President Jennifer Adair. "It promotes just blatant discrimination, and it is just full of hate."
Susan Kleine, a retired clinical counselor from Milford, voiced support for the resolution.
"Encouraging the choice of 'pronouns' and encounters with opposite sex kids in bathrooms, locker rooms, and showers actually makes schools culpable for the anxiety, bullying, and possible physical abuse which school authorities are tasked to prevent," said Kleine.
How the Respect for Marriage Act will affect Ohio
Executive Director of the Ohio School Psychologists Association, Rachel Chilton, spoke against the resolution and said reports show youth who attend schools who support the LGBTQ+ community have lower rates of attempted suicide.
"Banning affirming behavioral and medical care for minors goes against widely recommended medical advice and would harm the mental and physical well-being of all LGBTQ+ youth across the state, especially transgender and nonbinary youth," said Chilton.
The resolution underscores the several anti-LGBTQ+ bills introduced in the Ohio legislature in 2022, including House Bill 616, a "divisive concepts" bill opponents have dubbed a "Don't Say Gay" bill. In addition, Ohio has statutes and constitutional amendments prohibiting same-sex marriage that would be reenacted if Obergefell v. Hodges — the Supreme Court case legalizing gay marriage — were overturned.
After Ohio sues Dollar General, stickers warning of overcharging being added
LGBTQ+ young people are known to have difficulty finding safe spaces. Research shows LGBTQ+ youth are five times more likely to die by suicide due to their inability to be out among family members and peers. In addition, 92% of transgender youth have attempted suicide before age 25.
The vote comes on the same day President Joe Biden is set to sign the Respect for Marriage Act, a bill protecting the legitimacy of same-sex marriage. The bill requires a state to recognize a marriage from elsewhere regardless of the sex, race, ethnicity, or national origin of the individuals.
Media | 43 mins ago
State Watch | 1 hour ago
Police seek suspect in Beavercreek Twp. crime spree
Columbus Zoo offering 'penguintines'


The black and white animation in Jay-Z's "The Story of O.J." establishes a clear metaphorical statement that American society continues to be greatly influenced by slavery and racism. The depiction of the characters parallel that of picaninny cartoons with motifs of cotton, burlesque shows, the KKK, and slavery abstractly merging with Jay-Z's accomplishments in the form of cars, boats, and artwork.
In this way, "The Story of O.J." speaks directly to black Americans trapped in a cycle of perpetual poverty, "The odds are staked against you; you have been born into a system that has neglected to give you the knowledge you need to break the cycle. Here is how you escape…"
Who is responsible for providing the poor with the education necessary to become financially wise?
How do you reach this group when higher education institutions are out of reach and the accessible education fails to educate?
The legacy of slavery and racism has been and still is embedded institutionally in our society, while progress has been made, large barriers still exist for many, given that these still exist is it possible, how alive is the American dream, if we all start from different positions in the game of life?
Mission: To empower high school students from under-served communities to become future leaders. Our programs focus on character development, social impact, healthy living, technology, financial literacy, creative arts, and global leadership.
Mission: We help people respond effectively to injustice in the world around us. As a national online force driven by over one million members, we move decision-makers in corporations and government to create a more human and less hostile world for Black people in America.
Through all the chaos that is "This is America" Childish Gambino aka Donald Glover stitches together a brilliant piece of thought-provoking work that represents present-day America. In the new visual he brings political undertones on gun violence and the black experience in America to the forefront. After watching for the first time you are left gazing at the screen searching for answers focusing on the dancing throughout the video. On second listen you are able to zero in on what is going on in the backdrop. This is symbolism for Americans paying more attention to material things and their social status instead of the greater social issues like gun violence which is highlighted in the video. When Gambino says "This a celly, that's a tool" it is in reference to the March 18th shooting of Stephon Clark, an unarmed black man gunned down in Sacramento, CA by police only to later be found carrying a cell phone which was mistaken for a gun. Gambino shoots a guitarist and a choir in two separate frames and gently places the guns in a cloth, while the victims are dragged away. This ties into the notion that guns are valued more than human life in America. Gambino does a great job in shedding light on a problem that has been around for centuries.
Should we follow the lead of our fellow countries and enact policies to have better gun control when it comes to automatic weapons in this country?
Lamar incorporates South African voices into his album, not only to pay homage to the home of Black Panther but also to indicate that we are all part of a larger picture. It's impossible to not be connected to other parts of the world now-a-days and groups like Aid For Africa are doing incredible work connecting those in need and those who are willing to help.
Both the movie and the album paint a picture of a world in which people are lifting one another up instead of bringing each other down. As I was listening to this album I found as many illustrations of despair as I did messages of hope for a better future. In Black Panther, the main character is faced with a choice of isolationism or cooperation and I'll spoil it for you, he makes the right decision. Lamar has shown this this is not only true in the Afro-futuristic society of Wakanda, but also in the real world. Be it Compton, Oakland, South Africa, or Wakanda the forces of good will always overcome those of evil.
From devastating forest fires to catastrophic storms that ravaged both Texas and Puerto Rico we have seen a fair amount of destruction recently. Lamar touches on this by calling out Government Aid efforts and its inability to provide relief to those that remain in peril. It's through sustained action of organizations like The Foundation for Puerto Rico, The National Forest Foundation, and The Red Cross that we can all be active participants in helping those in need and sacrifice a little bit of ourselves for the greater good.
"The big picture's in motion, are you playin' your part?
The meaning can be found in its very clear call-to-action to get involved in ensuring community trust and security. Change does not happen by itself, it requires the collective effort of every member in a community.
Groups like Run For Something are working hard to encourage people to reclaim their local politic and contribute to their communities. It is more relevant now than ever for the youth and those who are determined to see the change they want in their communities to get involved and be the catalyst for change.
Highlighting the attitude of gang culture, Lamar touches on a 'live by the code, die by the code' mentality. With this attitude deeply ingrained in the culture of ethics that govern gang's behavior, this begs the question of where to begin in trying to find solutions to quell violence in these communities and against other groups. This simple verse uncovers a deep truth that could help communities and law enforcement understand the value structure of gang mentality and perhaps provide a starting point for engagement. To build a more inclusive society, gangs and other notorious actors must, at times, be engaged with rather than isolated or characterized as a parasitic entity furthering the divided of 'us vs. them'. Understanding how these groups operate provides the opening door for diplomacy or, in more confrontational terms re: Sun Tzu's age old saying, the ability to "know thy enemy".
Compton has had a violent reputation, a reputation that reached the national spotlight in the late-1980s with the prominent rise of local 'Gangsta Rap' groups. The city became notorious for gang violence, primarily caused by the Bloods and Crips. According to the LA Times, between 2000 and 2016, 91.5% deaths in Compton were due to gun and gang related violence. Compare this to the national average of 67.7% and a picture of a violent setting becomes crystal clear.
What role do movies like Black Panther and music videos like All the Stars play in discussions about societal organization and community violence? Are they effective in guiding community groups toward increased understanding and discourse?
While these statistics are troubling, there are great organizations such as the Compton YouthBuild and The Compton Initiative that are initiating grassroots movements to better their communities through charitable work, outreach, and engagement. In fact, social outreach is a huge theme that runs throughout these songs and the film.
Can we get one day they don't try us?
Set in a imagined world named Wasteland where the imagery of modern times comes with a dystopian twist, "Happy Wasteland Day" feels like a cool new Mad Max prequel, while representing what Open Mike Eagle calls "the new ideal of normal." The imagery of people living in garbage, but acting fine in daily life harkens back to the days of the wild west. In this world, glorified shootouts are celebrated and lauded as the only way to solve problems. This kind of entertainment construes violence as the main form of entertainment for the masses, led by the garbage king himself.
Open Mike Eagle's recent album Brick Body Kids Still Daydream takes inspiration from Chicago's Robert Taylor Homes and the southside where he grew up. After watching this neighborhood be demolished, he was left to wonder what happened to all the displaced people. To make matters worse, the rebuilding of this neighborhood is behind schedule and there is nothing in its place but ruble. He feels that no one is talking about this issue on a national level due to race and people can't seem to handle bad news anymore due to the volume of issues surfacing daily. Robert Taylor Homes used to be one the nation's largest housing project with 11,000 residents. Open Mike Eagle uses his platform to humanize these black residents rather than discard them like the city has. This issue isn't just happening in Chicago, it's happening across the nation due in large part to policies that encourage gentrification, thereby displacing lower socio-economic residents that currently reside in these areas.
The roots of this song are based in the idea of power. In the current political climate, it seems like people in positions of power have the upper hand. This pervasive belief can cause feelings of hopelessness and isolation. Living in this kind of "garbage fantasyland", people are easily 'dragged into the dirt.' So what do you when everyone around seems to be of ugly moral character and/or complacent? You learn that you can only control what you do as an individual. You can make your own surroundings better and build up what you have. Being in the right mindset is critical so that you can become the king of your own garbage which can turn the negative into treasure.
Open Mike Eagle states that "gathered folks and they caught my vibe, If it wasn't for y'all I would've lost my mind". Without finding people that raise you up and reassure your ideals it would have been hard to stay positive for the future. These people can be the fuel to your fire when your light seems low. Is it important to find a community and what effects does community have on your values?
Violence and hate shouldn't be normalized, but many fear that this has become the reality within the media over the past few years. Whether it be from protests or police shootings, we see or hear something tragic on a daily basis. Is violence and hate featured too predominantly in current media?
Another area of conversation has been on the apparent dearth of programs serving lower income housing. This sentiment has been felt and can be seen in several cities across the United States and has been connected to violence level, particularly within the inner cities. What are the real effects of housing policies?
In an Los Angeles based open mic workshop established in 1994. It featured rappers, music groups, and dancers. It was created for performers to gain skills and test out new material. They have released various records and a documentary on these artists.
MTO helps educate, organize and empower tenants to have a voice in the decisions that affect the affordability and availability of decent and safe housing.
Steeped in social commentary, personal exploration and quick witted word play, "Who's Watchin'" uses powerfully crafted lyrical stanzas to present a host of today's most pressing issues. Backed by a powerful beat and flow, Monty creates a powerful persona that he "demands respect", a sentiment often felt by those who have been systematically disenfranchised and discriminated against in this country. Perhaps most poignant is his reference to the Colin Kaepernick drama that has been brewing in the NFL in the recent months. For those unfamiliar with Kaepernick's ongoing social justice movement, it is best synopsized with Kaepernick's own words: "I'm going to continue to stand with the people that are being oppressed. To me, this is something that has to change. When there's significant change and I feel that flag represents what it's supposed to represent, and this country is representing people the way that it's supposed to, I'll stand." Monty's solidarity with the athlete on this issue is incredibly relevant.
He continues his commentary by going straight to the heart of the issue - racism. His heartfelt and topical commentary ties well into the current national dialogue on racism and its legacy in the U.S. From the bombardment of videos on our Facebook timelines to the images of students in blackface making the rounds on the news, these are difficult images to grapple with. As our nation continues to come to terms with our legacy of slavery and how that has impacted our social and economic system.
"Who's Watchin'" closes with a poignant reflection on systemic silencing of minority groups in modern day U.S. society. Monty strikes back at the passivity and lifelessness he has found in our national dialogue that when coupled with the "shhh" sound effect, seems to suggest that white people who choose to be quiet and inactive, when it comes to speaking up and fighting for human rights, are also part of the problem. In just a few lines, Monty manages to simultaneously acknowledge the prevalent social commentaries happening today, state his thoughts on the root of the problems he has observed and lived, and demonstrate to his listeners that these basic human liberties are worth fighting for. After this stern call to action to bring about vast ideological change, he promptly keeps going.
All without missing a beat.
Monty, drawing inspiration from Kaepernick's social movement, is supportive of speaking out against social and civil inequities. His call to action for social upheaval is especially relevant given the current political climate in the United States. Is our current national dialogue adequately reflecting and supporting solutions to lingering dissatisfactions over civil rights and cultural identity?
Is it important to speak out on any inequalities on a theoretical post-racialized America?
Hailing from Brooklyn, and currently residing in Los Angeles, Monty XXL is a HipHop and spoken word artist who prides himself on preaching a message through his work. His brand of hip-hop harkens back to the golden age of the early 90's where the beats were funky and the lyrics mattered. While his vocals have a raspy timbre to them, his low tenor allows his lyrics to shine through and impact the listener while effortlessly floating on top of the beat, unperturbed by the weight of his words. This selection is one of his original songs entitled Who's Watchin' and from beginning to end he fills the bar lines with thought provoking content.
Check out Monty's other stuff! Hes got a ton of music on his Youtube channel as well as his Soundcloud and his Instagram.
We're all a canvas would you paint me red if I was darker?
If I saw Martin would he tell me that he's had a dream?
Jorja Smith's thought provoking song "Imperfect Circle" highlights the age-old saying that history repeats itself. In light of current events regarding race relations (e.g. #BlackLivesMatter, Trayvon Martin, Charlottesville, etc.), "Imperfect Circle" grapples with the question of race relations, and in particular, can, or even more provocative, has anything changed since the days of Martin Luther King?
Does simply having more awareness about an injustice help in solving the issue (e.g. The Kony 2012 Movement; Occupy Wall Street)?
Can (digital) social media really create change to the extent that (physical) sit-ins and marches did during the 60's and 70's?
How have inherent biases in institutional practices embraced and perpetuated discrimination over the years and how can we play a part in changing the system?
Let's get the discussion going! Feel free to comment on Twitter, Facebook, or send your thoughts to us at thesocietyofsound@gmail.com.


(AP) -- The final day of the regular season has arrived, with one playoff spot to decide, seven of the eight first-round matchups still unknown and nine different seeds still not clinched.
It also is the last day that Dallas' Dirk Nowitzki and Miami's Dwyane Wade will be NBA players before retirement. Dallas is in San Antonio, Miami is at Brooklyn. Nowitzki and Wade played their final home games on Tuesday night, both scoring 30 points apiece.
It is the first day of the offseason for a few teams, including the Los Angeles Lakers -- whose season ended Tuesday with a loss to Portland and team president Magic Johnson stepping down in a move that few could have predicted. Washington, Cleveland, New Orleans and Phoenix also are done.
The only known first-round matchup is in the Eastern Conference, where Indiana and Boston meet in Round 1. Every other matchup remains to be determined.
There are no major individual races left to decide: Houston's James Harden is the scoring champion, Detroit's Andre Drummond the rebounding champion and Oklahoma City's Russell Westbrook the assist champion.
But as for the playoff picture, it comes down to the last day in both conferences.
-- Brooklyn is No. 6 with a win over Miami.
-- Orlando is No. 6 with a win over Charlotte and a Brooklyn loss.
-- Orlando is No. 6 if the Magic and Nets both lose and Detroit wins.
-- Brooklyn is No. 6 with a loss, combined with losses by the Magic and Pistons.
-- Detroit's only path to No. 7 is if it wins, the Nets win and Charlotte wins. That is also the only scenario where the Magic finish No. 8.
-- Charlotte gets in only with a win and a Detroit loss. The Hornets cannot get higher than No. 8.
6. Oklahoma City or San Antonio.
7. Oklahoma City, San Antonio or the LA Clippers.
8. Oklahoma City, San Antonio or the LA Clippers.
-- Denver is the No. 2 seed with a win.
-- Houston is the No. 2 seed with a Denver loss. Denver is the No. 3 seed with a loss.
-- Portland is the No. 3 seed with a win and a Denver win.
-- Portland is the No. 4 seed with a win and a Denver loss.
-- Portland is the No. 4 seed with a loss.
-- Oklahoma City is the No. 6 seed with a win or a San Antonio loss.
-- San Antonio is the No. 6 seed with a win and an Oklahoma City loss.
-- San Antonio is the No. 7 seed with a win and an Oklahoma City win.
-- LA Clippers are the No. 7 seed with a win and a loss by either San Antonio or Oklahoma City.
-- Oklahoma City is the No. 7 seed with a loss, a San Antonio win and a LA Clippers loss.
-- San Antonio is the No. 7 seed with a loss and a LA Clippers loss.
-- San Antonio is the No. 8 seed with a loss and a LA Clippers win.
-- Oklahoma City is the No. 8 seed with a loss, a Spurs win and a Clippers win.
-- LA Clippers are the No. 8 seed with a loss, or if the Clippers, Thunder and Spurs all win.


It's Almost Year-End. Do You Know Where Your Strategic Plan Is? — Public Communications Inc.
It's Almost Year-End. Do You Know Where Your Strategic Plan Is?
Fall is a good time, as we approach year-end, for organizations to think about their long-term and short-term planning.
Whether you're developing your three-year strategic plan or putting those strategies into place for the coming year, here are some insights from PCI's transformation team for tackling a strategic planning process that will bring clarity, priorities and success.
Involve outside counsel. You can't be a prophet in your own land, and yet nobody knows your business better than you. Your inside, in-depth knowledge teamed with outside perspective and facilitation can bring out your organization's best thinking.
Avoid cookie cutters. Too many plans are poorly crafted or generic so they sit on a shelf and collect dust instead of being put to work. Your association and its needs are unique; your process and plan should be as well.
Embrace inclusion and diversity. Have a steering team comprising senior leaders, rising stars, multi-generations and diverse thinkers. Choose at least one person you know will challenge and push the group. Find multiple pathways to maximize participation—focus groups, surveys and stakeholder interviews.
Don't talk amongst yourselves. Look at the competition, talk to members, hear from front-line employees. Consider external and internal perspectives and treat them as equals.
Allow time for planning—but not too much. Plan and go! Three years flies by quickly and in today's environment, five to seven years is too far out to see.
Planning is an art and a science. Don't dive down every rabbit hole or fall into analysis paralysis, but don't under think either. Involving the right number of voices, ideas and approaches without getting bogged down or overwhelmed can be a delicate balancing act.
Connect the dots between strategic priorities and annual plans. The strategic plan should be your roadmap for building annual plans for the years ahead. If you don't put your strategic plan into action and focus on it in daily life, you'll never get where you want to go. Think both big picture and bite-sized chunks.
Be your plan's chief cheerleader. It's okay to be a broken record. Talk the plan, workshop it, evaluate and report progress against it. Share big and small wins. Share losses, and how you will course correct. Be flexible and recognize when you need to shift slightly or do an about face. Own mistakes, apologize and move on.
Voila, three-years. Time to start over. Avoid this trap. A well-constructed strategic plan is not an employee slogan or a marketing campaign to be dumped on a whim. It's a living, breathing roadmap that allows for evolution into the next planning phase. You'll know you're on the right path to a good plan when you can see the horizon ahead.
This site and its contents © Public Communications Inc.


text:
Food Safety Registry
Food Safety Consultancy
Management's responsibility for food alert
Food alert network systems have been established as efficient and rapid mechanisms for the transmission of information between competent authorities. Through these systems, a location and withdrawal of food products from the market that may pose a risk to the health of consumers can be carried out.
These systems are currently implemented nationwide through the Coordinated Rapid Information Exchange System (SCIRI), community based on the Rapid Alert System for Food and Feed (RASFF) and international (INFOSAN). The main feature of these systems is that they allow selective removal of those affected products.
SCIRI is a system designed in the form of a network, which allows constant monitoring against any risk or incidence that, related to food, may affect the health of consumers. To generate an alert through this system, it is necessary that the country in question or EU Member State has information regarding the existence of a serious risk, direct or indirect, for human health derived from food or feed . The alert is generated by notifying the country to the European Commission.
The notification of the food alert must be accompanied by a detailed explanation of the reasons for the action taken by the competent authorities of the Member State where it was issued. The Spanish Agency for Consumer Affairs, Food Safety and Nutrition (AECOSAN) is the centralizing and coordinating point of the SCIRI. Thus, Article 30.5 of the Statutes of AECOSAN attributes to it, through its Executive Director, the power to "trigger the implementation of the National Food Alert Network" or SCIRI, either on its own initiative, of the Communities Autonomous or of the European Commission. On May 30, 2006, the Institutional Commission of AECOSAN approved the Protocol of action of SCIRI ex Article 2.2.n) of Law 11/2001 whose management of SCIRI is carried out at three levels: food alert, information and rejection.
Alerts are all notifications related to food in which a risk is detected for the consumer, whether serious and immediate or not, but in which the product involved is originally or has been distributed in the national territory, so it is required immediate action by the competent authorities.
The objective of the transmission of the alerts is the immediate action to remove the affected products, destruction or re-shipment or employment for other purposes. The legal basis for the operation of this system is Article 50 of Regulation (EC) 178/2002 of the European Parliament and of the Council of January 28, 2002, which establishes the general principles and requirements of the food legislation, the European Food Safety Authority is created and procedures related to food safety and Commission Regulation (EU) 16/2011 of 10 January 2011 are established, establishing the Implementation of the Rapid Alert System for Food Products and Animal Food.
In addition to the AECOSAN, the SCIRI is the national coordinator, the competent Authorities in the field of food safety of the Autonomous Communities and the Autonomous Cities of Ceuta and Melilla, the Ministry of Defense (through the Inspection General of Defense Health), the European Commission (through the General Directorate SANTE) and the General Subdirectorate of External Health, General Directorate of Health, Quality and Innovation, of the Ministry of Health, Social Services and Equality, for notifications of risks related to the importation of food products from third countries.
In addition, another series of organizations / organizations participate through specific collaboration agreements within the framework of the SCIRI. It is important, in any case, that the health authorities when conducting a health alert on a product, are fully safe and thus confirm that there could be an irrigation for the consumer. A food alert can cause, and so it happens in practice, major damages to the company that distributes, manufactures or stores that product. If this alert is not confirmed, it is verified that there is no risk for consumption or it is perpetuated in time without justified cause, it may cause a patrimonial responsibility of the Administration and be obliged to indemnify the company for the damages and losses caused. This happened in a case in which a food alert was generated due to the appearance of two cases of botulism due to the alleged consumption of a well-known infusion.
These cases of botulism were associated with this infusion without, at any time, proving that there was a relationship between the product and the cases. The only explanation that AECOSAN gave to maintain the food alert for almost a year was based on bibliography and on the relationship of the consumption of the product with the intervention of several hospitalized consumers who apparently had ingested the same batches. The company, meanwhile, credited with clinical reports that there was no relationship between the cases and the product. But even so, the Administration maintained the health alert.
The National Court in its Judgment of 2014 determined after analyzing this case, that there was no reason to maintain this food alert and, therefore, the company should be compensated for all the damages caused. It was stated in this case that the company should be compensated at 1,096,654.13 euros for the health alert in accordance with the following amounts: 1. As for the expenses of withdrawal, storage and destruction of the product, 8,237.36 euros 2. As for the value of the cost of the destroyed product, 17,214.41 euros. 3. Regarding shipping and communications expenses, 23,262.57 euros 4. Regarding personnel expenses, 1,036,167.65 euros. 5th for travel expenses, 1,610.04 euros. 6. As for Other expenses, for legal and financial advice, 6,981.25 euros are recognized and as for those incurred in the expert report of damages, 3,180, 85 euros.
One of our added values as food safety consultancy is that in addition to technicians, we are lawyers specialized in administrative law and more specifically, in food law. If you are faced with a threat of alert or an immobilization or unfair or disproportionate action by the health authority, we can help you recover all the damages caused to you through a claim of patrimonial responsibility for normal or abnormal operation of the Administration.
Recient posts
EU bans the use of titanium dioxide by 2022
TITANIUM DIOXIDE: EU BANS IT AS A FOOD ADDITIVE
WE ARE OPENING A BRANCH IN FRANCE!
Why ask for a food lawyer?
New European expert opinion on food supplements
food alerts
food consultancy
food legislation
general food safety registry
internet commerce
Lawyers in Granada
Lawyers in Madrid
notification of food supplements
registration of food supplements
Fill in this form and we will contact you within 24 hours.
I accept to receive commercial emails.
GRUPO LEGALEGO 16 SL has been the beneficiary of the European Regional Development Fund, whose objective is to improve the use and quality of information and communication technologies and the access to them, thanks to which it has developed a Corporate Website for improving the company's competitiveness and productivity. [22/11/2018]. In this endeavour it was supported by the TicCámaras Programme of the Granada Chamber of Commerce.

redpajama_set_name: RedPajamaCommonCrawl


text:
Bill Clinton UN Secretary General
I think not
#1 Jun 1st, 2005
In 2001, in the opening months of his ex-presidency, Bill Clinton confided to an aide that he had decided on his dream job for the next chapter of his life: secretary general of the United Nations.
The goal may not be realistic, he acknowledged, but he then went on to analyze all the factors in minute detail, as though he were preparing for a political campaign: whether a U.S. president would ever see fit to back him, for one, and what it would take to persuade other nations to bend the long-standing tradition that the top job does not go to someone from a country with permanent status on the U.N. Security Council.
His ambition, as the aide described it, was both breathtaking and entirely logical for a natural-born politician who had reached the top of the American political ladder: "president of the world."
Four years later, say several associates who have spoken with him in recent months, Clinton regards his dream of leading the United Nations as something more than a flight of fancy and something less than a serious prospect. Already, however, he has succeeded to a surprising degree in fashioning his ex-presidency to make himself a dominant player on the world stage.
His ambitions are no less obvious than when he was on the rise as a domestic politician. Clinton wants to present an alternative face of America to the rest of the world -- in implicit opposition to President Bush, and to create a legacy that builds on his eight years in office.
His recent appointment as the U.N. representative on tsunami relief is the highest-profile example of Clinton's travels and activities abroad. The extent to which the 42nd president has preserved influence even after leaving the White House will be far more obvious in September. That is when a large delegation of world leaders, U.S. politicians, business leaders and celebrities of various stripes will arrive in New York for the first Clinton Global Initiative.
The event, as Clinton recently described it, is modeled after the famous annual World Economic Forum in Davos, Switzerland. But Clinton has said he wants his three-day event to be more focused on concrete results. "I'm telling people not to come unless they are prepared to make a commitment to do something when they leave" on the conference's themes of fighting poverty, religious conflict and environmental degradation.
Among those planning to attend are British Prime Minister Tony Blair, King Abdullah of Jordan, U.N. Secretary General Kofi Annan and California Gov. Arnold Schwarzenegger (R). Even Rupert Murdoch, whose New York Post and Fox News network are favorite platforms for many of the harshest Clinton critics, plans to be there.
Jimmy Carter, the 39th president, also organized his post-presidency around international endeavors. But, as the upcoming meeting illustrates, Clinton's post-presidency is in many ways without precedent.
Carter, whom Clinton has described as the most impressive modern ex-president, eventually won a Nobel Peace Prize, but first he spent several lonely years recovering from his 1980 reelection defeat by toiling in relative obscurity. Much of his work has been in remote Third World villages, with no cameras. Clinton, by contrast, relishes the headlines that invariably follow from his overseas jet-setting. So far this year, he has visited 22 nations and met with more than 30 current or former heads of state.
Aides say Clinton's aim is to use his celebrity and networking talents with heads of state and various other famous and wealthy people on behalf of causes such as clean energy and AIDS relief. His Clinton Foundation, for instance, has negotiated steep discounts with pharmaceutical companies on antiretroviral drugs and is facilitating their delivery to about 110,000 people with AIDS in the developing world, with a goal of reaching 2 million by 2008.
Viewed from a long perspective, Clinton's post-presidential career contains an interesting historical twist. In the early years of his administration, the wide perception was that he was predominantly a domestic president.
The conventional wisdom was never quite accurate. Even in the opening months of his first term in 1993, Clinton routinely huddled late into the evening with his advisers on Russia, which he regarded then as the central foreign policy challenge.
It was true that the world abroad was a vexation to a young president who aides said regarded foreign policy as a kind of priesthood, and who had not learned to trust his instincts. The years 1993 and 1994 produced a parade of painful episodes abroad. There was the debacle of a peace mission gone awry in Somalia, two years of hand-wringing over ethnic cleansing in Bosnia, an averted gaze from a genocide that killed 800,000 in Rwanda. Clinton has called failing to act in Rwanda his greatest regret as president.
But, starting with the Dayton accords that ended the Bosnian war in 1995, Clinton began gaining confidence in foreign policy. His signal insight, as veterans of his administration describe it, was the realization that foreign policy was not in the end so different from the subject he knew best, domestic politics. As Clinton saw it, both involved public salesmanship and required leaders who could frame issues to make difficult decisions -- such as persuading people to accept a peace accord with historic enemies -- politically possible.
Beneath the surface, there is a deep vein of politics in Clinton's international activities as ex-president. While he has mostly supported Bush on the Iraq war -- and says that all Democrats should be supporting full victory even if they first opposed the war -- almost every speech he has given in recent months has contained the same refrain, delivered in nearly identical language.
"We can't relate to the rest of the world only through a negative prism, and only through telling them to do things," he told the Chamber of Commerce in Lancaster, Pa. "Why? Because if you live in a world where you can't kill, jail or occupy all your enemies, security will never be enough. You've got to make a world where you've got more friends and fewer enemies, where you make partners."
The veiled criticism of Bush is unmistakable. Clinton, associates say, thinks Bush has weakened U.S. standing in the world by being too dismissive of allies and projecting an image of American arrogance abroad. Bush says he welcomes allies but will not let dissenters abroad stop him from doing what he thinks is necessary to protect security.
For all the new rapport in the Bush-Clinton relationship -- Bush throwing regular rhetorical bouquets to his predecessor and assigning him to visit tsunami-stricken areas -- the two presidents represent twin poles in a pointed ideological debate. Since Sept. 11, 2001, has been at the center of national politics, this argument about the relative balance of force vs. persuasion in U.S. foreign policy has been at the middle of domestic politics.
The debate is reflected in the records of both Clinton and Bush. Many of Clinton's foreign policy achievements were rooted in the America-as-friend philosophy he espouses now. He expanded the NATO alliance and sought to use his rapport with the erratic Boris Yeltsin to establish a cooperative relationship with Russia -- efforts that paid dividends when Moscow helped the United States resolve ethnic conflicts in the Balkans by sending peacekeepers to Bosnia in 1995 and intervening to force a capitulation by Serbia in the 1999 Kosovo war.
One of the guiding principles of Bush's foreign policy was that his predecessor was possessed of a naive worldview. As Bush and his lieutenants see it, Clinton's attempts to coax the late Palestinian Authority chairman Yasser Arafat to a peace deal with Israel were folly, while he did not do enough to confront rising threats from Iraq and the al Qaeda terrorist network.
Clinton also was criticized for passivity in running his government -- including on issues of terrorism. He was not on speaking terms with then- FBI director Louis J. Freeh, whom he appointed. The commission investigating the Sept. 11 attacks found that Clinton and his top aides thought they had ordered that Osama bin Laden could be killed if there was an opportunity to do so in a covert mission, but that the White House expressed its preference with so many cautionary notes that the CIA believed it did not have permission.
Richard A. Clarke, a former anti-terrorism official who served under Clinton and in both Bush administrations, recalled that "Clinton would make requests, and just assume that these were being done, or that the people around him knew best." He said Clinton should have fired Freeh rather than tolerate a dysfunctional relationship with an essential national security official.
While the debate continues about Clinton's record as president, his activities as ex-president suggest a man who sees redemptive possibilities on the world stage. Even while president, amid the Monica S. Lewinsky scandal, he described Middle East talks as part of "my personal journey of atonement." One of the people helping Clinton raise money for tsunami relief is former White House chief of staff Erskine B. Bowles. He told associates that he was so appalled by Clinton's behavior during the scandal that their nearly fraternal relationship for a time became coolly correct, confined to business.
The role of Ira Magaziner also reflects the theme of second chances. He was famous as the policy architect of the 1993-1994 health care initiative, one of Clinton's most extravagant failures. These days, Magaziner is working nearly full time on the Clinton Foundation's policy programs. He said Clinton has a stature that allows him to draw attention to AIDS treatment and issues that most people never could.
"Some of the problems that have bedeviled him at home and made him controversial don't really exist abroad," Magaziner said. "My sense is he wants to make his ex-presidency one where he has really major accomplishments in the world."
In the United States, the debate over Bush's approach to the world and Clinton's -- between force and persuasion -- remains unsettled. But it seems apparent which approach is more winning abroad. While Bush has generated deep suspicion, especially in Western Europe, Clinton is highly popular, European commentators said.
Europeans who chafe at Bush respond to Clinton's "inclusive, soft-toned way of communicating with the world, and especially with Europeans," said Arnout Brouwers, a prominent Dutch editor who has studied American politics in Washington with the German Marshall Fund. "His personal history, his charms, even his personal failings, helped people identify with him as 'one of us.' "
Former German chancellor Helmut Kohl, a friend of Clinton's, agreed. "The reason Bill Clinton is popular in Europe is very simple: He just is. He is a man of great charisma," Kohl said in a brief interview after a meeting with Bush in Washington.
Asked about Clinton's dream of heading the United Nations, Kohl said: "I do not know if Bill wishes to go to the United Nations. If he wants, I would support him."
#2 Top Rated Post
Re: Bill Clinton UN Secretary General
Jeffrey Epstein Charged With Trafficking Underage Girls
https://townhall.com/tipsheet/mattve...erage-n2549614
Where's Bill gonna get his lolitas now?
Curious Cdn
You're really stuck in the deep, dark past all of the time.
Free Thinker
Quote: Originally Posted by Curious Cdn
July 6th is the deep dark past ?
Quote: Originally Posted by pgs
June 2 2005 sure as shyte is.
Epstein is a big Dem donor and fund-raiser and a great friend of Slick Willie.
Katie Couric and George Stephanopoulos were guests at Epstein's getting out of jail dinner party.
https://www.bloomberg.com/opinion/ar...r-donald-trump
Although a court filing says Mar-a-Lago eventually dumped Epstein from its ranks after he approached an underage girl there, Trump has generally spoken about Epstein fondly – to me and to others. "I've known Jeff for fifteen years. Terrific guy," Trump told New York magazine in 2002. "He's a lot of fun to be with. It is even said that he likes beautiful women as much as I do, and many of them are on the younger side."
Quote: Originally Posted by Kreskin
Anything else, or is that it?
Hoid
Er....how did the prosecutor who got Epstein the sweetheart plea bargain end up on Trumps staff?
Is that the quid?
That's what happens after you drain the swamp.
Maher Joked About Bill Clinton's Visits To Epstein's 'Sex Island'
https://www.dailywire.com/news/49394...tons-paul-bois
Slick Willie was a known diddler for decades.
Sex, Lies, and Epstein/Clinton Flight Logs
https://www.americanthinker.com/arti...ight_logs.html
Clintons love to lie.
Clinton Dashes Into The Bunker When Pressed About Jeffrey Epstein 'Lolita Express' Flights
https://townhall.com/tipsheet/mattve...ights-n2549989
My mother always said, "Yer sins will find you out." Schadenfreude.
Quote: Originally Posted by Hoid
My mother always said, "Yer sins will find you out." yup.
How many times did Trump fly on the "lolita express"?
Here ya go ya bull sh!t tard;
Trump Was 'Only One' To Help Prosecutor In 2009 Epstein Case
Epstein has spent the bulk of his adult life cultivating relationships with the worlds most powerful men. Flight logs show that from 2001 to 2003, Bill Clinton flew on Epsteins private plane, dubbed The Lolita Express by the press, 26 times. After Epsteins arrest in July 2006, federal tax records show Epstein donated $25,000 to the Clinton Foundation that year.
House Speaker Nancy Pelosi's Superdelegate daughter Christine quipped on Twitter "It is quite likely that some of our faves are implicated but we must follow the facts and let the chips fall where they may."
https://www.zerohedge.com/news/2019-...9-epstein-case
"He was a fixture in Palm Beach," Trump said of Epstein, who is also known for having been friends with former President Bill Clinton.
"I had a falling out a long time ago with him," Trump said. "I don't think I've spoken to him in 15 years."
"I was not a fan of his," Trump said.
https://www.cnbc.com/2019/07/09/trum...rafficker.html
EPSTEIN IS YOUR trumpgate WEENER THERE BUBBLES. but YOU already knew that - funny you would lie anyway. Say, are YOU a pedo from Israel too like eppie boi?
The extent of Israeli spying directed against the United States is a huge story that is only rarely addressed in the mainstream media.
The Jewish state regularly tops the list for ostensibly friendly countries that aggressively conduct espionage against the U.S. and Jewish American Jonathan Pollard, who was imprisoned in 1987 for spying for Israel, is now regarded as the most damaging spy in the history of the United States.
http://www.unz.com/pgiraldi/did-pedo...rk-for-mossad/
Last edited by Danbones; 4 days ago at 09:33 PM..
You lie about trump like that while you are defending freakin' pedos?
...and everyone says gay sailors are bad enough, but that fakenews pedophilia is way way way worse.
So how did you like epstien's weener parties billie boob?
...and why did THEY neck name you George anyway?
Who was that pedo working for when he was told Epstein was working for the trumphate intell people there ya lying lil racist treacletard? Umm...you aren't one of them baby renters too are you? like I keep asking your fellow trumphater Cliffy:
What about the one third of the children that are rented HOIDSIE???
Cliffy still hasn't answered the question either. Funny that.
Borrowed kids: DNA testing shows a third of those migrant 'families' aren't related
https://www.americanthinker.com/blog...t_related.html
Hungary? Here, have some of George's monkey spy Pizza.
All you little effers are defending pedophilia for political reasons...like catholic priests but infinitely worse...you are ALL behaving like genocidal nazicommieglobalist tyrant brownshirt stooges. Hi OB.
Dag Hammarskjold UN Secretary General
by Jersay | Jun 7th, 2006
UN Secretary General Proposals
by Jersay | May 18th, 2006
Dag Hammarskold: Only Secretary General to die
by Jersay | Apr 22nd, 2006


Authors: Mónica GARCÍA-ÁLVAREZ 1; Juan BERENGUER 2,3; María A JIMÉNEZ-SOUSA 1, Daniel PINEDA-TENOR 1; Teresa ALDÁMIZ-ECHEVARRIA 2,3, Francisco TEJERINA 2,3, Cristina DIEZ 2,3, Sonia VÁZQUEZ-MORÓN 1; Salvador RESINO 1(*); (*) Corresponding author.
Current affiliations: (1) Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain. (2) Unidad de Enfermedades Infecciosas/VIH; Hospital General Universitario "Gregorio Marañón", Madrid, Spain. (3) Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
The mechanisms involved in the chronic hepatitis C progression are incompletely understood. The aim was to analyze the association between 2'5'oligoadenylate synthetase 1,2 and 3 (OAS1-3) and myxovirus resistance proteins 1 (Mx1) polymorphisms and severity of liver disease in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients. We performed a cross-sectional study in 219 patients that underwent a liver biopsy. DNA genotyping for Mx1 (rs469390), OAS1 (rs2285934), OAS2 (rs1293762) and OAS3 (rs2010604) was performed by using GoldenGate assay. The outcome variables ion liver biopsy were: i) significant fibrosis (F>=2); ii) moderate activity grade (A>=2). Additive model of inheritance for genetic association test was used. The likelihood of having significant fibrosis (F>=2) was lower in patients carrying OAS2 rs1293762 A allele [adjusted odds ratio (aOR)=0.51; p=0.040]. Besides, the likelihood of having moderate activity grade (A>=2) was higher in patients carrying Mx1 rs464397 C allele (aOR=1.63; p=0.028) and Mx1 rs469390 G allele (aOR=1.97; p=0.005), while it was lower in patients carrying OAS1 rs2285934 A allele (aOR=0.64; p=0.039) and OAS2 rs1293762 A allele (aOR=0.41; p=0.009). In conclusion, Mx1 and OAS1-2 polymorphisms were associated with the severity of liver disease in HIV/HCV-coinfected patients, suggesting a significant role in the progression of hepatic fibrosis.
Only a minority of patients may spontaneously clear the hepatitis C virus (HCV) during the acute phase of infection, which correlates with a rapid induction of innate response, especially interferon-stimulated genes (ISGs) . However, the majority of patients is unable to clear the HCV and develops chronic hepatitis C (CHC), which may cause irreversible fibrosis, leading to cirrhosis and hepatocellular carcinoma [1, 2]. Moreover, CHC is accelerated in human immunodeficiency virus (HIV)/HCV coinfected patients, resulting in higher rates of disease progression than HCV mono-infected patients .
The pathogenic mechanisms involved in this progress are incompletely understood, but it is known that the alternations of liver inflammatory profiles and the impaired immune responses are thought to be an important determinant of the rate of fibrosis progression . Among others, chronic HCV infection has a pronounced effect on gene expression of a subset of ISGs such as 2'5'oligoadenylate synthetase (OAS) family and myxovirus resistance proteins (Mx) . The Mx1 protein is a GTPase that acts at an early step of the virus life cycle, prior to the genome replication, by trapping viral components and preventing them from reaching their cellular destination . OAS proteins are able to synthesize 2′,5′-oligomers, which specifically activate the latent form of RNaseL, which may then mediate RNA degradation, contributing to decay of viral RNA. Single nucleotide polymorphisms (SNPs) in the OAS gene (chromosome 12) and Mx gene (chromosome 21) have been related to severity and/or outcome of viral infections such as tick-borne encephalitis , West Nile virus , dengue virus , coronavirus , and hepatitis B . Regarding to HCV infection, Mx1 rs2071430 polymorphism has been related to HCV clearance during acute HCV infection and after interferon (IFN) therapy, and higher severity of liver disease in HCV-monoinfected patients [10-13]. However, to our knowledge, there is no report related to OAS/Mx SNPs and severity of liver disease in HIV/HCV coinfected patients.
The aim of this study was to analyze the association between Mx1 and OAS1-3 polymorphisms and severity of liver disease in HIV/HCV coinfected patients.
We performed a cross-sectional study in 219 HIV/HCV-coinfected patients that underwent a liver biopsy between September 2000 and November 2008. The study was conducted in accordance with the Declaration of Helsinki and patients gave their written consent for the study. The Institutional Review Board and the Research Ethic Committee of the Instituto de Salud Carlos III approved the study. Each participating patient signed an informed consent form.
Liver biopsies were performed on patients who were potential candidates for anti-HCV therapy and had not received previous IFN therapy (naïve for HCV-treatment). Selection criteria were: no clinical evidence of hepatic decompensation, detectable HCV RNA by polymerase chain reaction (PCR), negative hepatitis B surface antigen, availability of DNA sample, CD4+ lymphocyte count higher than 200 cells/µL, and stable combination antiretroviral therapy (cART) for at least 6 months before study entry or no need for cART according to treatment guidelines used in the study period [14, 15]. Patients with active opportunistic infections, active drug addiction, and other concomitant severe diseases were excluded. All subjects included in our study were European white.
Clinical and epidemiological data were obtained from medical records. The duration of HCV infection for patients with a history of intravenous drug use was estimated starting from the first year they shared needles and other injection paraphernalia, which are the most relevant risk practices for HCV transmission . The duration of HCV infection was not calculated when the date of initiation of their HCV infection could not be determined with certainty. Consumption of more than 50 g of alcohol per day for at least 12 months was considered as a high intake. Body mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters.
Biochemistry panel was measured using an autoanalyzer Hitachi 912 (Boehringer Mannheim, Germany), while patients were fasting. The degree of insulin resistance was estimated for each patient using the homeostatic model assessment (HOMA) : fasting plasma glucose (mmol/L) times fasting serum insulin (mU/L) divided by 22.5.
HCV infection was documented in all patients by enzyme-linked immunosorbent assay and PCR test. HCV genotype was determined by hybridization of biotin-labeled PCR products to oligonucleotide probes bound to nitrocellulose membrane strips (INNO-LiPA HCV II, Innogenetics, Ghent, Belgium). Plasma HCV-RNA viral load was measured by PCR (Cobas Amplicor HCV Monitor Test, Branchburg, NJ, USA) and real-time PCR (COBAS AmpliPrep/COBAS TaqMan HCV test); and results were reported in terms of international units per milliliter (IU/mL). The limit of detection varied between 10 IU/mL and 600 IU/mL depending on the HCV diagnostic test used at the time of biopsy. There was no patient with HCV viral loads below the limit of detection. The HCV RNA level of 500,000 UI/ml was chosen as cutoff for low vs. high viral load (circulating HCV RNA) [18, 19].
Liver biopsies were performed as we described previously . The samples were always evaluated by the same pathologist, who was unaware of the patients' clinical or laboratory data. Liver fibrosis and necroinflammatory activity were estimated according to Metavir score as follows : F0, no fibrosis; F1, mild fibrosis; F2, significant fibrosis; F3, advanced fibrosis; and F4, definite cirrhosis. The degree of necroinflammation (activity grade) was scored as follows: A0, no activity; A1, mild activity; A2, moderate activity; A3, severe activity.
The most common SNPs in Mx1 gene (chromosome 21) and OAS1-3 genes (chromosome 12) were selected using the databases of HapMap Project (http://snp.cshl.org/cgi-perl/gbrowse/hapmap_B35/) and NCBI (dbSNP) (http://www.ncbi.nlm.nih.gov/entrez/). The selection criteria were: i) SNPs located in putative regulatory regions, or splicing control elements (SCE), or missense variants; ii) minor allelic frequency (MAF) greater than 20% in European people in order to have guarantees to obtain significant associations when working with small sample sizes . With this setting, we found three SNPs in Mx1 gene (rs464397 in intron 3, rs458582 in intron 5, and rs469390 in exon 13 (missense)) and other five SNPs at OAS genes (OAS1 rs2285934 in intron 3, OAS2 rs1293762 in intron 2, OAS3 rs739903 in 3'UTR, OAS3 rs2285933 in exon 6 (missense), and OAS3 rs2010604 in 3'UTR). Finally, five polymorphisms were selected as tagSNPs according to linkage disequilibrium (LD) (Figure 2): two SNPs at Mx1 (rs464397 and rs469390) and three SNPs at OAS (OAS1 rs2285934, OAS2 rs1293762, and OAS3 rs739903). Three SNPs (Mx1 rs458582, OAS3 rs2285933, and OAS3 rs2010604) were discarded for the analysis of individual association because these SNPs were at high linkage disequilibrium (LD) (Figure 1).
Figure 1. Pairwise linkage disequilibrium (LD) patterns for genetic polymorphisms of MX1 and OAS1-3. Each diagonal represents a different SNP, with each square representing a pairwise comparison between two SNPs.
Abbreviations: OAS, 2'5'oligoadenylate synthetase; Mx1, myxovirus resistance proteins.
Genomic DNA was extracted from peripheral blood with Qiagen kit (QIAamp DNA Blood Midi/Maxi; Qiagen, Hilden, Germany). DNA samples were sent at the Spanish National Genotyping Center (CeGen; http://www.cegen.org/) for DNA genotyping by using GoldenGate assay with VeraCode Technology (Illumina Inc., San Diego, California, USA).
Moreover, for healthy subjects, the frequencies of alleles and genotypes for studied polymorphisms were obtained using the 1000 Genomes Project website (http://www.1000genomes.org/home), which provide a broad representation of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations . We select the IBS (Iberian populations in Spain) population that included 107 individuals.
The primary outcome variables were related to severity of liver disease: significant fibrosis (F>=2) and moderate activity grade (A>=2). These outcomes were developed after a minimum follow-up time of 10 years with HCV infection.
Chi-square test, Chi-square test for trend (linear by linear association), Student's t-test, and multivariate logistic regression analysis were used to investigate the relationship among Mx1 and OAS polymorphisms and severe liver disease. We included the SNP with the Enter algorithm (Forced Entry) and the covariables with the Stepwise algorithm (at each step, factors are considered for removal or entry: a p-value for entry and exit of 0.15 and 0.20, respectively). Thus, each logistic regression test was only adjusted by the most significant co-variables associated with each one of the outcome variables, avoiding the over-fitting of the regression. The covariables used were gender, age, alcohol intake at biopsy study, BMI, HOMA, nadir CD4+ T-cells, AIDS, undetectable HIV-RNA (<50 copies/ml), CD4+ T-cells, time on cART, type of cART, HCV-RNA >=500,000 IU/ml, time of HCV infection, and HCV genotype. Besides, we also used data of the PNPLA3 rs738409 polymorphism and the IL28B rs12980275 polymorphism, which have already been published by us and showed significant association with liver fibrosis in HIV/HCV coinfected patients [24, 25]. The genetic association study was carried out according to the genetic model that best fit our data (additive, recessive, dominant, codominant, and overdominant). These analyses were tested according to the goodness of fit evaluated by Akaike information criterion (AIC) value and Bayesian information criterion (BIC). These analyses were performed by using the IBM SPSS Statistics for Windows, Version 21.0 (IBM Corp, Chicago, Armonk, NY, USA).
Hardy-Weinberg equilibrium (HWE) for all SNPs was assessed by a Chi-square test, considering equilibrium when p>0.05. In addition, pair-wise linkage disequilibrium (LD) analysis was computed to detect the inter-marker relationship using the standardized D' and r2 values by Haploview 4.2 software. Haplotype-based association testing was performed using Plink software (http://pngu.mgh.harvard.edu/~purcell/plink/) comparing each haplotype with the rest of haplotypes (there was no reference category). All p-values were two-tailed and statistical significance was defined as p <0.05.
The in silico analysis for possible functional implication of each polymorphism was evaluated by using two web-tools: a) VarioWatch (http://genepipe.ncgm.sinica.edu.tw/variowatch/); b) rSNABase (http://rsnp.psych.ac.cn/).
Table 1 shows the epidemiological and clinical characteristics of 219 HIV/HCV-coinfected patients at the time of liver biopsy. Regarding liver biopsy, 49.8% had significant fibrosis (F>=2), 52.6% had moderate necroinflammatory activity (A>=2), and 15.3% had alanine aminotransferase (ALT)>=150 IU/L.
Table 1. Clinical and epidemiological characteristics of HIV/HCV-coinfected patients.
Values are expressed as absolute numbers (%) and median (percentile 25; percentile 75). Sometimes, the percentages were not calculated from all patients because some data was missing.
Abbreviations: BMI, body mass index; HOMA, homeostatic model assessment; HCV, Hepatitis C virus; CDC category C, centers for disease control and prevention classification system, clinical category C which includes any condition listed in the CDC´s 1897 surveillance case definition of AIDS; PI-based, protein inhibitor-based therapy; NNRTI-based, non-nucleoside reverse transcriptase inhibitor -based therapy; 3NRTI-based, triple nucleoside regimen; HIV; Human immunodeficiency virus; HIV-RNA, HIV plasma viral load; HCV-RNA, HCV plasma viral load; ALT, alanine aminotransferase; AST Aspartate Aminotransferase.
Table 2 shows the characteristics of SNPs, which displayed missing values <5% and were in HWE (p>0.05). When SNPs frequencies in HIV/HCV coinfected patients were compared to the SNPs frequencies in healthy subjects from the IBS, we only found differences between groups for Mx1 rs469390 AA (p=0.011) and Mx1 rs469390 AG (p=0.036) genotypes.
Table 2. Summary of Hardy Weinberg Equilibrium and frequencies of alleles and genotypes for Mx1 and OAS1-3 polymorphisms in HIV/HCV coinfected patients compared to Iberian populations in Spain from HapMap data (http://www.ncbi.nlm.nih.gov/bioproject/59819).
Statistically significant differences are shown in bold. P-values were calculated by Chi-squared test; (a), differences between allele frequencies; (b), differences between genotype frequencies.
Abbreviations: HWE, Hardy Weinberg Equilibrium; HIV, human immunodeficiency virus; HCV, hepatitis C virus; IBS, Iberian populations in Spain; OAS, 2'5'oligoadenylate synthetase; Mx1, myxovirus resistance proteins.
Table 3 shows the relationship of Mx1 and OAS1-3 polymorphisms with severity of liver disease under a model of additive inheritance, which was the genetic model that best fitted our data. The trend of having significant fibrosis (F>=2) was lower in patients carrying of OAS2 rs1293762 A allele (p=0.023). The trend of having moderate activity grade (A>=2) was higher in patients carrying Mx1 rs464397 C allele (p=0.015) and Mx1 rs469390 G allele (p=0.003); while it was lower in patients carrying OAS1 rs2285934 A allele (p=0.026), OAS2 rs1293762 A allele (p=0.002), and it was nearly significant for OAS3 rs2010604 C allele (p=0.095). Moreover, the likelihood of having significant fibrosis (F>=2) in liver biopsy was lower in patients carrying OAS2 rs1293762 A allele [adjusted odds ratio (aOR)=0.51; p=0.040]. Besides, the likelihood of having moderate activity grade (A>=2) was higher in patients carrying Mx1 rs464397 C allele (aOR=1.63; p=0.028) and Mx1 rs469390 G allele (aOR=1.97; p=0.005), while it was lower in patients carrying OAS1 rs2285934 A allele (aOR=0.64; p=0.039) and OAS2 rs1293762 A allele (aOR=0.41; p=0.009).
Table 3. Summary of the differences of genotypic frequencies (Mx1 rs464397, MX1 rs469390, OAS1 rs2285934, OAS2 rs1293762 and OAS3 rs2010604) in relation to severity of liver disease and the adjusted logistic regression analysis for the polymorphisms in HIV/HCV coinfected patients.
Statistically significant differences are shown in bold. (a), P-values were calculated by Chi-squared test for trend (linear by linear association); (b), P-values were calculated by multivariate logistic regression adjusted by the most important clinical and epidemiological characteristics (see statistical analysis section). Sometimes, the percentages were not calculated from all patients because some data was missing.
Abbreviations: 95%CI, 95% of confidence interval; aOR, adjusted odds ratio; p-value, level of significance; A>=2, moderate activity (Metavir); F>=2, significant fibrosis (Metavir); OAS, 2'5'oligoadenylate synthetase; Mx1, myxovirus resistance proteins.
Figure 2 shows the relation between MX1 and OAS1-3 genetic polymorphisms and serum ALT. We found that patients carrying Mx1 rs464397 CC genotype and Mx1 rs469390 GG genotype had higher values of serum ALT and percentage of patients with ALT >=150 IU/L. However, we did not find any significant association in multivariate regression analysis (data not shown). Moreover, we also analyzed the relation between MX1 and OAS1-3 polymorphisms and serum aspartate aminotransferase (AST), but we did not find any association (data not shown).
Figure 2. Summary of the differences of serum ALT according to genotypes of Mx1 rs464397, MX1 rs469390, OAS1 rs2285934, OAS2 rs1293762 and OAS3 rs2010604 in HIV/HCV coinfected patients. P-values were calculated by Student's t-test and Chi-squared test.
Table 4 shows the relationship among haplotype of Mx1 gene (rs464397, rs458582, rs469390) and OAS1-3 cluster (rs2285934, rs2285933, rs2010604, rs739903, rs1293762) and severity of liver disease. The likelihood of having moderate activity grade (A>=2) in liver biopsy was higher in patients with Mx1 CTG haplotype (aOR=1.44; p<0.001) and lower in patients with Mx1 CTA haplotype (aOR=0.62; p=0.007). Moreover, the likelihood of having moderate activity grade (A>=2) in liver biopsy was lower in patients with OAS1-3 AGCTA haplotype (aOR=0.78; p=0.008).
Table 4. Association of haplotype of Mx1 gene and OAS1-3 cluster with severity of liver disease in HIV/HCV coinfected patients.
Statistically significant differences are shown in bold. P-values were calculated by multivariate logistic regression adjusted by the most important clinical and epidemiological characteristics (see statistical analysis section). Haplotypes with frequencies less than 5% have not included.
Abbreviations: aOR, adjusted odds ratio; 95%CI, 95% of confidence interval; p-value, level of significance; A>=2, moderate activity (Metavir); F>=2, significant fibrosis (Metavir); OAS, 2'5'oligoadenylate synthetase; Mx1, myxovirus resistance proteins.
To our knowledge, this study is the first description of the relationship between Mx1 and OAS1-3 polymorphisms and severity of liver disease in HIV/HCV-coinfected patients. The major findings of the present study were that Mx1 rs464397 C allele, Mx1 rs469390 G allele, and Mx1 CTG haplotype were associated with higher odds of having moderate activity grade (A>=2) in liver biopsy, while OAS1 rs2285934 A allele, OAS2 rs1293762 A allele, and OAS1-3 AGCTA haplotype were related to lower likelihood of having moderate activity grade (A>=2). Besides, OAS2 rs1293762 A allele was related to lower likelihood of having significant fibrosis (F>=2) in liver biopsy. Thus, Mx1 and OAS1-2 polymorphisms might play a role in developing of liver disease in HIV/HCV-coinfected patients.
In our study, we included a control group to show that our study cohort had allelic and genotypic frequencies similar to the general population. However, we found significant differences in allelic and genotypic frequencies of Mx1 rs469390 between HIV/HCV coinfected patients and Iberian populations in Spain from HapMap data. This observation might suggest that Mx1 rs469390 could be associated to innate resistance to HCV infection. However, our study design is not adequate to draw such conclusions due to a number of factors that we do not control. For example, our cohort may have a survival bias because patients were more than 20 years of median with HIV and HCV infections. In addition, patients were selected due to they were candidates for antiviral treatment against HCV because progression of liver disease was suspected.
In the setting of CHC, the immune system initially attempts to eradicate the HCV, but besides, probably promotes hepatocyte damage and fibrosis through direct cellular toxicity and the release of inflammatory cytokines . The innate immune response against viruses produce type I IFN (alpha, beta), which induces the expression of Mx1 protein [4, 26]. Although its effect against HCV is not well documented, high levels of Mx1 protein have been detected in IFN-treated HCV patients with sustained virological response . In fact, Mx1 rs2071430 polymorphism, in the promoter region, has been related to Mx1 gene expression, spontaneous viral clearance during acute HCV infection, higher hepatic fibrosis score and hepatitis activity grade, and response to IFN therapy in HCV-monoinfected patients [10-13]. In the in silico analysis performed, we found that Mx1 rs464397 seems to be implicated in both proximal (open chromatin region, transcription factor binding sites and histone markers) and distal regulation. Furthermore, rs464397 seems also be involved in RNA binding protein-mediated post-transcriptional regulation as well as to be a SNP with experimental expression quantitative trait loci (eQTL) evidence. On the other hand, Mx1 rs469390 polymorphism is a missense variant (V379I) that might not affect protein structure; but it seems influence an exonic splicing enhancer motif and it might be involved in protein domain abolishing. In this way, MX1 rs469390 polymorphism could decrease expression of MX1, getting worse the control of HCV, and might therefore be related to the increase of sustained inflammation and progression of liver disease.
The OAS proteins play an important role in the innate immune response and genetic variants in the OAS genes are known to affect OAS activity and are associated with outcome of viral infections . The OAS1 rs2660, rs10774671, and rs3741981 polymorphisms have been related to persistent HCV infection [11, 29] and progression of HCV disease ; and OAS1 polymorphism at exon 7 splice acceptor site with response to IFN therapy in HCV infected patients . The OAS2 polymorphism rs1293762 has been associated with predisposition to CHC . In our study, OAS1-3 polymorphisms were related to lower likelihood of having significant liver disease (A>=2 and/or F>=2), indicating that the A-allele conferred a protective effect with respect to liver disease progression. OAS1 rs2285934 and OAS2 rs1293762 polymorphisms are located in intron 3 and intron 2, respectively. In the in silico analysis, both SNPs seem to be involved in RNA binding protein-mediated post-transcriptional gene regulation. In this way, OAS1 rs2285934 and OAS2 rs1293762 polymorphisms could increase expression of OAS1 and OAS2, improving the control of HCV, and might therefore be related to the decrease of sustained inflammation and progression of liver disease.
As discussed above, the presence of Mx1 and OAS1-3 polymorphisms may be related to have moderate or significant liver disease. This association that we observed might be due to the proximity to other SNPs that may modulate Mx1 gene expression, or a direct effect of Mx1 and OAS1-3 polymorphisms analyzed in this study. On the one hand, haplotype analysis showed a stronger association with liver disease than that found with each polymorphism alone. On the other hand, the in silico analysis showed that polymorphisms alone could have some influence on the expression of the proteins involved. However, it would be necessary to demonstrate if these Mx1 and OAS1-3 polymorphisms may modify the expression of Mx1 and OAS1-3 genes.
The impact of OAS/MX1 SNPs on fibrosis progression in CHC has not been picked up in the GWAS previously carried out [33, 34]. However, we found a relatively strong association between OAS/MX1 SNPs and the severity of liver disease in our HIV/HCV coinfected patients. This could be because: a) GWAS usually does not have the power to detect all, only the biggest effects. Besides, note that strong statistical adjustments on the p-value are carried out for correcting multiple testing; b) we studied a SNP candidate with MAF greater than 20%. In these cases, an individual effect is more easily detected when the size of sample is small ; c) we should not discard the effect of HIV infection on the immune system, which could show the influence of OAS/MX1 polymorphisms on CHC progression.
Finally, several aspects have to be taken into account for the correct interpretation of the results. Firstly, this is a cross-sectional study with a limited number of patients, which could limit achieving statistically significant values. Besides, the cross-sectional design nature of the analyses may be a confounding factor. Secondly, data were collected retrospectively, which entails a lack of uniformity. Thirdly, all selected patients met a set of criteria for starting HCV treatment (e.g., no alcohol abuse, high CD4 cell counts, controlled HIV replication, and good treatment adherence), and this may have introduced a selection bias. Fourthly, regarding the statistical significance, there is a considerable controversy about adjusting the "p-value" after multiple tests on clinical-orientated studies [36, 37]. In our study, there was a hypothesis supported by theory and previous reports that related Mx1 and OAS1-3 polymorphisms to severity and/or outcome of viral infections [5-9], including HCV infection [10-13]. Therefore, we were not literally doing a random search of a meaningful result, and our results should not be affected by the fact of carrying out a high number of statistical tests. Fifthly, this study was performed on patients with European ancestry, and it would be interesting to perform these analyses on different ethnic groups. Finally, our study only included HIV/HCV-coinfected patients and it would be interesting to know the role of studied polymorphisms in HCV monoinfected patients, but we did not have access to a cohort of HCV monoinfected patients.
In conclusion, Mx1 and OAS1-2 polymorphisms were associated with the severity of liver disease in patients coinfected with HIV and HCV, suggesting that these polymorphisms might play a significant role in the progression of hepatic fibrosis. Further analysis involving large numbers of patients are needed to corroborate these associations that we have found.
1. Heim MH, Thimme R. Innate and adaptive immune responses in HCV infections. J Hepatol 2014,61:S14-S25.
2. Mengshol JA, Golden-Mason L, Rosen HR. Mechanisms of Disease: HCV-induced liver injury. Nat Clin Pract Gastroenterol Hepatol 2007,4:622-634.
3. Lo Re V, 3rd, Kallan MJ, Tate JP, Localio AR, Lim JK, Goetz MB, et al. Hepatic decompensation in antiretroviral-treated patients co-infected with HIV and hepatitis C virus compared with hepatitis C virus-monoinfected patients: a cohort study. Ann Intern Med 2014,160:369-379.
4. Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 2014,32:513-545.
5. Barkhash AV, Perelygin AA, Babenko VN, Myasnikova NG, Pilipenko PI, Romaschenko AG, et al. Variability in the 2'–5′-Oligoadenylate Synthetase Gene Cluster Is Associated with Human Predisposition to Tick-Borne Encephalitis Virus-Induced Disease. Journal of Infectious Diseases 2010,202:1813-1818.
6. Lim JK, Lisco A, McDermott DH, Huynh L, Ward JM, Johnson B, et al. Genetic variation in OAS1 is a risk factor for initial infection with West Nile virus in man. PLoS Pathog 2009,5:e1000321.
7. Thamizhmani R, Vijayachari P. Association of dengue virus infection susceptibility with polymorphisms of 2′-5′-oligoadenylate synthetase genes: a case-control study. Braz J Infect Dis 2014,18:548-550.
8. Hamano E, Hijikata M, Itoyama S, Quy T, Phi NC, Long HT, et al. Polymorphisms of interferon-inducible genes OAS-1 and MxA associated with SARS in the Vietnamese population. Biochem Biophys Res Commun 2005,329:1234-1239.
9. Chen LB, Peng XM, Cao H, Zhang YF, Xu QH, Gao ZL. [Relationship between SNP rs10774671 on OAS-1 gene and spontaneous HBeAg seroconversion in chronic HBV infection]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 2009,23:35-37.
10. Bader El Din NG, Salum GM, Anany MA, Ibrahim MK, Dawood RM, Zayed N, et al. Association of Myxovirus Resistance Gene Promoter Polymorphism with Response to Combined Interferon Treatment and Progression of Liver Disease in Chronic HCV Egyptian Patients. J Interferon Cytokine Res 2015.
11. Knapp S, Yee LJ, Frodsham AJ, Hennig BJ, Hellier S, Zhang L, et al. Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR. Genes Immun 2003,4:411-419.
12. Hijikata M, Ohta Y, Mishiro S. Identification of a Single Nucleotide Polymorphism in the MxA Gene Promoter (G/T at nt –88) Correlated with the Response of Hepatitis C Patients to Interferon. Intervirology 2000,43:124-127.
13. Suzuki F, Arase Y, Suzuki Y, Tsubota A, Akuta N, Hosaka T, et al. Single nucleotide polymorphism of the MxA gene promoter influences the response to interferon monotherapy in patients with hepatitis C viral infection. J Viral Hepat 2004,11:271-276.
14. Panel de expertos de Gesida Plan Nacional sobre el Sida y Asociación Española para el Estudio del Hígado. [Recommendations of Gesida/PNS/AEEH for the management and treatment of the adult patient co-infected with HIV and hepatitis A, B and C virus]. Enferm Infecc Microbiol Clin 2010,28:31 e31-31.
15. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009,49:1335-1374.
16. Thorpe LE, Ouellet LJ, Hershow R, Bailey SL, Williams IT, Williamson J, et al. Risk of hepatitis C virus infection among young adult injection drug users who share injection equipment. Am J Epidemiol 2002,155:645-653.
17. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985,28:412-419.
18. Ascione A, De Luca M, Tartaglione MT, Lampasi F, Di Costanzo GG, Lanza AG, et al. Peginterferon alfa-2a plus ribavirin is more effective than peginterferon alfa-2b plus ribavirin for treating chronic hepatitis C virus infection. Gastroenterology 2010,138:116-122.
19. Jimenez-Sousa MA, Berenguer J, Rallon N, Guzman-Fulgencio M, Lopez JC, Soriano V, et al. IL28RA polymorphism is associated with early hepatitis C virus (HCV) treatment failure in human immunodeficiency virus-/HCV-coinfected patients. J Viral Hepat 2013,20:358-366.
20. Resino S, Seoane JA, Bellon JM, Dorado J, Martin-Sanchez F, Alvarez E, et al. An artificial neural network improves the non-invasive diagnosis of significant fibrosis in HIV/HCV coinfected patients. J Infect 2011,62:77-86.
21. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996,24:289-293.
22. Hong EP, Park JW. Sample size and statistical power calculation in genetic association studies. Genomics Inform 2012,10:117-122.
23. Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, et al. A global reference for human genetic variation. Nature 2015,526:68-74.
24. Jimenez-Sousa MA, Berenguer J, Garcia-Alvarez M, Gutierrez-Rivas M, Aldamiz-Echevarria T, Tejerina F, et al. Impact of patatin-like phospholipase domain-containing 3 gene polymorphism (rs738409) on severity of liver disease in HIV/hepatitis C virus-coinfected patients. AIDS 2016,30:465-470.
25. Guzman-Fulgencio M, Berenguer J, Garcia-Alvarez M, Fernandez-Rodriguez A, Jimenez-Sousa MA, Alvarez E, et al. IL28B polymorphisms are associated with severity of liver disease in human immunodeficiency virus (HIV) patients coinfected with hepatitis C virus. J Infect 2013,66:170-178.
26. Haller O, Staeheli P, Schwemmle M, Kochs G. Mx GTPases: dynamin-like antiviral machines of innate immunity. Trends Microbiol 2015,23:154-163.
27. Fernandez M, Quiroga JA, Martin J, Herrero M, Pardo M, Horisberger MA, et al. In vivo and in vitro induction of MxA protein in peripheral blood mononuclear cells from patients chronically infected with hepatitis C virus. J Infect Dis 1999,180:262-267.
28. Sadler AJ, Williams BRG. Interferon-inducible antiviral effectors. Nat Rev Immunol 2008,8:559-568.
29. Zhao Y, Kang H, Ji Y, Chen X. Evaluate the relationship between polymorphisms of OAS1 gene and susceptibility to chronic hepatitis C with high resolution melting analysis. Clin Exp Med 2013,13:171-176.
30. Li C-Z, Kato N, Chang J-H, Muroyama R, Shao R-X, Dharel N, et al. Polymorphism of OAS-1 determines liver fibrosis progression in hepatitis C by reduced ability to inhibit viral replication. Liver International 2009,29:1413-1421.
31. El Awady MK, Anany MA, Esmat G, Zayed N, Tabll AA, Helmy A, et al. Single nucleotide polymorphism at exon 7 splice acceptor site of OAS1 gene determines response of hepatitis C virus patients to interferon therapy. J Gastroenterol Hepatol 2011,26:843-850.
32. Barkhash AV, Kochneva GV, Chub EV, Mikhailova SV, Romaschenko AG. Association between polymorphisms in OAS2 and CD209 genes and predisposition to chronic hepatitis C in Russian population. Microbes Infect 2014,16:445-449.
33. Rueger S, Bochud PY, Dufour JF, Mullhaupt B, Semela D, Heim MH, et al. Impact of common risk factors of fibrosis progression in chronic hepatitis C. Gut 2014.
34. Patin E, Kutalik Z, Guergnon J, Bibert S, Nalpas B, Jouanguy E, et al. Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection. Gastroenterology 2012,143:1244-1252 e1241-1212.
35. Park JH, Gail MH, Weinberg CR, Carroll RJ, Chung CC, Wang Z, et al. Distribution of allele frequencies and effect sizes and their interrelationships for common genetic susceptibility variants. Proc Natl Acad Sci U S A 2011,108:18026-18031.
36. Perneger TV. What's wrong with Bonferroni adjustments. BMJ 1998,316:1236-1238.
37. Sterne JA, Davey Smith G. Sifting the evidence-what's wrong with significance tests? BMJ 2001,322:226-231.
The authors thank the Spanish National Genotyping Center (CeGen) for providing SNP genotyping services (http://www.cegen.org).
MGA and SR performed all statistical analysis, interpretation of the data and wrote the manuscript. JB and SR participated in the study concept and design. JB, TAE, CD, and FT, participated in patient selection, collection of samples and acquisition of data. DPT, MAJS, and SVM participated in sample preparation, DNA isolation and genotyping pre-procedure, and contributed with critical revision of the manuscript. SR supervised the study. All authors revised the manuscript from a draft by SR.
This work has been supported by grants given by Fondo de Investigación de Sanidad en España (FIS) [Spanish Health Founds for Research] [grant numbers PI14/01094, PI14CIII/00011] and Red Española de Investigación en SIDA (RIS) [AIDS Research Network] [grant numbers RD16CIII/0002/0002RD16 and RD16/0025/0017].
This work has been (partially) funded by the RD12/0017 project as part of the Plan Nacional R + D + I and cofinanced by ISCIII- Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER).
JB is an investigator from the Programa de Intensificación de la Actividad Investigadora en el Sistema Nacional de Salud (I3SNS). MGA, DPT, and MAJS are supported by "Instituto de Salud Carlos III" [grant numbers CD12/00442, CM12/00043, CD13/00013, respectively].
The authors do not have a commercial or other association that might pose a conflict of interest.
Meetings at which parts of the data will be presented: Some parts were presented in the 22th Conference on Retroviruses and Opportunistic Infections (CROI 2015). García–Álvarez M, Berenguer J, Pineda-Tenor D, Jiménez-Sousa MA, Guzmán-Fulgencio M, Carrero A, Aldámiz-Echevarria T, Tejerina F, Diez C, Resino S. Mx1 and OAS1-2 SNPs Are Related with Severity of Liver Disease in HIV/HCV Coinfection. 22th Conference on Retroviruses and Opportunistic Infections (CROI 2015). Seattle, Washington, USA. February 23-26, 2015.


We're using diesel for our heating, and guess what… it costs now more than a euro a liter in Chile. We're at 1.0175 a liter… Esso is coming to our place to fill up the tank. 500-700 liters… pain in the wallet.
We had an earthquake last night, not a really heavy one but look how close to Santiago… You can see all the details about this quake overhere.


A short story about holding on to life's moments.
"Am I five yet?" My son asked last night while walking to dinner.
"Nope. Why do you ask?"
"Oh," I laughed, and continued pushing the stroller. "You will have to be bigger than five for that."
He did a mix of a grunt and a growl. "How old?"
"I don't know. Maybe twelve?"
"Twelve is too big! I can't wait that long." I looked at my little boy. His maple-syrup-eyes were wide, mouth frowning. He was losing some baby fat but his elbows still had dimples. I couldn't imagine him older than that moment.
"Don't rush things, bud. Try to enjoy life right now," I said sounding like a school teacher, but feeling like this lesson was important.
"Two more roads until were there, Mom."
"Yep. Listen, you know what I like about right now?"
"Walking with you and baby. How the sun is shining through those leaves. How there isn't any wind, and it's not too hot or cold. What do you like?"
He thought for a moment, one eyebrow raised.
"Being here with you, too," he answered. My heart grew another size.
Today he was eating mac 'n' cheese while we chatted about how the baby would soon turn one.
He asked me, "When will I be one again?"
I thought to myself, exactly.


Today there was the last lecture of the ShanghaiTech Summer School 2017, Prof. Luigi Luisi conclude the course with his 'Science and Spirituality' lecture.
Today we left really early to go to Aquileia. There we met Prof. Paola Pellegrini. She guided us through the Roman Foro and Porto, the Basilica and the Museum.
Today Prof. Luigi Luisi gave the first of his two lectures 'What is Life'.
This morning we left the hotel at 8:30 to go visit the Botanical Garden. There Prof. Barbara Baldan was waiting for us and gave the students a lecture on 'The Botanic Garden of Padova: from 1545 to the future'.
Prof. Ernesto Carafoli gave a lecture on 'The Evolutionary Choice of Cellular Signals: why Calcium'.
Afterwards there was Prof. Nicola Elvassore lecture: 'Engineering Stem Cell Potential'.
The first day in Padova was dedicated to human history and human evolution. The first lecture on this topic was held by Prof. Giorgio Manzi: 'Apes-like Ancestors and Extinct Humans of Deep Time'.


text:
Q: Any reward for repeating the Nightfall strike? I know that in the list of rewards it doesn't mention any kind of reward, such as an engram or ascendant materials, but do you really earn absolutely nothing at the end of the nightfall if you've already done it that week? Nothing randomly drops from the last boss of the strike?

A: No, you are rewarded only once.
Nightfall only gives rewards at the end of strike. Before you go first time, you can see that it has 'Unknows Rewards' in Director, but has none after completion.
You can still get random engram drops from enemies during the strike, but that's not nightfall specific.
Strike bosses do not drop gear in Destiny, but you can get race-specific item from them (e.g. Ether Seeds or House Banner from Sepiks Prime, etc).
So the answer is: yes, you gain absolutely nothing at the end of nightfall strike if you've already done it.

A: The quick answer is No you don't get anything for running the Nightfall Strike more than once before the reset. (It resets every Tuesday.)
One thing I'd like to add though, is that you can run the Nightfall Strike 3 times a week if you have 3 different characters to run it with. I have 1 of each class and I run it once with each of them each week before the reset.

A: No You will be rewarded for the first NightFall for that week after that you can still do the nightfall but you will not get rewards on till the weekly reset on tuesday 5AM PST

redpajama_set_name: RedPajamaStackExchange


text:
PA PIAA State High School Cross Country Championships
By Annaliese Alexander On Nov 8, 2022
The PIAA Cross Country championships were contested Saturday in Hershey. While runners often worry about facing windy, rainy conditions during a November race, this year's event featured an unseasonably warm day. The warmer-than-normal day didn't seem to affect the participants, judging by the elite times produced.
PIAA Girls Tennis:Full court press: Lansdale Catholic's Ella Moran handles pressure on and off the tennis court
Boys Class 1A:
Thomas Smigo, Palisades, first place
For the second year in a row, Palisades' Senior Thomas Smigo is the Class 1A boys cross country champion. Smigo crossed the finish line at 16:33.40, concluding his senior season with another gold medal. In his four years running cross country for Palisades, Smigo set numerous records and reached many milestones. He won the Colonial League cross country championship for four consecutive seasons.
Other Class 1A finishers:
64. Andreas Quattrocchi, Bristol, 18:46.80
82. Daniel Ringenberg, Dock Mennonite, 19:01.40
Girls Class 1A:
84. Giada Smith, Palisades, 22:56.00
141. Marlyse Giesbrecht, Dock Mennonite, 24:06.00
Ciaran Chambers, Holy Ghost, 23rd
Holy Ghost senior Ciaran Chambers medaled in the Boys Class 2A race, finishing 23rd with a time of 17:17.10. Chambers placed second in the District One Class 2A championships.
38. Stephen Heckler, Lansdale Catholic, 17:40.50
59. Matthew Gorman, Conwell-Egan, 17:58.00
132. Daniel Perez, Holy Ghost, 18:55.90
136. Colby Michels, Archbishop Wood, 18:58.70
Gwen Hamilton, Archbishop Wood, 22nd
Archbishop Wood freshman Gwen Hamilton Capped off an impressive season with a medal in the Girls 2A race. Hamilton finished 22nd with a time of 20:32.10. Hamilton won all four PCL meets this season, and added a fifth by winning the Catholic League Championship.
121. Sarah Hock, Gwynedd Mercy, 22:38.70
138. Ruby Keddie, New Hope-Solebury, 23:00.70
148. Kate McManus, Lansdale Catholic, 23:12.90
152. Meredith Glunz, Villa Joseph Marie, 23:19.10
178. Isabella Greco, Lansdale Catholic, 24:04.20
192. Megan Werner, Conwell-Egan, 24:38.60
193. Constance Wojton, Conwell-Egan, 24:38.60
Brian DiCola, Hatboro-Horsham, first place
Hatboro-Horsham senior Brian DiCola added a coveted medal to his collection in the Boys Class 3A race.
More:Cross Country: Hatboro-Horsham's Brian DiCola charts new course with record-setting run
DiCola not only won the race with a time of 15:24.20, but broke the Hershey Parkview course record. The win capped off an incredible season for DiCola, who recently committed to Penn State. In addition to winning the boys District One Class 3A championship, DiColawon completed the prestigious Paul Short Boys Brown Run at Lehigh University and set a new course record with his elite time of 14:43.20.
Drew Bill, LaSalle, 16:28.60, 7th
Ryan McGinley, La Salle, 16:56.50, 22nd
Jack Czarnecki, Council Rock North, 17:00.20, 24th
27. Cole Casadei, La Salle, 17:05.10
32. Justin Landis, North Penn, 17:007.20
38. Achilles Shui, North Penn, 17:10.20
47. Owen Donaher, Central Bucks West, 17:18.30
66. James Kuduk, Stouderton, 17:28.70
67. Aidan Kearns, Stouderton, 17:29.30
69. Bryce Keenoy, Neshaminy, 17:30.60
77. Brady Ott, Council Rock North, 17:32.80
80. Sacchith Miryalkar, North Penn, 17:35.60
98. Brady Sweeney, North Penn, 17:51.20
105. Brayden Perry, La Salle, 17:54.20
116. Matthew Landis, North Penn, 17:56.70
124. Joe Crowne, Council Rock North, 18:01.20
131. Will Palopoli, La Salle, 18:03.30
132. Evan Morrow, Central Bucks South, 18:03.50
134. Christian Cerrullo, Pennsbury, 18:05.00
139. Thomas Cresko, La Salle, 18:08.30
143. Nolan Yeagle, La Salle, 18:13.20
157. Jayden Neels, Council Rock North, 18:21.70
158.Joey Sharkey, North Penn, 18:22.60
159. Colin Fisher, North Penn, 18:23.10
169. Matt Gosling, Council Rock North, 18:31.40
180. Lucas Poliseno, Council Rock North, 18:39.80
District One Girls Soccer:Neshaminy beats clock, CB East for first district title since 2016
Emily Simko, Hatboro-Horsham, 19:15.10, 12th
Simko, a senior, finished her season with an impressive 12th place finish in the Girls 3A race. Simko, who finished ninth in the District One Class 3A championships, placed 16th in last year's PIAA championship.
Lillian DiCola, Hatboro-Horsham, 19:27.20, 16th
The Hatters' sophomore, who finished 7th in the District One Class 3A championships, earned a medal in the PIAA state tournament.
Bailey Gassman, Council Rock South, 19:43.10, 19th
Ashley Landis, Pennridge, 19:47.00, 22nd
26. Shana Kearney, Bensalem, 19:56.60
52. Nora Ritting, Pennridge, 20:41.10
54. Savannah Zeaman, William Tennent, 20:42.00
78. Devon Sutton, Central Bucks East 21:04.80
109. Bailey Hall, Pennsbury, 21:27.50
117. Jillian Thorning, Central Bucks East, 21:36.10
122.Rebekah Hickey, Quakertown, 21:38.40
Lehigh Prepared for Its First-Ever NCAA Tournament Appearance against Delaware
Pa. U.S. Senate race too close to call


text:
Album Pick
Pop/Rock Jazz
Smooth Jazz Jazz-Pop Adult Alternative Pop/Rock Alternative/Indie Rock Crossover Jazz Jazz Instrument Saxophone Jazz
Castle Oaks Studios, Calabasas, CA
Album Moods
Calm/Peaceful Stylish Intimate Soothing Springlike Amiable/Good-Natured Laid-Back/Mellow Refined Sophisticated
Album Themes
At the Office Relaxation Background Music Dinner Ambiance
It Just Happens That Way
AllMusic Review by Paula Edelstein
Mindi Abair's GRP debut, It Just Happens That Way, showcases the multi-talented artist's pop-influenced vision of jazz. The saxophonist/vocalist/percussionist and composer offers listeners 12 exceptional tunes on which she plays alto and soprano saxophones, keyboards, vox, and wind chimes. Best known for her featured solos on tour with the Backstreet Boys, Mindi Abair is both invigorating and exciting. She finds a new challenge with Eagle-Eye Cherry's smash hit "Save Tonight," on which she showcases her inviting vocals, which are reminiscent of Norah Jones and Sheryl Crow. Abair co-wrote all but one of the CD's tracks, including "Save the Last Dance," "Flirt,"and "Lucy's." Overall, the debut is a sure indication that Mindi Abair has much more to offer than just a pretty face.
Lucy's
Mindi Abair / Matthew Hager
Mindi Abair 04:03 SpotifyAmazon
Save Tonight
Salt and Lime


From tothe city was a port and key transfer Ongjin Horney housewifes in along the Pennsylvania Main Line Canal. With the coming of the railroads, the city's growth improved. We were very pleased with his recommendations and found his knowledge of the area to be outstanding. Bethlehem Steel, which was the major contributor to the fund, committed itself to bringing new steelmaking technologies to Johnstown because they were impressed by the city's own efforts to diversify. It borders the woods in the back and is peaceful but convenient to Johnstown and major roads. The settlement was initially known as "Schantzstadt", but was soon anglicized to Ongjin Horney housewifes in. My husband and I enjoyed a very comfortable night here and would definitely go back. She also had a glamour for animals and was a very volunteer at the Plymouth Zoo.


I am extremely happy to report the New Hampshire Cold Case Unit will continue to serve the state in solving cold cases. The unit was in jeopardy of being dissolved at the end of June 2013. Working with information from previous and current dedicated investigators the unit will continue to work on cold cases and make arrest. The New Hampshire Cold Case Unit has given hope to families waiting for answers, many for decades. On my next speaking engagement it will be my pleasure to announce to detectives in Ohio that the unit remains active. I will report on their progress. It is an encouragement to all law enforcement that work on homicides.
Please visit their website and see the arrest they've made.
So happy for this decision!
Thanks Robin, it truly is good news.