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Pub Date: Thursday, Aug. 11, 2016
Authors: Sarah D. de Ferranti, MD MPH
Affiliation: Harvard Medical School, Boston Children's Hospital, Dept. Cardiology, Boston, Ma.
Article Text
In an effort to move the needle on cardiovascular disease, in 2010 the AHA set as an overarching goal "by 2020, to improve the cardiovascular health of all Americans by 20% while reducing deaths from cardiovascular disease and stroke by 20%".3 Seven key drivers of cardiovascular outcomes were identified including four health behaviors – smoking, obesity, diet and physical activity, and three health factors - lipids, blood pressure, and fasting glucose. Ideal, intermediate and poor categories were defined for "Life's Simple 7" as a way to describe and track the cardiovascular health of an individual and the population (Table 1). By using this strategy, the AHA has tried to create a paradigm shift to re-orient thinking towards improving health, and away from a focus on treating disease.
In a parallel process, a body of work has emerged that describes the concept of ideal CV health. Exploring these concepts in longitudinal cohorts reveals that once lost, ideal CV health is difficult to regain.4 However, individuals who are able to maintain ideal CV health into middle age have a low risk of lifelong CV disease events.5 These concepts are particularly important for youth as - at least in theory - most children start out with ideal cardiovascular health. Unfortunately, national data show that by age 11 years no children met ideal criteria in four cardiovascular categories, blood pressure, weight, diet and total cholesterol,6 and rates of ideal cardiovascular health decline further over the first and second decades.1 Thus it appears the seeds of cardiovascular disease are sown in childhood.
Five years after the publication of the AHA 2020 goals, Drs. Steinberger et al. have written a scholarly manuscript that surveys the state of cardiovascular health in US youth using the framework of the 2020 goals, explores issues of puberty, and identifies evidence gaps in the cardiovascular health of youth (Steinberger et al. Circulation 2016). This statement helps illuminate opportunities for intervention to improve the cardiovascular health of children and adolescents in the U.S.
The writing group describes that with the notable exception of the healthy diet score, the majority of US children and adolescents score in the ideal range for Life's Simple 7, but argues that the population remains vulnerable to adverse health effects that are not completely captured by the metrics. For example, rates of current smoking among adolescents are declining;7 however, one third of adolescents have tried a cigarette in the prior month (Steinberger et al. Circulation 2016) and 4.8 million children under 12 are exposed to second-hand smoke in their homes, an exposure known to be associated with sub-clinical measures atherosclerosis (AHA pediatric SHS statement, unpublished). The prevalence of non-ideal weight, as defined in the AHA 2020 goals as ≥85th%tile, has stabilized,8 yet still 40-48% of teens have non-ideal BMI and the rates of severe obesity continue to climb, particularly in girls.9 Measuring physical activity by self-report suggests two-thirds of boys and half of adolescent girls meet the goal of 60 or more minutes per day of moderate to vigorous intensity physical activity including muscle strengthening and bone-loading activities at least 3 days per week.10 However, measured physical activity (by accelerometry) shows a different picture, with under half of school-aged children boys and a third of school-aged girls meeting the mark for ideal levels of physical activity. By age 16-19 years, only 5-10% manage an hour a day of physical activity 5 days a week (Steinberger et al. Circulation 2016). A healthy diet is the metric U.S. children and adolescents are least able to achieve. Less than 1% of 2-19 year olds meet the criteria for an ideal diet and ~80% of youth have what the AHA metrics describe as a poor diet.1 Fortunately there has been some improvement over time, with an increase in the proportion of children falling in the intermediate diet score, from 31% to 45%.7
Similar issues are identified in the three cardiovascular risk factors, cholesterol, blood pressure and glycemia. Ideal cholesterol levels, defined as TC<170 mg/dL, are present in 65-73% of US youth. However, HDL, an important indicator of CV health is not reflected in the TC metric and in fact the prevalence of high non-HDL is higher than that of high TC, suggesting that looking at TC alone may miss higher risk youth.11 Furthermore, TC levels decrease during puberty, so using a single measure across all of childhood may miss higher risk adolescents. Non-ideal blood pressure, defined as ≥90th%tile, is the cardiovascular health metric most likely to be met by the pediatric population (89% are in the ideal category).11 Non-ideal blood glucose (≥100 mg/dL) is seen in 20-38% of children, with boys being more affected. However, this is a single measure in time and is affected by fasting status; arguably its utility is limited and glycosylated hemoglobin could better convey abnormal glucose homeostasis over time.
The AHA 2020 goals for youth would benefit from refinement, as would be expected for any set of national health metrics, and Steinberger et al. suggest factors to consider. For example, exposure to 2nd hand smoke and use of electronic smoking should be included in the smoking risk score. The adiposity measure could be narrowed to focus on obesity and extreme obesity and not include "overweight". A better choice for the cholesterol metric might be non-HDL as it better represents the atherogenic portion of the lipid profile. Hemoglobin A1C could better represent exposure to hyperglycemia over time. Physical activity should focus on measured as opposed to self-reported activity. These targets should be evidenced based.
Permeating the topic of ideal cardiovascular health in youth, and in fact the entire field of pediatric prevention, is the issue of evidence. Policy makers, researchers, and guideline writers raise concerns about gaps in the existing evidence and about the types of studies available to justify recommendations about cardiovascular risk in youth. Evidence gaps include issues of implementation of healthy lifestyle behaviors, and about how to maintain heart healthy behaviors over the long term. Future research should include bigger sample sizes in racially and ethnically diverse populations, and should include young children less than 5 years old. While the impact of extreme cardiovascular risk behaviors and risk factors (e.g. familial hypercholesterolemia, severe hypertension, diabetes) has been studied, how mild or moderate abnormalities affect risk is a relatively unexplored area. In addition to gaps in evidence, there are issues about evidence quality. The research gold standard, the randomized controlled trial using clinically important outcomes (cardiovascular events), is not likely to be realized in the pediatric population because the time to event is so long, the event rate is low, and because of issues surrounding consent of children for long term follow-up. Different methodologies must be considered to choose clinically meaningful cutpoints for intervention and to investigate the utility of interventions to change behaviors and risk factors. Ultimately a wider range of evidence will need to be used to address the field of pediatric prevention.
Fortunately, high quality studies can inform these issues. For example, rigorous feeding studies can test the effect of diet on cardiovascular risk factors and preclinical vascular measures. Accelerometers and direct observation can better quantify the dose of activity levels than self-report and new technologies can help solve logistical issues around measuring physical activity. In many areas, observational data, long-term cohorts, and the use of pre-clinical outcomes should continue to be used to address questions of pediatric prevention, but high quality methodology must be used. Adequate funding is required to do these studies well, and federal and foundation sources will need to dedicate adequate resources to pediatric prevention if we are going to advance the cardiovascular health of the nation.
While we are gathering the highest quality evidence to preserve ideal cardiovascular health, we need to go on with the tasks of assessing the health of our population, providing recommendations about diet, physical activity, and health-related policy and advising to our patients in the clinic. Fortunately, actions to improve risk factors and risk behaviors are, for the most part, low risk. Few young people meet the current guidelines for pharmacotherapy12-15 and healthy lifestyle behaviors have diverse benefits not only for cardiovascular health but also for cancer prevention, brain and physical development, and prevention and amelioration of mental health disorders. As described in this statement, the 2020 goals for children and adolescents are an important tool for measuring the cardiovascular health of the population and for promoting health at the national, community, family and individual level
Table 1: Poor, Intermediate, and Ideal definitions: Health metrics in children and adolescents
|Smoking status
|Tried in the prior 30 days
|Never tried; never smoked whole cigarette
|Body mass index
|>95th percentile
|85-95th percentile
|<85th percentile
|Physical activity level
|>0 and <60 min/day moderate or vigorous activity every day
|≥60 min/day moderate or vigorous activity every day
|Healthy Diet Score
|0-1 components
|2-3 components
|4-5 components
|Total cholesterol
|≥200 mg/dL
|170-199 mg/dL
|<170 mg/dL
|Blood pressure
|>95th percentile
|90-95th percentile
|<90th percentile
|Fasting blood glucose
|≥126 mg/dL
|100-125 mg/dL
|<100 mg
Table 2: Call to Action
|Parents & Families
|Towns and cities
|Healthcare Providers
|Healthcare Industry
|Food and recreation industry
|Policy Makers
|Know your score!
|Parents – know your score!
|Use 'best practices' physical education
|Use zoning that promotes access to affordable healthy foods
|Ask about healthy behaviors and track Life's Simple 7 over time
|Provide healthy cafeteria options in hospitals and clinics
|Offer healthy options at restaurants
|Measure risk factors and behaviors reliably over time
|Prioritize research in youth
|Promote prominent product placement of healthy foods
|Try something new (a new vegetable, a new activity), even if it isn't comfortable
|And know your child's score!
|Provide daily physical activity in addition to physical education
|Require healthy childcare environments
|For areas of deficit, work with families to set concrete and specific goals
|Provide gym reimbursements as part of benefits package
|Provide nutrition labeling
|Refine measures to reflect partial success, be more relevant to pediatric populations, and be measurable by practitioners
|Fund projects to prevent risk factors
|Subsidize the price of fruits and vegetables
|Help your friends follow a healthy lifestyle
|Create a food safe environment
|Use recess as a reward instead of unhealthy treats
|Build walkable streets and other built environment elements that promote an active lifestyle
|For areas of success, acknowledge and applaud accomplishments
|Provide free smoking cessation programs
|Create more active gaming options
|Develop and propose actions to address vulnerabilities at the population, local and family level
|Require rigorous and practical research methodologies
|Remove barriers to physical activity
|Facilitate an active lifestyle
|Adhere to or exceed federal and state guidelines on healthy school meals and alternative foods
|Make physical activity offerings available to the community that are convenient and affordable
|Know your local resources, if there are gaps advocate to fill them
|Engage with the community on heart health promotion
|Continue to create and refine devices to track and promote activity
|Test interventions to prevent development of risk factors (primordial prevention)
|Promote work to develop novel ways to estimate long term, lifetime risk
|Legislate increased access to fresh safe water
|Model healthy eating and activity
|Avoid supporting fund raising that includes unhealthy food and drink
|Emphasize cardiovascular health over disease
|Test screening strategies to identify risk factors
|Impose taxes on sugary beverages
|Set developmentally appropriate limits on unhealthy behaviors
|Used rigorous methods to test treatment interventions (primary prevention)
|Mandate and financially support daily physical activity in schools
|Applaud successes
|Discover practices to promote maintenance of healthy behaviors
- Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB, American Heart Association Statistics C, Stroke Statistics S. Heart disease and stroke statistics-2016 update: A report from the American Heart Association. Circulation. 2016;133:e38-60
- Huffman MD, Capewell S, Ning H, Shay CM, Ford ES, Lloyd-Jones DM. Cardiovascular health behavior and health factor changes (1988-2008) and projections to 2020: Results from the national health and nutrition examination surveys. Circulation. 2012;125:2595-2602
- Lloyd-Jones DM, Hong Y, Labarthe D, Mozaffarian D, Appel LJ, Van Horn L, Greenlund K, Daniels S, Nichol G, Tomaselli GF, Arnett DK, Fonarow GC, Ho PM, Lauer MS, Masoudi FA, Robertson RM, Roger V, Schwamm LH, Sorlie P, Yancy CW, Rosamond WD. Defining and setting national goals for cardiovascular health promotion and disease reduction: The american heart association's strategic impact goal through 2020 and beyond. Circulation. 2010;121:586-613
- Gooding HC, Shay CM, Ning H, Gillman MW, Chiuve SE, Reis JP, Allen NB, Lloyd-Jones DM. Optimal lifestyle components in young adulthood are associated with maintaining the ideal cardiovascular health profile into middle age. Journal of the American Heart Association. 2015;4
- Fang N, Jiang M, Fan Y. Ideal cardiovascular health metrics and risk of cardiovascular disease or mortality: A meta-analysis. Int J Cardiol. 2016;214:279-283
- Ning H, Labarthe DR, Shay CM, Daniels SR, Hou L, Van Horn L, Lloyd-Jones DM. Status of cardiovascular health in us children up to 11 years of age: The national health and nutrition examination surveys 2003-2010. Circulation. Cardiovascular quality and outcomes. 2015;8:164-171
- Writing Group M, Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB, American Heart Association Statistics C, Stroke Statistics S. Executive summary: Heart disease and stroke statistics--2016 update: A report from the American Heart Association. Circulation. 2016;133:447-454
- Skinner AC, Perrin EM, Skelton JA. Prevalence of obesity and severe obesity in us children, 1999-2014. Obesity (Silver Spring). 2016;24:1116-1123
- Skinner AC, Skelton JA. Prevalence and trends in obesity and severe obesity among children in the united states, 1999-2012. JAMA pediatrics. 2014;168:561-566
- U.S. Department of Health and Human Services. 2008 Physical Activity Guidelines for Americans. In: U S Department of Health and Human Services, ed 2008.
- Kit BK, Kuklina E, Carroll MD, Ostchega Y, Freedman DS, Ogden CL. Prevalence of and trends in dyslipidemia and blood pressure among us children and adolescents, 1999-2012. JAMA pediatrics. 2015;169:272-279
- Gooding HC, Rodday AM, Wong JB, Gillman MW, Lloyd-Jones DM, Leslie LK, de Ferranti SD. Application of pediatric and adult guidelines for treatment of lipid levels among us adolescents transitioning to young adulthood. JAMA pediatrics. 2015;169:569-574
- Joyce N, Wellenius GA, Dore DD, Newburger JW, Zachariah JP. Patterns of lipid lowering therapy among children ages 8-20 years. J Pediatr. 2015;167:113-119 e111
- Zachariah JP, McNeal CJ, Copeland LA, Fang-Hollingsworth Y, Stock EM, Sun F, Song JJ, Gregory ST, Tom JO, Wright EA, VanWormer JJ, Cassidy-Bushrow AE. Temporal trends in lipid screening and therapy among youth from 2002 to 2012. J Clin Lipidol. 2015;9:S77-87
- McCrindle BW, Tyrrell PN, Kavey RE. Will obesity increase the proportion of children and adolescents recommended for a statin? Circulation. 2013;128:2162-2165.
-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association --


text: UPS claims 209,043 members were eligible to vote and only 92,604 voted. Or roughly 11,917 votes short of a 50% turnout. Of those 11,917 votes 7,892 (or 2/3) of them would of had to of been a yes vote for this thing to even be a tie. A tie! Which would have never happened. Pretty clear the majority wasn't for this and its sad the union isn't pushing that narrative, instead only mentioning that we didn't hit 50% voter turnout. Truth is even if we hit that made up 50% turnout it would of been the same result obviously. What kind of union leader tries to hide that?

subset: commoncrawl


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The stupid, lying media all attacked Donald Trump because he mentioned what is going on in Sweden. They all falsely accused him of saying that Sweden had suffered a terror attack.
He was, of course, talking about the changing demographics of Sweden through immigration from incompatible Muslims. That didn't matter they went all in and then two nights ago Trump was proved right….again.
A photographer for?Dagens Nyheter, one of Sweden?s largest newspapers, was the victim of an attack by rioters at the notorious Stockholm migrant-populated suburb of Rinkeby.
The?continued?riots in the densely migrant-populated?Stockholm suburb of Rinkeby has seen multiple cars set on fire and a photographer from Swedish newspaper?Dagens Nyheter was attacked. The photographer said the attack occurred just after 10:00 pm at night and said, ?I was met with a lot of punches and kicks on both the body and the head. I have spent the night in the hospital,? Dagens Nyheter?reports.
The photographer says he arrived in the troubled suburb by car and parked away from the riots. After walking to Rinkeby square where the riots were occurring, he claims he was attacked by up to fifteen men. ?
According to the photographer, he hid his camera under his coat though the attackers discovered it and stole it from him. Journalists have been attacked in Rinkeby before in broad daylight. A television crew from Australia were attacked by several masked men last year and were even rammed by a car.
After the attack, the photographer managed to escape to a nearby petrol station where he called the police. Police told the man that no patrols were available to help him and that he would have to get to the hospital on his own.
?I was shocked for hours afterwards. The police eventually came and I made a complaint about the assault and aggravated theft. They said that the chances of the perpetrators or the camera is found is small. Non-existent,? he said.
Police have also been attacked in Rinkeby multiple times and as recently as just over a week ago.? Stockholm police spokesman Eva Nilsson said that officers were beaten by a mob of between 20 and 30 people who kicked and punched them while they were doing a routine check on an individual.
?Of course, it?s a serious thing when police officers who are just acting in their official capacity are attacked in this way. It is a reality which, unfortunately, exists as something which happens now and again for colleagues who work there,? Nilsson said.
U.S. President Donald Trump commented on the fracturing of Swedish society due to mass migration only days before the Rinkeby riots broke out. The Swedish establishment mocked the president assuring the foreign public that Sweden was fine.
The Swedish establishment have a problem and mocking Donald Trump and hiding the truth from their citizens is only going to lead to a backlash at the polls.
The problem has been there for a while.
An Australian TV station has released a shocking report showing its crew being attacked by masked men in a Stockholm suburb know as ?Little Mogadishu? due to it?s primarily Somali population.
Since the report was filmed last month, Swedish police have dropped all charges, despite the migrants throwing missile and punches, fly kicking the journalist, and even running one over with a car.
The Channel Nine crew and high-profile Australian news correspondent, Liz Hayes, had traveled to the Swedish capital to investigate how the migrant ?overload? has affected Swedish society.
Upon entering a migrant area, Rinkeby, they were quick to discover some of those effects, and why it is that they have become known as ?no-go zones?.
?They were confronted by a group who objected to them filming. There was a series of scuffles and the police were called.
?The 60 Minutes cameraman and producer were slightly injured but filming continued with police at the scene. The crew have now returned to their hotel and are all fine,? a spokesman for the channel told the Local.
Sweden has a problem, they have?imported sectarian and religious violence by importing people who come from countries whose belief system is incompatible with Western liberal democracies.
To deny it is to further subjugate our heritage.
Sweden hasn't suffered a single terror attack, it suffers ongoing and daily terror attacks.
– Breitbart
As much at home writing editorials as being the subject of them, Cam has won awards, including the Canon Media Award for his work on the Len Brown/Bevan Chuang story. When he's not creating the news, he tends to be in it, with protagonists using the courts, media and social media to deliver financial as well as death threats.
They say that news is something that someone, somewhere, wants kept quiet. Cam Slater doesn't do quiet and, as a result, he is a polarising, controversial but highly effective journalist who takes no prisoners.
He is fearless in his pursuit of a story.
Love him or loathe him, you can't ignore him.
To read Cam's previous articles click on his name in blue.


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Last updated on May 8th, 2019
Dark Blue Games' Infected Shelter is a randomly generated rogue-lite set in a post-apocalyptic setting. The game is an action-RPG shooter and dungeon brawler. Defeat enemies to loot more than 150 different blueprints of permanent improvements and other goodies like outfits, pets, and relics. Infected Shelter can be played either solo or with up to 3 other players.
Infected Shelter: Early Access Preview
Developed by: Dark Blue Games Ltd.
Published by: Dark Blue Games Ltd.
Release date: May 8 2019 in Early Access on Steam for PC; Q4 for Nintendo Switch, PlayStation 4, and Xbox One
Platforms: Steam, Nintendo Switch, PlayStation 4, Xbox One
Website: http://infectedshelter.com/
Infected Shelter Features
- Randomly generated post-apocalyptic environments
- Fast paced, violent and complex 2D brawler-like combat with lots of firearms and melee weapons
- Rogue-lite / rouge-like elements, play-learn-die-unlock-improve-repeat
- Permanent upgrades that change how you play the game in the following runs
- 150+ blueprints to unlock new weapons, clothes, skills, relics and RPG-like character improvements
- 50+ brutal, ultra-violent executions
- 50+ character traits
- 4 different playable characters (Only had 2 when I tested/played the game)
- Tons of guitars, wheelchairs, pets, drinks, active items
- 200+ areas and shelter rooms
- Fully supported singleplayer experience
- Local co-op with up to 4 players
Story & Setting
Walk in the shoes of a member of a group surviving a post-apocalyptic world. One pivotal morning the shelter is raided and your fellow people are kidnapped for reasons unbeknown. It's up to you to leave the shelter and face the harsh infected wild lands, aiming to save those who were captured. Your journey will consist of infected animals, humans, even technology, challenging to get back your friends and won't be easy.
Infected Shelter takes its inspiration from a combination of titles which includes Mortal Kombat, Dead Cells and Castle Crashers. Bringing you a beat 'em dungeon crawler with RPG and rogue-like elements. Letting players take on the post-apocalyptic world on their own, or with a friend in local co-op.
Gameplay is fairly straightforward with players choosing 1 character out of the 4 available. Infected Shelter then presents 3 versions of each character which receives random gear, skills, traits, and more. The early access build currently allows you to choose between 2 of those characters. Players must defeat a boss before traits become available.
Each run consists of a checkpoint for reaching 50% of the way and one right before the boss. This allows the player to purchase upgrades with their infected sample currency and the ability to heal for up to 60 HP. Those willing to explore, can find side rooms that will contain goodies but beware as these rooms may contain environmental traps to impair your progress.
Every run is different because of the randomly generated content affecting every part of the game. By defeating enemies players can loot more than 150 different blueprints of permanent improvements, this will improve your chances to extend your run. This, and the multiplayer aspect is a key to Infected Shelter's replayability. In the beginning you want to learn the basics of the game and figure out what character suits your playstyle while unlocking improvements. This will make each run slightly easier as long as the RNG complies.
Each character has their own set of attributes depending which you will pick:
Guitarist Girl
- Endurance ☆
- Strength ☆☆
- Dexterity ☆☆☆
- Intelligence ☆☆
- Serendipity ☆
Grandpa & Granddaughter
- Endurance ☆☆
- Strength ☆
- Dexterity ☆☆
- Intelligence ☆☆
- Serendipity ☆☆☆
Big Biceps Builder
- Endurance ☆☆☆
- Strength ☆☆☆
- Dexterity ☆
- Intelligence ☆
- Serendipity ☆
Smiling Soldier
- Endurance ☆☆
- Strength ☆☆☆
- Dexterity ☆
- Intelligence ☆☆
- Serendipity ☆☆
In Early Access players get to test their mettle against three available bosses which include a crazed helicopter type boss, a bull ready to charge you down and a droid. Each boss brings its own types of attacks letting the chaos ensue.
The shelter starts off empty but as you continue your runs continue you will find your fellow shelter-mates trapped in cages. Hitting the cage enough times grants them freedom and you'll see them back at the shelter. They will assist you in future runs as each person is in charge of certain randomized wares. These wares consist of:
- Weapon Store: provides you 4 random weapons you may choose
- Box Store: places 4 boxes that must be destroyed in order to obtain whats inside. Normally consist of nothing, relics, consumable items, and golden badges.
- Skill Store: provides you 4 random skills you may choose
- Drink Store: provides you with 4 random drinks you may pick up
- Gold Store: allows you to purchase relics and consumable items with gold currency. (Invest in gold saving improvements to start your run with higher gold)
Audio & Visuals
The game's visual are completely comprised of 2D images, simple yet eye catching. You'll see a geometric designed cactus and instantly you will know what you are seeing, so no problem identifying objects. Runs can be either take place during the daytime or night, which adds to the mayhem as venturing out at night makes it more difficult to see enemies. The colorful minimalist art-style suits the game as well as it puts more emphasis on the gameplay. As you can expect for a zombie filled post-apocalyptic game, there's plenty of hack 'n' slash visuals drawing on its Mortal Kombat influence.
The audio suits the title as you have each weapon with their its very own sound effect and most of the music playing during your run is subtle, allowing you to focus on the enemies attacking. I really enjoyed it when it rained in the game as it adds a relaxing atmosphere to the hectic world. I wish my RNG for rainfall was higher as it didn't happen as often as I would have liked. Hopefully Blue Games will add more environmental audio as it really helps to add to the atmosphere.
Final Thoughts
For an early access game the price is pretty good for what you get. At the time of writing this the game build has 3 bosses to fight, if you manage to defeat them in a single run, players will reach an enclosed area with a "Work in Progress" sign. Several elite enemies will spawn and attempt to defeat you as I believe the developers planned on the enemies being quite difficult to take down, adding a surprise challenge towards the end which may lead to your demise.
However, if you manage to defeat them, you will be stuck and need to return to the main menu to start a new run. This build also only had 2 of the 4 characters playable as well as only local coop that I get to try. This will be a great game to play with friends to unwind after a long day. At the time of writing I accumulated 5 hours on this build and haven't obtained more than about 60% of the blueprints, so while players can beat the game in a short time, it should take them longer to obtain everything in the game opening up more upgrades and ways to play.
The only issue I found was that if the screen has too many enemies and they all die at once, the drops tend to slow down the frames. It could be my hardware but at the least its should be stated. Sometimes its easy to lose your character in the frenzy of fighting but this can be remedied by rolling to a safe spot to recover. Finally, while the executions are cool to witness, the zoom in camera focus tends to strain my eyes, hopefully they give further options for camera control.
To watch this game in action see:
Infected Shelter releases on May 8 2019 in Early Access on Steam for PC; Q4 for Nintendo Switch, PlayStation 4, and Xbox One
If you're interested in games with a punch be sure to see to check out our recent Days Gone Review: A Saphire In The Rough. You can also check out more previews in Warhammer Chaosbane Preview – Venturing Into The Fantasy Universe and The Surge 2 Preview: Stronger, Faster, Character Creation!.


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Kevin Wagstaff from Spectora.com provides insight into what the rapidly growing Millennial homebuyer looks for in a home inspector. Kevin gives you deeper insight into how they think and how you can win over the largest buying cohort in the next few years. For more information, visit www.nachi.org/spectora.
Month: August 2019
Achieving Success as a New Member of InterNACHI
Take advantage of the free, online resources for all InterNACHI members in order to be successful home inspectors, including accredited training and certification programs, business and marketing services, and legal documentation and advice. Welcome to InterNACHI at www.nachi.org. If you like the video, please tell us on Facebook. Download Achieving Success as a New Member of InterNACHI SLIDES.
Franchise Opportunity for Home Inspectors with TheInspectionBoys
Learn about a franchise opportunity for home inspectors with Brigitte Malik from TheInspectionBoys.com.
3D Inspection Software with CEO Carl Fowler
August 6, 2019
3D Inspection Software CEO Carl Fowler demonstrates the 3D Inspection Software.


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Starting in the late summer, the amount of the scholarship will convert to an actual named scholarship award. For example, your 6,000 berkeley undergraduate scholarship may be converted to two different scholarships, like a campanile scholarship for 4,500 and a phoebe hearst scholarship for 1,500.
Most ut austin forty acres scholars major in plan ii or business honors. I am a new chancellor, so i am going to take that opportunity to re-open that look.
Learn about the university of texas at austin essay prompts and get started on.
Forty acres scholars develop a unique connection with their alma mater.
You must first submit the texas exes entering freshman scholarship application before you can access the forty acres scholars program supplemental short answers. To ensure consideration for the forty acres scholars program, applicants must have applied for admission to the university of texas via applytexas or coalition by the priority deadline.
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Scholarship application directions applying for scholarships is the responsibility. Give your references no less than 5 days to write a quality letter. Criteria students who are interested must apply for the forty acres scholars program.
The scarlet e, part ii 40 acres, june 14th, 2019 part 1 the myth of the frontier,. Plus, we hear why legal scholars think this case deserves to be honored by. Leaders begin drafting articles of impeachment, examples from the nixon and.
Meet the 2012 recipients of the forty acres scholars program.
Yes, this scholarship is kind of modeled after the mcdermott scholarship at ut dallas. How to write the ut austin supplemental essays 2017-2018 ut austin. Students are required to write a 650 word response quotwhat was the ut. If you applied for the forty acres scholars program, you will see the word. In this guide, well cover how to write a winning scholarship essay, so you can feel. Located on a 40-acre campus just west of oklahoma city, snu grew out of.
To ensure consideration for the forty acres scholars program, applicants must have applied for admission to the university of. Most families look for needs-based financial aid or scholarships to cover tuition costs. People together, application answers and essay, and recommendations received as part of the admission application. It is open to students from canada, great britain, and north carolina. Junior cert irish essay samples, how to write a conclusion for history essay.
Mentioned in my primary app or i dont feel like i can get a good essay out of it. And manages over 500,000 square feet of indoor and 40 acres of outdoor space. Ta1 ut -tyler faculty and staff are eligible to compete in open division. The turing scholars program is a computer science honors program at the. Hey cc, i applied for the 40 acres scholarship for ut and i just want to get. Well on the scholarship essays and have gotten a bhp interview.
I was wondering if i was competitive at all for the 40 acres scholars program. Everyone with a car once the moody center starts construction.
Ten new longhorns will start the fall semester as forty acres scholars. Revise essays, provide homework assistance and teach reading and. The texas exes scholarship comes in three forms forty acres scholars. Each year, candidates are given essay topics to write and submit an application for the. Open to every high school student in the united states, this is a monthly online. The forty acres scholars program is the premier full-ride, merit-based.


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Safety Policy
Safety First is Safety Always
Whilst you may be in the business to make money, you will have no money if you do not consider safety. We work tirelessly to protect the safety of both our customers and our staff. We will ensure that there is a safety data sheet with every chemical that is formulated and supplied for your needs. We follow the latest legislative requirements and ensure that all labels carry the correct up to date hazard symbols. We constantly explore opportunities to develop products, which deliver increased cleaning or disinfection performance whilst trying to reduce the chemical classification in order to protect personnel and the environment within which we work and live. We make sure all our business activities are carried out thoughtfully and responsibly, and in accordance with relevant statutory legislation.
As accredited safe contractors we ensure all manual work completed on customer sites is safe and we always supply all necessary RAMS prior to any work commencing.


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2020 Kia Telluride Gas Mileage
2020 Kia Telluride Gas Mileage Contemplating the L is particular order only, and the LS doesn't add much for a substantial worth bump, we think it is worth skipping straight to the LT mannequin. Its list of added features isn't extensive, however you do get upgraded headlights for higher nighttime visibility, together with satellite radio and tinted glass. The LT also opens the doorways to several worthy choice packages. The Confidence and Comfort bundle stands out, with extra luxurious features and blind-spot monitoring.
Fortune doesn't essentially favor the bold within the compact crossover segment — the Honda CR-V, the Nissan Rogue and the Toyota RAV4 are perennial best-sellers thanks partly to their all-around competencies and historical past of reliability. Still, automakers try to make their small SUVs distinct. The 2020 Kia Telluride Gas Mileage stands out by bringing high-end luxurious options and a few distinctive engines to this sometimes price-conscious class.
Redesigned just last 12 months, the 2020 Kia Telluride Gas Mileage is without doubt one of the newer entries in this section. As such, all the newest safety features can be found, from a surround-view parking camera to ahead collision warning system that can establish pedestrians. In contrast to some opponents, most of these features can solely be ordered on the top trim level, but at least you can get them. Additionally out there are a panoramic sunroof, a surround-view parking digicam and ventilated entrance seats — rare options in this class.
We additionally like that the 2020 Kia Telluride Gas Mileage offers two different powertrains if you happen to aren't satisfied with the bottom turbocharged 1.5-liter engine. At one finish of the spectrum is a fuel-efficient diesel that achieves 32 mpg in mixed driving (the standard engine earns 28 mpg); on the other, a turbocharged 2.Zero-liter with a further 80 horsepower. Be careful, however: When you start checking the choices boxes, the 2020 Kia Telluride Gas Mileage may be substantially costlier than rival crossovers. An engine stop-start system that can't be disabled and disappointing materials high quality additionally might give prospective consumers pause.
2020 Kia Telluride Gas Mileage fashions
The 2020 Kia Telluride Gas Mileage is a five-passenger compact crossover that prices a bit greater than most rivals. It's sold in 4 trims: L, LS, LT and Premier. The base L mannequin looks like an important deal until you understand that it's a custom-order model and you'll have to attend for it to be constructed. You may find the LS at practically any vendor, but it's more expensive and would not add a lot. Best to skip straight to the LT, which is only a bit dearer and includes extra features and entry to additional choices. If you want the LT and its two packages, the leather-trimmed Premier consists of it all.
Three engines are offered on the 2020 Kia Telluride Gas Mileage. The standard engine is a turbocharged 1.5-liter four-cylinder (170 horsepower, 203 pound-feet of torque) matched to a six-speed automatic transmission. A more highly effective turbocharged 2.0-liter engine (252 hp, 260 lb-ft) is elective and comes normal with a nine-speed automatic transmission. Additionally optional is a fuel-efficient 1.6-liter diesel (137 hp, 240 lb-ft) mated to a six-speed computerized. Each of those engines will be ordered on LT and Premier trim levels.
Dealing with


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- Price$85,000
- Acres0.18
27215 Park Drive Lot 34 Blk 7, Orange Beach
The location of this lot is one of the best in Orange Beach! PLUS you have TWO bay accesses to Bay la Launch bay. One access has all the boat facilities. The second access is almost a half of acre lot directly on Bay la Launch with a fishing pier, gazebo, large, fenced area for kids and pets. PLUS, you are just a couple of minutes away from The Orange Beach Recreational Center, Orange Beach Elementary School, numerous restaurants: Anchor, Barefoot Bar & Grill, Master Joes, Playa at Sportsman Marina and Bear Point! This is an active community and you will see a lot of people driving their golf cart around. This fenced lot is cleared, level and ready to be built on. You can store your boats, etc on this lot.
Essential Information
- Price$85,000
- Acres0.18
- TypeLand & Lots
- Sub-TypeResidential Lots, Lot
- StatusActive
- AmenitiesGazebo, Other-See Remarks, Water Access-Deeded
- UtilitiesSewage-City Available, Water-City, Baldwin EMC, Orange Beach Water Auth
- ViewNone
- WaterfrontBay Access (Wlk <=1/4 Mi), Bayou Accs (Wlk <=1/4 Mi), Canal Accs (Wlk <=1/4 Mi), Creek Accs (Wlk <=1/4 Mi), Deeded Access
School Information
- ElementaryOrange Beach Elementary
- HighOrange Beach
Listing Details
- Listing OfficeRE/MAX of Gulf Shores
Community Information
- Address27215 Park Drive Lot 34 Blk 7
- AreaOrange Beach 1
- SubdivisionEast Orange Beach
- CityOrange Beach
- CountyBaldwin
- StateAlabama
- Zip Code36561
- Lot Description58X140, Less than 1 acre, Level
Additional Information
- HOA Fees195.00
- HOA Fees Freq.Annually
Price Change History for 27215 Park Drive Lot 34 Blk 7, Orange Beach, Alabama (MLS® #289729)
|Price Reduced from $98,500 to $85,000
The data relating to real estate for sale on this website comes from the Baldwin County Association Of REALTORS®. The information being provided is for consumers' personal, non-commercial use and may not be used for any purpose other than to identify prospective properties consumers may be interested in purchasing. Information deemed reliable but not guaranteed.
Listing information last updated on April 2nd, 2020 at 9:30am CDT.


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Note: Some of the graphical elements of this site are only visible to browsers that support accepted web standards.The content of this site is, however, accessible to any browser or Internet device.
Royal College of Science (1890 - )
The Royal College of Science was established in 1890, having previously been known as the Normal School of Science. In 1907 the College merged with the Royal School of Mines and the City and Guilds College to form Imperial College of Science and Technology. The three institutions retained their separate identities after the incorporation.
Previous and Subsequent Entities
1881 - 1890 Normal School of Science
1881 - 1890 Normal School of Science
1890 - Royal College of Science
1907 - 1988 Imperial College of Science and Technology
1988 - Imperial College of Science, Technology and Medicine
Structure based on ISAAR(CPF) - click here for an explanation of the fields.
Prepared by: Ailie Smith
Created: 14 October 2003
Modified: 18 February 2004
Created: 14 October 2003
Modified: 18 February 2004
Published by Imperial College, London
Comments, questions, corrections and additions: firstname.lastname@example.com
Updated: 19 June 2006


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Hp C7280 Out Of Paper Error
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Freehand Pipes
Each ePipeMods pipe is hand crafted and one of a kind.
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Hand Crafted, One of a Kind, Mechanical Vape Pipe.
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Customized Cakes
Never say no to Customization Cakes!
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Fluconazole Diflucan For sale
Fluconazole diflucan forsale Information Blog
What is Online Pharmacy? Online Chemist, Internet Pharmacy, or mail-request drug store is one sort of drug store which is being worked over the web and send the medications to the clients by request got. Same as other Internet Business, Online Pharmacy is likewise raising its bar over the web and on the Global economy too. Today, rather than visiting a neighborhood store by and by, individuals requested their prescriptions on the web.
What's more, the principle purpose for the expanding pattern of Online Pharmacy is, they give astounding arrangements and limits and moreover, their client administrations is Fluconazole Diflucan For sale likewise quick and exact. As the web is developing enormously, the fame of Internet Pharmacy is additionally expanding. When anyone needs quick master exhortation and data about any illness from the medicinal services proficient around then Online Pharmacy Uk is conceivable.
Focal points
Aside from sparing the expense and time of visiting any neighborhood drug store and getting the medications, beneath are a portion of the advantages of Online Pharmacy:
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One of the fundamental points of interest of Online Pharmacy is, it conveys the medications in all respects rapidly. With the assistance of quick delivering, clients get their meds on time which makes an extraordinary impact on the client's brain. The site of Online Pharmacy is additionally easy to understand which gives a smooth Online Medicine requesting background. The Online Pharmacy UK is too basic that individuals normally visit for purchasing the prescriptions Online.
2. Expert Advice and Guidance:
At the point when there is any medicinal crisis happens, and one needs the master exhortation without visiting the specialists or facilities, different Online Pharmacy sites offer the best restorative guidance inside no time. This Online Pharmacy Uk site is accessible every minute of every day 365 days a year to give any master direction to their clients.
3. Quick Treatment Just One Click Away:
Online Pharmacy benefits as much as possible from the most recent innovation and offers treatment to their clients. Presently with Online Pharmacy, abstain from visiting GP, center or medical clinics. You can get a similar treatment you get at any center or clinics from Online Pharmacy. The board of specialists is holding back to fix your sickness without squandering a solitary snapshot of time.
4. 100% Convenient:
Visiting the nearby store or therapeutic frequently cause burden to the patient just as for the relatives too. Presently with Online Pharmacy, you can bring the Pharmacy store on your cell phones, workstations, tablets, and PCs. Therapeutic Services Uk gives a stage to their clients of requesting any prescriptions and drug directly at their doorstep.
At the point when any framework has numerous preferences, it holds a few weaknesses also. The following are a portion of the inconveniences.
1. Experiencing Rogue Pharmacies:
When you are associated with web, there are chances that you may run over with misrepresentation drug stores organization who guarantee to be a genuine one. Alongside taking requests they likewise gather cash from the client and don't convey the prescriptions which frequently bring a tempest of issues for the clients.
2. High danger of Counterfeit Drugs:
At the point when any individual is purchasing any prescription on the web, the odds of getting the fake medications is likewise expanded. It is seen that a lot of unlawful Online Pharmacies and offices are offering Counterfeit medications at high costs to the clients. To keep away from such circumstances, individuals ought to abstain from acquiring the prescriptions from the outside sites who sell old and polluted meds at exceptionally shabby expense.
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Unlawful Chemist Shop offices regularly produce shrouded cost, for example, shipping charges, handling expenses, interview expenses from their clients. Prior to buying any prescriptions from Medical, one should clear every one of the questions with respect to all the installment and cost he/she is paying to the specific site. For more info clik the link below...
Visit here: https://fluconazole-diflucan-forsale.com/


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Made in India, for the Indian user
From Ed Sheeran to Kishore Kumar and everything in between, the Indian consumer is quintessentially different in her likes and dislikes from rest of the world. Whether it is her prudence for saving data, her dislike of bulky apps or her love for songs in her native language, the Indian consumer is not one but a mix of hundreds of different user personas. It is this challenge of creating a beautiful and usable product for our varied user bases that keeps us busy everyday.


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The area of PentaJPK - Standard Audit File for Tax
PentaJPK solution is based on the system architecture used in proven PentaTax implementation developed by Pentacomp for the group of the biggest Polish enterprises. The source data are gained from tables or CSV files enabled by Financial/Accounting or ERP systems and aggregated then in proper SAF-T files. Created files are digitally signed, divided and packed in accordance with the requirements given by Ministry of Finance.
PentaJPK functionality
PentaJPK solution includes the following functionality:
- creation of SAF-T (JPK) files from data source files (source files are described further)
- reporting errors of SAF-T files creation based on source data
- handling of SAF-T files prepared by external systems
- visualization of data contained in SAF-T files (to verify the correctness of the data before submitting SAF-T to the tax audit authority)
- technical validation of SAF-T (XSD compliance)
- basic business validation of SAF-T
- automated delivery of SAF-T files to the Ministry of Finance
- convenient user interface for SAF-T management, enabling:
- search by file type, the reporting period, creation date
- verification of the processing status
- electronic signing
- collecting and downloading of electronic confirmation of reception (UPO)
- review of file metadata
- review of the event log associated with the SAF-T (the log includes all events associated with the file including information about the files / source tables, information about the outcome of the various processing steps, users who perform operations on SAF-T, information about the status of transmission etc.)
- ability to work within the framework of many companies (holdings etc.)
- administrative interface allowing users the management of individual companies
- single login (SSO) based on Active Directory
Task processing control in PentaJPK
PentaJPK enables the control of tasks processing via WWW-based GUI (by user) or through dedicated Web Service (by the system).
Task submissions are then accepted and queued in asynchronous mode. System interface provides the opportunity to process one step only (i.e. electronic signing only) or the entire track (from XSD verification to sending SAF-T file to Ministry of Finance). XSD verification is optional and can be disabled in the system configuration.
Transfering messages to Ministry of Finance
A dedicated Web Service based on the required specifications performs the dispatching the messages to the appropriate systems of the Ministry of Finance.
For user's convenience the service has been developed in the form of a dedicated communication module.
The specification for data exchange was officially published by the Ministry of Finance on 20th of July 2016 but now PentaJPK is integrated with JPK project conducted on site of the Ministry.
Accounting data source for PentaJPK
PentaJPK requires the provision of the necessary accounting data from IT systems that support Finance, Accounting and Warehouse Management. Analysis and mechanisms for extracting data from ERP systems can be made by the customer's IT department, provider of ERP, external consulting firms, or by Pentacomp.
PentaJPK is able to read and acquire data formatted as database tables compatible with SAF-T files and/or CSV files and/or XML files.


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All together now ISBN: 9780744578577
Published by Walker, 2001
Useful for either adopted or fostered children, this lovely picture book celebrates the differences in families. Bunny is Mummy Rabbit's first baby, or 'little Honey' as she calls her children. Little Duckling came next, found by Bunny when hatching out, and then Miss Mouse, discovered alone one summer morning. The family all have different talents, and they all look quite different, but the thing they share in common is BIG FEET. They sing a song as part of their games: 'We're the little Honeys. A little Honey is sweet. Quack, quack, squeak, squeak, Thump your great big feet!' The superb illustrations, show a loving, tactile family, and a mum who accepts her children's differences with joy.
Age: 2+


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Form Digital Body Weight Bathroom Scale
The Form is a white tempered glass 400 lb capacity scale. Features include auto on/off function, low battery indication, and large LCD display. Basic yet modern in design, a perfect fit for any bathroom!
- Capacity: 400LB/181KG
- 6mm tempered glass platform construction
- Auto on/off function, no buttons needed
- Low battery and overload indication
- LCD screen
- Powered by (1) CR2032 lithium battery (included)
- Certifications: CE, RoHS, FCC
- Model number: FM-400
- Max Capacity: 400 lbs (180 kgs)
- Overall Size: 11.8"L x 11.8"W x 1.2"H
- Weight: 3.5 lbs
- 10 year warranty
What is a Bathroom Scale?
A type of scale and product created and designed in various colors, materials, mechanisms, shapes, sizes and styles for a person to stand on to confirm their body weight.
$14.99 Regular Price
$8.99Sale Price


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Historical Fiction Competition - please click here for full details
(deadline 19 June 2020)
The History department prides itself on offering a high quality learning experience for students throughout their time at TOA. History is a popular subject in Key Stage 3 and has a strong uptake at Key Stage 4 - with the 2014-2015 GCSE cohort forming the largest in the past five years. The department is staffed by two full time experienced teachers.
Each History classroom has SMART technology and access to laptops.
In History, students will enhance their existing numeracy and literacy skills, whilst also developing skills specific to History and in particular the use of sources. The emphasis is upon providing stimulating lessons that to ensure that students are able both to access History and to appreciate the formation of the modern world whilst making good or better progress. Assessment is varied with unseen formal exams; source analysis and overview of Historical claim and counter claims.
Lessons in this year offer increasing levels of stretch and challenge to prepare students for Key Stage 4 should they choose History as a GCSE subject. As well as embedding skills developed in Year 7 there is the emphasis on key social topics: that explain from slavery to freedom and the experience of African Americans, whilst in Term 5 the Holocaust is taught. Lessons are increasingly delivered to encourage independent learning and as in Year 7 assessment is varied with unseen formal exams; source analysis and overview of Historical claim and counter claims.
Should you wish to know more, please contact the Head of Humanities, Andy Harrison via E Mail: firstname.lastname@example.com
Link to AQA website
Link to GCSE specification
Links to revision guides
Link to BBC bitesize GCSE History
Other revision sites


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CLEARFIELD – The Clearfield Hospital will present a series of three Diabetes Classes in March. The classes will include information/instruction on the following: definitions & terms, medications, laboratory testing and self monitoring, foot & skin care, high & low blood sugars, foot care, sick day management, stress, complications, dietary management, and ongoing self-care/management.
All with Diabetes and a friend/family member are invited to attend the classes. Attendee participation is encouraged. The classes are presented as a public service by Clearfield Hospital and there are no charges for the classes or literature.
Classes will be held from 1:00 p.m. to 4:00 p.m. on March 5, March 12 and March 19. To register, please call the Clearfield Hospital Education Department at 768-2345.
Classes will also be presented on April 2, 9, and 23, 2008. The times will be from 6:00 p.m. to 9:00 p.m.


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In a concerted effort to fight incidents of Trio crimes in this Province head-on as part of the Festive Seasons Operations, the ongoing Intelligence Led Joint operations have yielded positive results. A Trio Crime syndicate was intercepted this afternoon along Polokwane and Mogwadi Road during a sting operation led by …Read More »
Body of woman found in Umkomaas River Mouth
The body of a woman, believed to be in her 30s, was found floating in the Umkomaas River Mouth in Umkomaas, KwaZulu Natal. ER24 paramedics arrived on the scene shortly after 08h00 after they were alerted to the incident by members of the public. Paramedics and lifeguards utilized a Rescue Boat …Read More »
Suspect killed during foiled robbery and shooting at police from taxi
Yesterday afternoon, an intelligence driven operation was conducted by the Provincial Trio Crime Task Team at the intersection of the M4 North Coast and M27 for a wanted suspect who was originally from the Mandeni. According to information received, the suspect was on his way to commit robbery at KwaDukuza. …Read More »
Man dies in collision on the M7 near the Engen Garage in Seaview
A man has been killed in a collision on the M7 near the Engen Garage in Seaview on Monday afternoon around 4pm. Rescue Care Paramedics were called to the scene to find that a single vehicle had crossed from the West Bound Carriageway through the centre medium and come to …Read More »
SA and Zimbabwe Air Navigation Service Providers sign agreement
Air Traffic and Navigation Services (ATNS) SOC Ltd and the Civil Aviation Authority of Zimbabwe (CAAZ) have signed a Letter of Procedure on the coordination of aircraft and reviewed an existing Joint Bilateral Agreement on Search and Rescue between South Africa (SA) and Zimbabwe. The letter entails coordination procedures for …Read More »
Fatal taxi shooting at a busy intersection during peak afternoon traffic in Roodepoort
At approximately 16h30 on Tuesday, Netcare 911 responded to reports of a shooting on Hendrik Potgieter Road at the intersection of Gordon Road in the Roodepoort area. Reports from the scene allege that the driver of a minibus taxi had been shot a few times. He was in a critical …Read More »
Two arrests made and two vehicles recovered in Kwazakele
On the 14 November 2017, two stolen vehicles were recovered and two arrests were made. SAPS are appealing to vehicle owners to be vigilant during the festive season as criminals are stepping up their efforts to steal and hijack vehicles in the Nelson Mandela Metro. To effectively police these crimes, …Read More »
Trump Jr releases private WikiLeaks messages
Donald Trump's son has released private Twitter messages he exchanged with WikiLeaks in the run-up to the US election. Donald Trump Jr's response came after they were leaked to The Atlantic website. The Twitter direct messages began in September 2016 and ran through to July this year. The vast majority …Read More »
Elephant tramples safari tourists to death
Two tourists have been trampled to death by an elephant after they got too close to the animal while taking pictures. Police in Zambia said the holidaymakers were killed on Saturday while on safari. "A lady from Belgium aged 57 and a 64-year-old man from the Netherlands were killed as …Read More »
Allegedly Drunk Woman Crashes Vehicle outside schools in Verulam
A 42 year old drunk driver knocked into a vehicle outside two schools on Robin Street in Dawncrest – Verulam. Members of Reaction Unit South Africa were called to the scene by onlookers who witnessed the incident. Upon arrival it was established that a Toyota Corolla knocked into a stationary …Read More »


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CRISPR opens up new genetic engineering potentialpost by Jordan · 2013-11-19T00:56:42.202Z · score: 5 (8 votes) · LW · GW · Legacy · 10 comments
I've been hearing around the news about a new genetic engineering method called CRISPR. The method can purportedly edit any gene in a human genome (or other animal or bacterium genome) with very high accuracy. The new method may remove the risks associated with gene therapy, which can introduce undesired mutations by inserting genes into the middle of an existing gene sequence.
Here's a report:
Thoughts? There is already discussion about the use of CRISPR with IVF (in-vitro fertilization) for the purposes of germ-line engineering, but even without this the method may prove very efficacious for gene therapy on non-germ-line cells. What are the ramifications for human engineering? For germ-line intelligence enhancement?
10 comments
Comments sorted by top scores.
The lab next door to mine uses this system out the wazoo in mammalian tissue culture and someone in my lab is thinking of using a modified version of it in yeast.
Step #1 - hold your horses. Generally good advice in most biological circumstances.
This system when unmodified and vanilla is a great way to make a few germline modifications more efficiently than the usual methods. It is made from elements appropriated from a bacterial antiviral defense system. It consists of two segments, the Cas9 protein and guide RNAs. Cas9 is a nuclease, a DNA cutting enzyme, that requires a GGG triplet to exist directly next to its cut site (nobody's modded that that I've seen so far, I don't know enough about its structure to know if thats possible). The rest of its targeting is mediated by the guide RNA - a small 100ish base pair RNA that consists of a constant hairpin structure that latches into Cas9 and a 20 base-pair segment that you can modify to contain any sequence. With that 20 base pair sequence adjacent to the GGG cut-site, you can target the nuclease activity to anywhere in a large genome with pretty good specificity, about one in trillions of random base pairs (ignoring things like repetitive sequence which is all over the place in actual genomes).
The point for heritable genetic modification being that when you create a DNA lesion like this, the DNA repair mechanisms kick in and try to repair the chromosome off of any similar DNA in the cell (usually the other copy of the chromosome) via homologous recombination. A paper on zebrafish genetic modification I've seen with this system microinjects into eggs RNA coding for the CAS9 protein, guide RNAs, and DNA containing the transgene and chunks of homologous sequence bracketing it so that the genomic DNA just keeps getting cut until it repairs off the introduced DNA. They got mutagenesis efficiency between 75% and 99% with this method, a good deal higher than usual for zebrafish microinjections. I know it's been done in mice but I don't know how efficiently, although these days the main way you transform mouse germline DNA has been doing low-efficiency transformation and selection of embryonic stem cells in culture followed by 2 generations of mucking around making chimeric embryos from those stem cells and breeding the resulting animals so this definitely saves time if it works well. People are also using it along with the usual methods of getting nucleic acids into cultured cells to produce stable changes to such cultured cells at high efficiency and specificity - most introduction of DNA into tissue culture is either temporary with the DNA never making it into chromosomes and going away before too long, or done via retroviruses and thus is kind of random in terms of where and how frequently it inserts.
Course, any time you cut the DNA like this you have a reasonable subset of cells not actually repair off a template but just nonspecifically stitch any recently-cut DNA (not necessarily from the artificial cut site, DNA is breaking and repairing everywhere all the time) together via non-homologous end joining. I don't know how frequently this happens with this protocol and how frequently when it does happen it leads to something problematic. I would imagine that this would become more of an issue any time you are cutting at multiple sites at once with multiple guide RNAs (which you can do with this system) and care about getting the same number of outputs you got out as inputs you put in without lots of selection of successes from the failures. There's also apparently detectable levels of off-target effects, where a few base pairs difference between the guide RNA sequence and the DNA sequence still allows cutting at similar but not identical sites.
In short people are excited because of its sequence specificity and ability to target DNA changes via DNA repair in a single generation as opposed to multiple, it's cool, and works pretty efficiently as opposed to methods that need lots of selection. It's an incremental improvement, even if it is a pretty nice and big increment.
I have a hard time understanding how you could use this for somatic gene therapy with much more success than has already been done with retroviruses. No matter how you slice it, if you want to do gene therapy in a multicellular creature you STILL need to get a package of nucleic acids into a cell which is not easy at all in a living organism as opposed to a monolayer of cells in a controlled environment, or a population of microbes that you can just select the successes from and discard the more numerous failures. Perhaps it's a way to make the cells you do manage to modify less likely to turn all cancerous, but it doesn't solve the problem of actually getting the nucleic acids INTO them.
To me, work going on in which people are mutating Cas9 to kill its DNA-cutting activity and modifying it to use as a scaffold for programmable transcription factors/repressors for artificial regulatory systems is rather more interesting. Using these systems you can potentially arbitrarily target any gene and mess with its expression once you get the required bits into the genome. A major boon for research and artificial genetic systems. Cutting DNA in vivo can be a messy proposition compared to regulating it sometimes even if the artificial not-tuned-by-evolution regulation is at times low-precision.
Cutting DNA in vivo can be a messy proposition compared to regulating it sometimes even if the artificial not-tuned-by-evolution regulation is at times low-precision.
Agreed. large scale editing of the genome is unacceptably risky. I imagine that biological transhumanism, if we bother before uploading, would be more likely to something like a HAC (human artificial chromosome). There are plenty of steps in the network above to interfere with, we don't need to incur the risk of malignancy or cell damage that would result from large scale editing of the genome. Even a method that was 99% accurate would be unacceptable.
I know it's been done in mice but I don't know how efficiently, although these days the main way you transform mouse germline DNA has been doing low-efficiency transformation and selection of embryonic stem cells in culture followed by 2 generations of mucking around making chimeric embryos from those stem cells and breeding the resulting animals so this definitely saves time if it works well.
If you can do it in one generation that also means that you can start doing it in humans embryos.
For legal reasons probably not in the West, but I can imagine that the Chinese are willing.
Awesome, thanks for the detailed response. After reading about CRISPR's natural role in bacteria I was curious if it would have targeting limitations. It sounds like it does (needs GGG triplet), but that in practice this isn't a big deal.
You still need to get this system into a cell -- that's an issue as always, I agree -- but the reduced chance of unwanted mutation seems like a big step forward over retroviruses.
Thanks again for the great write up!
Could it be used to eliminate genetic load and create super-humans?
I get the impression that Crispr would be possibly faster for that than the gamete selection option, but slower than the 'find modal genome digitally, print it out to DNA' option. I imagine its primary usefulness is eliminating known genetic diseases / introducing known good genes.
I get the impression that Crispr would be possibly faster for that than the gamete selection option, but slower than the 'find modal genome digitally, print it out to DNA' option.
The price of synthesing DNA is at the moment at ~1 dollar/basepair. Given the size of a human genome it's to expensive to find the modal genome digitally and print it out the DNA.
I'm very curious how many genes can be targeted usefully. One paper succeeded in targeting 5 simultaneously in a mouse model. Given the purported accuracy that is already game changing, but if we can do 100 or 200 then maybe we can do more than merely eliminate some simple single gene disorders.
100 is much smaller than genetic load.


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Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 1
physical productivity Related Abstracts
1 Productivity, Labour Flexibility, and Migrant Workers in Hotels: An Establishment and Departmental Level Analysis
Authors: Natina Yaduma, Allan Williams, Sangwon Park, Andrew Lockwood
Abstract:This paper analyses flexible working, and the employment of migrants, as determinants of productivity in hotels. Controlling for the institutional environment, by focussing on a single firm, it analyses data on actual hours worked and outputs, on a weekly basis, over an 8 year period. The unusually disaggregated data allows the paper to examine not only inter-establishment, but also intra-establishment (departmental) variations in productivity, and to compare financial versus physical measures. The findings emphasise the complexity of productivity findings, sometimes contrasting evidence for establishments versus departments, and the positive but scale and measure-specific contributions of both the employment of migrants and flexible working, especially the utilisation of zero hours contracts.
Keywords: labour productivity, physical productivity, financial productivity, numerical flexibility, functional flexibility, migrant employment, cero-contract employmentProcedia PDF Downloads 230


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