DAILY BRIEFING: Plan to privatise Land Registry scrapped by Government after it was met by barrage of protest
A plan to privatise the Land Registry has been scrapped by the Government after it was met by a barrage of protest.
The plan has been left off the Neighbourhood Planning and Infrastructure Bill going before Parliament last night.
Change of heart: The plan has been left off the Neighbourhood Planning and Infrastructure Bill
The proposal was part of a programme of possible sell-offs under former Chancellor George Osborne, aimed at raising £5bn by 2020.
Struggling supermarket Asda saw underlying earnings fall by 1.5 per cent in 2015 after suffering record falls in sales.
In accounts filed for last year, the chain said revenues fell 3.7 per cent to £22.4bn while profits edged 3.3 per cent higher to £1.05bn. It suffered a 4.7 per cent drop in sales in 2015.
Construction equipment firm Ashtead is benefiting from the post-Brexit vote collapse in the value of sterling, which helped drive first quarter revenue up 12 per cent at £661m and profits up 4 per cent at £184m.
The company, which does the bulk of its business in the US said its end markets were strong. It expected full-year results to be ahead of expectations.
One of Britain’s biggest investors has urged governments to loosen the purse strings – arguing eurozone austerity in particular had made the recession worse.
Legal & General Investment Management said a public spending boost could revive growth and push up vitally-important inflation.
An unexpectedly calm summer has hit business at trading firm CMC Markets.
The firm said reduced volatility meant profits for the six months to September 30 would be lower than last year. New client numbers were up but ‘in line with many competitors, the value of client trades continues to be lower than the prior year’.
Shares fell 12.3 per cent, or 34.1p to 243p.
Microsoft has opened three new data centres – which hold information for computers – in the UK, and already has the Ministry of Defence on board as a customer.
The new centres – in Cardiff, Durham and London – will allow British customers from the legal, banking, public and utility sectors to run operations over the internet.
Bank chiefs met new Chancellor Philip Hammond for crunch talks on leaving the EU yesterday. The group – which included Barclays chairman John McFarlane and Douglas Flint, chairman of HSBC – discussed what the City wanted from Brexit negotiations.
Computing giant Dell has bought EMC Corp in the largest tech merger in history. The £45bn deal will see EMC renamed Dell Technologies.
Most watched Money videos
- Citroen unveil the My Ami Cargo, a dinky electric van
- Land Rover unveil prototype hydrogen powered Defender
- Audi showcases electric A6 e-tron concept with 'cinematic' headlights
- What the frunk!? Ford Lightning features a trunk on the front
- Take a look at £3.3 million Bugatti Chiron Super Sport hypercar
- Mercedes' new all-electric EQB is a seven-seater compact SUV
- Rare 1960 crashed Jaguar sells at auction for £90,000
- The all-new 7-seater SUV Kia Sorento with a panoramic sunroof
- Highway England catch dangerous drivers using unmarked supercabs
- Are unloved bank shares primed to bounce back?
- Prince William and Kate's Range Rover sells for £50,625
- Ineos Grenadier 4X4 is tested for sturdiness on the toughest roads


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Liên kết: Nước cân bằng Trắng Da White Seed Brightening Toner The Face Shop (160ml)


It’s imperative to use this quieter period to land key tech improvements.
The Brightstar Industry VLOG with guests Adrian Moloney, Steve Cox and David Whittaker. Hosted by Brightstar CEO Rob Jupp
Chancellor Sunak’s stamp duty holiday is a good thing, but there are other market challenges this does not address.
What starts off with seemingly good intentions can drop into the hands of a Dutch ‘hip hop’ duo and end up being voted Worst Video of 1986.
What role will technology have beyond the current lockdown?
We constantly asked ourselves during the pandemic was “How would I want to be treated?”
However, one thing that continually frustrates me is that whilst we have finally seen some improvements in sales of income protection cover, particularly the budget version, the same cannot be said for family income benefit.
Q&A between Adrian Moloney, group sales director at OneSavings Bank and Greg Cunnington, director of lending relationships and new homes, Alexander Hall
There may be a period where some of the elements of the lockdown months are genuinely missed.
It might be deeply unpopular but perhaps now is the time to cut the 3% surcharge that additional homeowners have to pay.


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It's a bird! It's a plane! It's SUPERGIRL! The superhero I always admired and wanted to be when I was a little girl. I had the privilege to work on the Main Title for the TV Series. It was an awesome experience.
Company: The CW
AGENCY: PIC Agency
Direction: Pamela Green
Designers: Sianey Montes de Oca, Martin Surya
Animators: Sianey Montes de Oca, Jeremy Bonham

domain: artistic


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Wow! Thatís an interesting pic! The best Model T water pump ever made ! Running off the crankshaft? Requires a water source - tanker truck or stock pond. Interesting Ďnon Fordí? rear window giving more visibility.
On the first picture is that some kind of small cow bell hanging off the front axle?
Saving basements since 1919....lol
I wonder if you could hand crank through the water pump, and pull the hand crank out or was it just electric start?
Probíly electric. No cowl lamps....
George -- the photos above do not have the cowl light brackets so yes, they were electric start from the factory (unless the windshield was replaced).
But page 129 of Robert C. Kreipke's book "The Model T" shows a 1919-1922 (straight windshield and wishbone below the axle) roadster with the cowl light brackets. So if the windshield brackets were original to the car -- it would have been a non-starter car.
In the photo in Kreipke's book, it appears to have an extension that sticks out past the pump where a removable hand crank may (or may not) have been available to start the engine? Reminds me of the later 1928-31 Model A Fords that have the removable hand crank. But there was not enough detail in the photo and no explanation of how you would hand crank it. But it looks possible to me.
In the first photo of this thread note that the lower hole lines up with the crankshaft. I think that is where a removable crank would be inserted.
Hap l9l5 cut off

domain: hobby


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Mumbai: With non-bank financial companies (NBFCs) and housing finance companies becoming risk averse towards lending to real-estate sector, developers are likely to face liquidity crisis, says a report.
Majority of the developers with weak balance sheet depend on the parallel banking sector for funds. These players are likely to be affected the most if situation persists.
“Liquidity risk is increasing for the country’s real- estate developers, as non-bank financial institutions (NBFIs; including housing finance companies) are shying away from lending to the sector,” global rating agency Fitch Ratings said in a report.
Defaults by two NBFIs – Infrastructure Leasing & Financial Services (IL&FS) in September 2018 and Dewan Housing
Finance Corporation (DHFL) in June 2019 – have contributed to the sector-wide liquidity squeeze, as investors have become more risk averse.
NBFCs have disproportionately increased their share of real-estate sector credit in the previous few years, owing to heightened risk aversion by banks.
Banks’ low appetite for lending to real-estate developers is due to the usually high risk weights attached to such loans.
The report said NBFCs are also shying away from refinancing maturing debt of even large, proven developers to limit concentration risk to the sector, which is pushing developers towards alternative funding channels, such as private equity.
“The availability of such funding could be more limited than the value of maturing debt and may only be available to established developers with sufficient unpledged assets,” it said adding that it would also come at a higher cost.
The availability of unencumbered assets among large developers may be of limited use, as NBFCs are looking to shed their already-high exposure to the sector, especially to large borrowers, the agency said.
Developers that are focused on high-end projects may face higher risk, as sales of such projects have slowed in the last two years.
It said the government has announced measures to improve NBFC-sector liquidity, but their efficacy remains to be seen.
“We believe the government’s July 2019 announcement to provide a first-loss guarantee of 10 per cent on securitized assets issued by NBFCs to banks could ease funding pressure for NBFCs in the short term,” the report said.
However, the provision refers only to financially sound issuers and there is a lack of clarity about the duration of the guarantee and the definition of what comprises a ‘financially sound’ entity, it said.
The report said substantial bank recapitalisation to increase lending capacity could benefit NBFCs as well as real-estate developers, subject to the banks’ risk appetite; although a structural improvement in NBFC asset books would take time.
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domain: finance


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ST. LOUIS (Oct. 15, 2009)—Solutia Inc. said it plans to reopen its Crystex insoluble sulfur plant in Monongahela, Pa., by early November because demand for the product has improved significantly since the first quarter of the year.
Solutia idled the Flexsys America facility in June after a dramatic drop in product demand. The insoluble sulfur prevents sulfur migration and is used in radial tire manufacturing.
“We look forward to welcoming back our employees and serving our customers,” said Greta Senn, vice president of Crystex. “Restarting the plant will continue to ensure a steady and reliable supply of insoluble sulfur to our tire customers worldwide.”

domain: economics


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Have sales flatlined? Staring at the charts isn't going to make it better.
Professional cartoonist Mark Anderson, owner of Andertoons, brings readers a new business cartoon each week. He also adds the “backstory” about how he came up with the creative idea behind the cartoon.
For a selection of cartoons you are free to download for use in blogs, presentations and newsletters, go to our Business Cartoons Gallery.


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Hiya crafty peeps! Happy Monday- hope everyone's week is off to a good start :) I'm just popping in to share that there's a new featured digi over at Some Odd Girl starting today which means you can pick this cutie- Indian Tia- up for 35% off...now that's a steal! I colored her up with my Copics and then paired her with some papers and embellishments from Doodlebug Designs- I just love their fun graphic style. I hope you like my card- make sure to stop by the SOG blog to check out some other fun projects showcasing this cute image...and don't forget to stop by and pick her up for yourself while she's on sale :) Thanks for stopping by!
Skin- E000, E00, E11, E13, E17, R30, R32, BV34
Hair- N1, N3, N5, N7, N9, 100
Clothes- E81, E84, E87, E89
Headpiece- Y21, Y23, Y26, Y32, Y35, YR27, BG70, BG72, BG75, BG78
Supplies: DP- Doodlebug Designs; Banner Sticker- Doodlebug Designs; Bling- Recollections; Washi- my stash


Microturbine Propulsion for UAVs
- Magazine Article
Seventy years ago, military aviation moved from reciprocating engines to vastly more reliable turbo jets and turboprops. Shortly after, the commercial air transport industry followed suit, enabling modern air transport. Today, virtually all large aircraft rely on turbine propulsion, yet small aircraft, both manned and unmanned, have not exploited the advantages of turbines for propulsion.
While UAVs have become integral for both commercial and military aerial missions, the continued use of reciprocating engines has limited the UAV market's ability to reach its true growth potential. The industry has been slow to innovate and develop turbine propulsion systems for small aircraft because it is far more difficult to design and produce high performance small turbines than large ones.


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Researchers at Birmingham University have unravelled important biological "clues" that could lead to the development of vaccines against cervical cancer.
A study, carried out by Cancer Research UK scientists, examined how the body's immune system responds to the human papilloma virus (HPV) - a major cause of the disease.
Scientists studied 41 women, each at different stages of progression from infection to cervical cancer and measured their immune system's response to various proteins. It revealed patients who are able to clear the infection have a different immune response to those in which the virus leads to cervical cancer.
Their findings will enable scientists narrow down which proteins potential vaccines should target to trigger the response that clears HPV infection - and stops the cancer from developing.
Cervical cancer is the second most common female cancer worldwide, with more than half a million new cases are diagnosed every year and causing more than 274,000 deaths.
Dr Jane Steele, of the university's Institute for Cancer Studies, said: "We've now found the patients with precancerous lesions are most likely to develop cervical cancer showed less immune activity from a population of immune cells called helper T cells than the women who were at much less risk.
"This could mean that helper T cells, which play a central role in the immune response, are critical in disease progression."
There are more than 70 different strains of HPV but researchers focused on HPV 16 which is present in up to 70 per cent of cervical cancers.

domain: medical


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DHS border security plan contains millions for technology
Homeland Security Secretary Janet Napolitano announced a plan today to spend more than $100 million for technology to help stop the growing drug-related violence near the border between the United States and Mexico.
DHS' effort is part of a larger plan the Obama administration announced today to deal with the problem. The interagency effort will be coordinated through the National Security and Homeland Security councils, the administration said.
Drug–related violence in Mexico has escalated, creating fears that it could spill over into the United States. Authorities have also become focused on stopping the flow of weapons from the U.S. to Mexico.
DHS said the program would cost as much as $184 million, with technology components totaling more than $100 million.
The technology aspects of the plan include:
- Enhancing the deployment of biometric identification equipment at locations with the highest risk for violence committed by criminals who are not U.S. citizens.
- Screening 100 percent of southbound rail traffic by using nonintrusive inspection equipment.
- Moving additional mobile X-ray units to the border to detect anomalies in passenger vehicles.
- Deploying upgraded license plate readers to identify suspected smugglers’ vehicles.
Department officials also said the program would focus on better coordination
with state, local and Mexican law enforcement authorities.
Ben Bain is a reporter for Federal Computer Week.

domain: politics


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1513 East Bert Kouns
Visa, MasterCard, American Express, Discover, Cash
El Chico is located at 1513 E Bert Kouns Industrial Loop, Shreveport, LA. This location is in the Springlake, University Terrace neighborhood. This business specializes in Mexican Restaurants.
by merchantcircle on June 10, 2015 from
Information from the business
El Chico in Shreveport on Bert Kouns is part of a fine tradition of serving the best Mexican food. Made with only the best ingrediants, you can savor Mexican food classic or new favorites of today.
by yahoolocal on August 10, 2015 from
Privacy & Terms

domain: food


Football star runs to the aid of sick ex-teammate
A MIDDLESBROUGH FC coach is using his daily exercise to run 100 kilometres around his Cockfield home in aid of a former teammate struck by a debilitating illness.
Tony McMahon was so moved by former Bradford City player Stephen Darby’s fight against motor neurone disease (MND) that he has roped in his entire family, including one-year-old daughter, into his challenge.
Within days of starting the fundraising effort, the footballer had already raised more than £6,000 for the Darby Rimmer MND Foundation.
The foundation launched a 100K in May challenge to raise cash for research into the illness, which affects the nerves in the brain and spinal cord and can leave sufferers unable to do basic things like wash, dress or feed themselves.
Mr McMahon said: “The response has been unbelievable. When I set it up, I had no idea it would take off the way it has. Some big names I have played with have put it on their social media and the sponsors just keep coming in.”
Mr McMahon is joined by his 11-year old son, Luca, in the challenge who aims to complete it through a mix of running and cycling.
Meanwhile his wife, Lindsey, is walking the challenge with six-year-old daughter, Myla, while pushing one-year-old, Luna, in a buggy. Of the 100K in May challenge, Mr McMahon said: “It is brilliant the amount of people doing it. It is inspirational.
“He [Stephen Darby] is an amazing fella – everyone who played with him will tell you he is the nicest guy, a real pro.
“As a captain everyone loved him; the fans loved him. I spoke to him this morning – it was the same banter as we always had.
“I can’t imagine what he and his family are going through.”
Elsewhere, Mr McMahon is using his contacts to help others in their fundraising efforts.
Among those he has helped is nine-year-old footballer Alfie Metcalfe, from Evenwood, who was surprised with a personal video message from Manchester United captain Harry Maguire offering words of encouragement for a cycle ride he did for a good cause.
To support Mr McMahon’s campaign visit justgiving.com


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News from Alberta, Canada.
Insurance costs may drive the pay for play warehouses out of business.
Red Deer’s indoor trampoline park has closed its doors.
… owners of Jump 360 say insurance rates “quadruple what we were paying” and higher employee wages have made it too costly for them to continue operating. …
Jump 360 had been open since May 2016 …
I’d love to see those dangerous parks close.
The downside for Alberta clubs with qualified, certified Trampoline coaches is a new limitation which states that only competitive gymnasts and trampolinists are insured to use tramps, tumbling trampolines, mini-trampolines, etc.
Recreational kids, birthday party kids, Parkour and drop-in participants are not covered for negligence. … I feel this goes too far. Alberta clubs should look for a new insurance agency.

domain: news


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The social media which was founded with the primary objective of networking with the people and making this world a smaller place has been used by cyber bullies to make fun of people with regards to their appearance or their disabilities. Many a time these derogatory remarks made by the Cyberbullies have had a deep impact on the targeted person which has also led to that person taking the extreme step of committing suicide. Though there have been thousands of instances where the choice of words by cyber bullies have had a negative impact on the people, they just refuse to stop making comments on people.
This story is one another example of how cyber bullies targeted a particular lady to insult her due to the long teeth that she has. But the cyber bullies did not understand that if there are people who want to spread negativity wherever they go, there are also people who want to change this world for better. This amazing story explains how the targeted person had the last laugh as she got operated without having to spend even a penny from her pocket.
This incident happened in May 2017 when a man got down on knees in an open area of St. Louis to express his feelings for his lady love. The adorable moment was captured by people around and also his friends to make it more special for them. The picture was later uploaded on Facebook to share the happy moment with the world. Jessica, who was standing behind the couple, clicking photographs to make it memorable for them was made the target by the cyber bullies. They went on to crop Jessica from the picture and wrote a caption insulting her.
Jessica who works as a hair stylist though had been mocked by others for her appearance did not know people would go this far in a picture which actually was all about spreading love and happiness. People started creating memes on her and mocked her in every possible way. Jessica even apologized to her newly engaged friends for the negative comments they received on their special photo. Jessica who was a hearing impaired as a child had to go through several surgeries on her ears. Though she wanted to undergo surgery to change the appearance of her teeth, she could not undergo surgery as her family could not afford the expenses of another surgery.
While a few people used social media to spread negativity, one of her friends used the same social media to start a GoFundMe page to help her undergo surgery. A local newspaper picked up this story and published it on their paper. As people got to know everything about Jessica, many of them came forward to help her; among them, one dentist, in particular, came forward to give her a brand new look – completely free of cost.
Watch the video below to see how the mocking helped Jessica get a brand new look that too free of charge. We always see the negative side of the social media but fail to witness the positive side of it. Do share this story of happy ending with your friends on Facebook to make them understand how social media can be used to spread love and happiness and also as a tool to help others.


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DoorStepAgents present 5 great reasons to own the stunning ABI Horizon 36x12 3 bed...
1) It is sited on the beautiful 5 star family owned Hornsea Leisure Park on the East Yorkshire coast.
2) We have the best value for money site fees on the entire coast, just £2736 for a full 12 month season!
3) We have some lovely spacious pitches available with some awesome views out to sea.
4) There will be no site fees to pay until 2018.
5) Finance packages can be arranged from just a 10% deposit with monthly payments from just £297 per month.
Hornsea Leisure Park situated on the East Yorkshire coast is the perfect place for relaxing family breaks- situated close by to miles and miles of uninterrupted sandy beach and the lovely seaside town of Hornsea is just a short stroll away. The stunning 5 star park is the perfect place to spend quality time together as a family doing the things that everyone loves during those much appreciated leisurely breaks. If you have any thoughts, questions or concerns on any of the above or would like to arrange a visit to the park to have a look round some of the holiday homes we have for sale then please just get in touch.
Deposit - £1,900
Monthly payment - £297 p/m*
Cash price - £18,995
*Finance available subject to status. Terms and conditions apply. Price quoted is over a 72 month period. 7.9% APR representative. Total amount payable £23,284.


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National Youth Orchestra of the USA with David Robertson, conductor and Gil Shaham, violin
Carnegie Hall’s Weill Music Institute brings together 120 of the brightest young musicians, ages 16-19, from across the country to form the National Youth Orchestra of the United State of America (NYO-USA). Following a comprehensive audition process and a two-week training residency at Purchase College, State University of New York, with faculty made up of principal players from top American orchestras, these remarkable teenagers embark on a tour to some of the great music capitals of the world, serving as dynamic musical ambassadors.
The 2014 orchestra hails from 33 states plus Washington, D.C. and Puerto Rico and features 26 returning musicians from the inaugural 2013 NYO-USA. They will travel to New York in early July to begin their training with finest players and section leaders from America’s greatest professional orchestras, including the Chicago Symphony Orchestra, Pittsburgh Symphony Orchestra, New York Philharmonic and National Symphony Orchestra.
Following the training residency, the orchestra will be led by dynamic American conductor David Robertson and joined by virtuoso violinist Gil Shaham as soloist on an eight-city, coast-to-coast US tour, introducing concertgoers across the country to the extraordinary music-making of their nation’s national youth orchestra.
About David Robertson: Conductor
A consummate musician, masterful programmer and dynamic presence, David Robertson has established himself as one of today's most sought-after American conductors. In past seasons, he has appeared nationally with the New York and Los Angeles Philharmonics, Boston and Chicago Symphonies and Philadelphia and Cleveland Orchestras, and internationally with the Berliner Philharmoniker, Staatskapelle Dresden, BBC Symphony Orchestra and the Hong Kong Philharmonic. In the 2013–2014 season, in addition to launching his first year at the helm of the Sydney Symphony Orchestra, he conducts the US premiere of Nico Muhly's Two Boys and appears with orchestras including the Royal Concertgebouw Orchestra, The Cleveland Orchestra and the Cincinnati Symphony. With over 50 operas in his repertoire, Robertson has appeared at many of the world's most prestigious opera houses including The Metropolitan Opera, La Scala, Opéra de Lyon, Théâtre du Châtelet and San Francisco Opera.
About Gil Shaham: Soloist
Gil Shaham is one of the foremost violinists of our time, whose combination of flawless technique with inimitable warmth has solidified his legacy as an American master. Highlights of his 2013–2014 season include Korngold’s Violin Concerto with the Vienna Philharmonic Orchestra at Carnegie Hall, The Cleveland Orchestra and the Orchestre de Paris; a continuation of his exploration of the “Concertos of the 1930s” with the San Francisco Symphony, Los Angeles Philharmonic and on tour with the Bavarian Radio Symphony; and a recital tour featuring Bach’s Sonatas and Partitas for solo violin. Shaham has more than two dozen concerto and solo CDs to his name, including bestsellers that have appeared on record charts in the US and abroad, winning him multiple Grammy awards, a Grand Prix du Disque, Diapason d’Or and Gramophone Editor’s Choice. Shaham was awarded an Avery Fisher Career Grant in 1990 and in 2008 he received the coveted Avery Fisher Award. He lives in New York City with his wife, violinist Adele Anthony and their three children.


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CNS Canada — Canada’s pulse crop trade hasn’t stopped, even though its biggest customer, India, isn’t taking large amounts anymore. Instead, buyers are finding themselves having to take business one day at a time and become a bit more creative.
“I think everyone is in the same boat; it’s not that the market has stopped. Every day you get up, you get something done, you don’t exactly know what that’s going to be,” said David Newman of Commodious Trading near Victoria.
Before India placed import restrictions on pulse crops last year, buyers were contracting sales months ahead of time; now, Newman said, he’s booking by the month. He is having to think more in the moment in terms of business and is just trying to keep his plant running.
Commodious, which exports lentils, peas and chickpeas as well as canary seed and flax, operates a processing facility at Weyburn, Sask.
“What we’ve done to keep our plant running is basically the margins for the processing and trading are in-house. So we’re staying busy but we’re running at cost,” he said, adding most of his counterparts are operating similarly. Some have multiple plants and are driving product to plants further away just to keep them running.
With India mostly out of the picture, Newman said sales are going all over the place, with no one big customer. Canadian pulses are going to destinations such as northern Africa, South America and Mexico, according to Newman.
“I never really know where it’s going to be from day-to-day. I think that’s the hardest part, people are finding little niches here and there (to sell to),” he said.
The market has changed, according to Newman, and it isn’t a regular commodity market anymore. The factors that usually drive a commodity market, such as weather and trade, aren’t driving sales anymore. There isn’t any way to forward-plan and sales happen as they come.
Wet and snowy weather on the Prairies isn’t affecting the pulse market like other grain markets, according to Newman. He has found most of the pulse crops are harvested and some producers are being forced to sell those pulses earlier than they would like, because they need the cash while they wait to harvest their other crops.
“If anything I think it’s had a bit of a negative impact on the pulses,” Newman said.
If farmers can do so, he said, they should be waiting — maybe not holding onto their pulse crops for a long time, but instead paying attention to prices and selling when they see a price which will work for them.
“I don’t think everybody rushing to the exits helps anyone. But I don’t also feel that holding on makes anything a lot better. So you pick your moment, you find something that works within a cent or a half cent (and sell),” Newman said.
— Ashley Robinson writes for Commodity News Service Canada, a Glacier FarmMedia company specializing in grain and commodity market reporting.


The OPERA neutrino detector in the underground Gran Sasso Laboratory (LNGS) has been designed to perform the first detection of neutrino oscillations in direct appearance mode through the study of the νμ →ντ channel. The hybrid apparatus consists of an emulsion/lead target complemented by electronic detectors and it is placed in the high energy long-baseline CERN to LNGS beam (CNGS) 730 km away from the neutrino source. Runs with CNGS neutrinos were successfully carried out in 2008 and 2009. After a brief description of the beam, the experimental setup and the procedures used for the analysis of the neutrino events, we describe the topology and kinematics of a first candidate ντ charged-current event satisfying the kinematical selection criteria. The background calculations and their cross-check are explained in detail and the significance of the event is assessed.


A witness who generally supports of the goals of the Patient Protection and Affordable Care Act of 2010 (PPACA) argued today in Washington that most employers that now offer health benefits will continue to do so once PPACA takes full effect.
Linda Blumberg, a health policy specialist at the Urban Institute, rejected the arguments of PPACA critics who contend that the law will burden employers and undermine employer-sponsored health benefits.
Blumberg, who refers to the law as the ACA, said at a hearing on PPACA and jobs organized by the House Energy & Commerce Committee that the law could give many employers some benefits cost relief, by slowing the growth in the underlying health care costs.
“Except for a cost increase to mid-sized employers, due largely to enrollment increases, the ACA benefits rather than burdens small employers who want to provide health insurance,” Blumberg said, according to a written version of her testimony posted by the committee.
Urban Institute simulations show that employer premium spending per person insured could hold steady at about $3,650, Blumberg said.
Large employers could end up spending about 4.3 percent more in total, but only because the number of people they cover is likely to increase, Blumberg said.
At small employers, new PPACA health insurance tax credits should help reduce per-person costs by 7.3 percent at employers that choose to offer coverage, and by 1.4 percent all small employers, Blumberg said.
Roughly 5 percent of the employers with 101 to 1,000 employers could end up paying the PPACA penalties to be imposed on “large employers” that fail to provide health benefits, and penalty payments and expanded enrollment could increase health benefits a total of about 9.5 percent at those midsize employers, Blumberg said.
But, even if some employers’ health benefits costs increase as a result of PPACA, Urban Institute analysts believe that the key to the effect of PPACA on employer plans will be whether most workers’ employers think the employees prefer traditional PPACA plans to the available alternatives created by PPACA, Blumberg said.
PPACA calls for health insurers to sell all new major medical coverage on a guaranteed-issue basis and will tightly restrict insurers’ ability to use personal information other than age and location when setting rates.
“Most workers’ firms will be dominated by workers who will receive better benefits and, through the tax system, better subsidies through employer-provided coverage than through newly created insurance exchanges,” Blumberg said.
Even if some workers would be better off getting individual coverage through the PPACA exchange system or through the individual health insurance market outside of the exchange system, in most cases, “a competitive labor market will not allow employers to save money by dropping employer-sponsored coverage,” Blumberg said.
“Employers pay workers a combination of wages and benefits at a level equal to the employee’s value to the firm,” Blumberg said. “The market will keep compensation at that level, whether employers pay a worker’s value only in wages or in some combination of wages and benefits. If, in total, an employer compensates workers less than their value, that employer will lose those workers to competitors who offer them more. If, alternatively, an employer pays workers more than their value, the firm will lose money. That means, plain and simple, that in a competitive market, employers cannot ‘come out ahead’ by dropping coverage and at the same time reducing compensation.”
PPACA could even help employer plans by, for example, changing Medicare provider reimbursement rules in ways that make hospitals and other providers more efficient, Blumberg said.
PPACA provisions requiring Medicare to experiment with new approaches to paying providers, such as setting up accountable care organizations, also could lead to overall health system changes that will help hold down employer plan costs, Blumberg said.
Diana Furchtgott-Roth, a health policy specialist at the Manhattan Institute, testified that she believes PPACA will hold down job growth, by increasing costs per employee by as much as 4 percent, and by rewarding employers that convert full-time jobs into part-time jobs with much lower labor costs.
- Employer-sponsored health insurance hits new low
- Some Obama Programs Embellished by Democrats
- EBRI: Part-Time Status Shuts More Out of Coverage


Happy Friday! We’re here with the Weekly Download to help you ease into the weekend. This week, we’ve got redesigns, updates to help creators, and “new energy.” (We’ll get there, we promise.)
Twitter Launches “Twitter Create”
Apart from dealing with Elon Musk’s will-he-or-won’t-he dithering about buying the platform, Twitter has been doing a lot of testing. So far it has tested a new “Explore” page, tweet labels, and multi-attachments on tweets.
Now it has launched “Twitter Create,” a mini-site for creators to maximize their presence on the platform. The mini-site has insights, design examples, and monetization and engagement tips for how creators can really highlight and strengthen their presence.
If you work as a creator, writer, or podcaster in music, gaming, news, nonprofits, or sports, this may be a site for you. If you’re a marketer, access to insights and other tips can only help your presence, engagement, and reach on Twitter.
All of these can be found on three tabs: Industries, Goals, and Products.
Instagram Aims for “New Energy” with Brand Refresh
Does anyone remember when Instagram changed from the old to the current logo in 2016? The platform has done it again, updating the overall brand look. The new version of the logo now features radiant colours, to “make it feel alive.” The company says the update to the logo signals moments of discovery.
In addition to the logo update, the platform also rolled out Instagram Sans, its new typeface, which will be used as part of its brand identity. To keep the brand identity consistent, creators can also use it in their Reels and Stories. The font is available in all languages.
TikTok to Offer Creator Subscription Option
TikTok is coming for other platforms beginning with “T.” (That’s Twitch, for those not familiar with the live-streaming site.) TikTok will soon offer live subscriptions, allowing creators to make recurring revenue from their top fans. Apart from Twitch, other platforms like YouTube offer similar options, such as subscriber-only chats, memberships, custom emojis, and badges.
How the pricing structure will work hasn’t been announced, but if it’s anything like YouTube’s and Twitch’s, the company is expected to take a percentage of a creator’s earnings.
TikTok LIVE Subscriptions went into beta testing yesterday, May 26, with a select group of creators.
Google Introduces Ads for YouTube Shorts
Speaking of YouTube, its Shorts have become very popular, generating 30 billion views per day, which is a lot of eyeballs. So it’s understandable that the platform has been investing in, improving, and testing the Shorts format. One recent update let creators use their own or another creator’s videos as background (credited) for their Shorts.
This week, app and video action campaigns will automatically scale to Shorts. That means advertisers can connect their product feed to their campaigns and make their Shorts shoppable.
That’s great news for marketers and sales.
Plus, advertisers can show new visual shopping ads to U.S. customers on Google search. They will be labeled as ads and placed in designated ad slots through the search results.
Reese Witherspoon is cute, but Lizzo remains the queen. [Note: NSFW]
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MIOX awarded research grant to commercialize onsite generated AOP chemistry
MIOX Corp. has received a Technology Enhancement for Commercial Partnerships (TECP) award from the Small Business Innovation Research (SBIR) program of the National Science Foundation (NSF) in the amount of $100,000. This research grant allows MIOX to move forward in the commercialization of lower cost advanced oxidation process (AOP) technology for groundwater remediation and water reuse applications.
NSF’s TECP program is specifically designed to provide bridge funding when a technology developed under the SBIR program stirs commercial interest. Partnering with global leaders in the microelectronics and aerospace industries, MIOX has identified and started developing applications for an economical AOP technology.
“This award from the NSF allows our project team to move the technology developed under the SBIR program out to a larger commercial arena,” said Dr. Susan Rivera, manager of research and development for MIOX. “MIOX’s AOP technology will be able to solve numerous water treatment challenges at a lower cost per gallon and with less environmental impact.”
The new AOP technology combines MIOX’s core technology of onsite generation of chlorine in a controlled environment with ultraviolet light to produce highly reactive hydroxyl radicals. These radicals are then harnessed to destroy a wide variety of organic contaminants found in water, including hydrocarbon chains, trichloroethylene, endocrine-disrupting compounds, pesticides and pharmaceuticals.
“Onsite generated chlorine-based AOP can be as effective as a traditional AOP at removing organics chemicals but has substantially lower operating expenses for many treatment scenarios,” said Dr. Andrew Boal, senior scientist and project leader for AOP technology development for MIOX.


text:
- freely available
J. Clin. Med. 2014, 3(3), 747-762; doi:10.3390/jcm3030747
Abstract: Prenatal diagnostic testing is a rapidly advancing field. An accurate diagnosis of structural anomalies and additional abnormalities in fetuses with structural anomalies is important to allow “triage” and designation of prognosis. This will allow parents to make an informed decision relating to the pregnancy. This review outlines the current tests used in prenatal diagnosis, focusing particularly on “new technologies” such as exome sequencing. We demonstrate the utility of exome sequencing above that of conventional karyotyping and Chromosomal Microarray (CMA) alone by outlining a recent proof of concept study investigating 30 parent-fetus trios where the fetus is known to have a structural anomaly. This may allow the identification of pathological gene anomalies and consequently improved prognostic profiling, as well as excluding anomalies and distinguishing between de novo and inherited mutations, in order to estimate the recurrence risk in future pregnancies. The potential ethical dilemmas surrounding exome sequencing are also considered, and the future of prenatal genetic diagnosis is discussed.
The incidence of congenital abnormalities in the UK is approximately 2.2% . These are frequently first identified by ultrasound scan during pregnancy. There is a wide range of potential outcomes for fetuses with abnormalities. Some abnormalities, such as isolated cleft lip, can be corrected in early childhood with a surgical procedure, and often has minimal long-term impact on the child . Other abnormalities, such as bilateral renal dysplasia or cerebral malformations, are associated with high morbidity and mortality [3,4]. There is little doubt that a chromosomal anomaly associated with a structural malformation significantly worsens prognosis.
Numerous genetic mutations have been associated with fetal structural abnormalities. These include aneuploidies, copy number variants (CNVs), loss-of-function single nucleotide variants (SNVs) and mis-sense SNVs [5,6,7,8,9]. Knowing the cause of a fetal structural abnormality may help clinicians to make an accurate prognosis regarding the pregnancy, and estimate recurrence risk for any future pregnancies. This helps the families to make informed decisions, including whether to terminate the pregnancy. Despite the importance of a diagnosis, currently only a minority of children affected by a developmental disease receive a genetic diagnosis, to the frustration of families, clinicians and researchers alike .
In this review, we will outline the current approaches used to investigate the genetic cause of prenatal structural abnormalities. We will then describe several studies that have recently used next-generation sequencing (NGS) for this purpose, and we will discuss advantages and disadvantages of this approach. Finally, we will outline some ethical issues that this technology raises, and discuss likely future directions of the prenatal genetic diagnostics field.
2. Current Techniques for Prenatal Genetic Diagnosis
2.1. Sampling Methods
Fetal DNA for genetic testing may be obtained invasively or non-invasively. Invasive methods include amniocentesis, fetal blood sampling and chorionic villus sampling (CVS). They yield cells from which fetal genomic DNA can be extracted. The major disadvantage of invasive sampling is that the risk of miscarriage increases by around 1% following a procedure [11,12,13,14]. Alternatively, fragmented cell-free fetal DNA (cffDNA) can be obtained non-invasively from maternal plasma , but there are presently limitations to its use in prenatal diagnostics.
One invaluable tool for the detection of chromosomal aberrations associated with fetal and congenital abnormalities is karyotyping, where whole chromosomes are stained and examined using a light microscope. In classical cytogenetics, the stains (such as Giemsa (G-) stain) reveal patterns of light and dark bands that are unique to each chromosome. The technique was developed in the late 1960s and early 1970s, and it allowed researchers to distinguish between chromosomes of similar sizes for the first time [16,17]. As conventional full karyotyping provides information on the number and gross appearance of chromosomes, it can be used to detect potentially pathogenic chromosomal aberrations including aneuploidy, deletions, duplications, and unbalanced translocations. Giemsa (G) banding has a highest resolution of 3–10 Mb .
A useful supplement to classical karyotyping is fluorescence in situ hybridisation (FISH). Fluorescent-tagged oligonucleotide probes complementary to a DNA sequence of interest are used to visualise chromosomal regions of interest. Locus-specific or gene-specific probes can be used to identify known aberrations that cause fetal or congenital abnormalities; for example, 22q11 deletions in DiGeorge syndrome, 7q11.23 deletions in Williams syndrome, and dystrophin mutations in Duchenne muscular dystrophy [19,20,21]. In another nice example of the clinical use of FISH, specific subtelomeric probes were used to identify an unbalanced subtelomeric translocation in a child with multiple congenital abnormalities, where classical cytogenetic analysis had indicated a normal karyotype . Because FISH has to be “targeted” to a specific chromosomal anomaly, it requires a clinician to have a high degree of suspicion of that specific anomaly from the phenotype of the patient. Generally, fetal chromosome karyotyping, along with FISH where appropriate, is offered to families when a significant fetal anomaly is identified on ultrasound, or when there is a high risk of such an anomaly. In this population, karyotyping identifies a chromosomal anomaly in around 9% of cases .
2.3. Chromosomal Microarray (CMA)
Chromosomal Microarray, also known as array comparative genomic hybridisation (aCGH), detects CNVs that may be pathogenic, benign, or variants of unknown significance (VOUS). CMA has a higher resolution than G-band karyotyping, and can detect deletions or duplications as small as 1 kb, depending on the platform used . However, these very high resolution arrays have disadvantages, including higher cost and increased detection of VOUS. Therefore, for clinical diagnostic purposes, microarrays with a resolution in the range of 10–400 kb are generally preferred [25,26]. The choice and resolution of the microarray “platform” used in prenatal diagnosis is the major discussion point occurring prior to CMA universal adoption for this role.
One limitation of CMA is that it is only able to detect unbalanced chromosomal rearrangements. Balanced rearrangements, such as reciprocal translocations, may lead to disease by disrupting genes, without detectable gains or losses at breakpoints [23,27]. However, in practice, many apparently balanced rearrangements detected by G-banding are not truly balanced at the DNA level, and CMA testing can be used to detect small regions of DNA loss or gain, and so clarify the exact nature of the rearrangement . Many CMA platforms may not detect triploidy or low-level mosaicism [23,29]. However SNP based CMA platforms will. In the UK, quantitative fluorescence polymerase chain reaction (QF-PCR) is used prior to CMA as a rapid and cost-effective screen for common aneuploidy and triploidy .
Despite the limitations, CMA has been the diagnostic test of choice for several years in children and adults with developmental delay . For fetuses with structural abnormalities, CMA has a diagnostic yield of ranging from 6% to 10% higher than chromosomal karyotyping [6,23,31]. Therefore, the UK is considering the introduction of prenatal CMA for all fetuses with structural anomalies only by the end of 2014 . This is slightly different to the guidance from the American College of Obstetrics and Gynecology who recommend that CMA should be performed as the diagnostic procedure of choice on fetuses with a structural abnormality, and may also be performed in structurally normal fetuses undergoing invasive prenatal testing .
2.4. Non-Invasive Prenatal Testing
Up to 50% of cell-free DNA in the plasma of a pregnant woman is fetal-derived [34,35,36]. It consists of DNA fragments with a size range of 30–510 bps, and a median of 162 bps . The cffDNA can be obtained non-invasively; therefore in recent years there has been huge interest in using it for prenatal genetic diagnosis. Non-invasive prenatal testing (NIPT) refers to sequencing cffDNA to identify genetic mutations in the fetus. NIPT is able to detect autosomal trisomies and sex chromosome aneuploidies [36,38,39,40,41], CNVs [42,43], identify the sex of the fetus , Rhesus status , and single gene disorders such as achondroplasia and cystic fibrosis [46,47,48].
Regarding clinical practice, in the United States and China, use of NIPT to detect aneuploidies and fetal sex is already widespread [49,50]. Implementation for single-gene disorders is much slower because of lower demand and higher technical challenges . In the UK, NIPT is currently only being provided by the National Health Service for sex determination, genotyping of fetuses at risk of Rhesus disease, and some single-gene disorders. However, the “Reliable accurate prenatal non-invasive diagnosis” (RAPID) and “Non-invasive prenatal diagnosis for single gene disorders” (NIPSIGEN) studies are investigating how to expand the implementation, and UK health professionals generally view NIPT positively, therefore it is likely that provision will be expanded to other genomic disorders in the near future .
Two proof-of-concept studies published in 2012 showed that it is possible to sequence the whole genome of a fetus non-invasively using cffDNA, to a sufficient depth to be able to call SNVs, using parental haplotypes to distinguish fetal from maternal variants [52,53]. However, the sensitivity and specificity of the SNV calling are as yet insufficient to consider using this approach in clinical practice. The sensitivity and specificity of identification of de novo mutations were particularly low , and yet for diagnostics this is very important, as de novo mutations are especially likely to be pathogenic [9,54,55,56,57,58]. Therefore, to identify potentially pathogenic SNVs in fetuses with structural abnormalities, NGS on fetal DNA obtained through invasive methods remains, for now, the superior choice.
3. Prenatal Exome Sequencing
3.1. Exome Sequencing as both a Research Tool and a Diagnostic Test
NGS can be used to identify SNVs throughout the genome, thus it has a much higher resolution than cytogenetic approaches. Exome sequencing is often favoured over whole genome sequencing, as it targets only coding regions, which represent 1%–2% of the entire genome, but contain around 85% of the mutations that cause known genetic disorders [59,60,61].
The first report of exome sequencing as a method to discover the genetic cause of a Mendelian disease was made in 2010, with the identification of mutations in DHODH as the cause of Miller syndrome . In the few short years since then, exome sequencing has proved to be a remarkably fruitful research tool. At least one hundred genes that harbour mutations causing Mendelian disease have been identified, and this rate of progress shows no signs of abating as yet . Additionally, exome sequencing is increasingly being used in the clinical setting as a diagnostic test for patients with rare diseases. It has a diagnostic yield of around 25% [55,64].
3.2. Prenatal Exome Sequencing: Proof-of-Concept
Despite the success of NGS, only a handful of studies have used it for prenatal gene discovery or diagnosis. The first two such studies, both published in 2012, used NGS to identify aneuploidy and chromosomal rearrangements. Dan et al., used very low-coverage whole-genome sequencing to detect aneuploidies and unbalanced chromosome variants in 13/62 fetuses , and Talkowski et al., used whole genome “jumping library” sequencing of amniocytes to identify an apparently balanced de novo translocation that disrupts CHD7, causing CHARGE syndrome in a single fetus .
The next two studies used exome sequencing at a depth sufficient to identify SNVs, in a very small number of fetuses. Yang et al., performed exome sequencing on 250 patients with Mendelian disorders, four of which were fetuses from terminated pregnancies . In one of the fetuses, which had Cornelia de Lange syndrome, they found the cause of disease, which was a de novo splicing variant in the known gene NIPBL. Finally, Filges et al., used exome sequencing to identify the cause of a recessive, lethal ciliopathy phenotype in one family . They sequenced the parents, their unaffected daughter, and post-mortem samples from two fetuses that were affected by the disease, and found compound heterozygous mutations in KIF14 in both affected fetuses.
3.3. Prenatal Exome Sequencing: Diagnostic Yield
In our recent study, we demonstrated that for fetuses with structural abnormalities, exome sequencing improves diagnostic yield over karyotyping and CMA alone . The study was collaboration between the University of Birmingham (Birmingham, UK) and the Wellcome Trust Sanger Institute (Cambridge, UK), and it is the largest published cohort of fetuses with structural abnormalities to have been exome sequenced to date.
We gathered a cohort of 30 euploid fetuses with a diverse range of structural abnormalities detected by ultrasound. We exome sequenced them using the Illumina HiSeq platform in a trio design. That is, maternal and paternal samples were sequenced in addition to the affected fetus. We considered de novo rare coding mutations, and inherited recessive and X-linked rare coding mutations. It is important to distinguish between de novo and inherited mutations, in order to estimate the recurrence risk for future pregnancies. We considered SNVs and CNVs (which were identified directly from the exome sequencing reads using the CoNVex software ). These mutations were classified through a systematic manual process as highly likely to be causal, possibly causal, or unknown.
A list of 77 potential candidate de novo coding or splicing variants (mean = 2.6 per fetus, range 0–5) was found. Thirty-four (mean = 1.13 per fetus, range 0–4) variants were then confirmed as truly de novo as a result of subsequent capillary sequencing, in-keeping with the known germline mutation rate [69,70]. For 3/30 fetuses we identified mutations that are highly likely to be causal . That is, similar mutations in the same gene have previously been shown to cause a very similar phenotype in humans. One of these mutations was in the FGFR3 gene which is a negative regulator of bone growth; the features of the fetus were that of a lethal skeletal dysplasia thus supporting that the genetic abnormality detected on exome sequencing was pathogenic. Another mutation was found in a different fetus in COL2A1, mutations in this gene are known to cause type II collagenopathies including heart and limb defects, although the particular mutation that we detected had not previously been reported. This second fetus had increased nuchal translucency, tricuspid regurgitation, abnormal hands and feet and bilateral talipes, again supporting the results of exome sequencing. A third fetus which had ventriculomegaly and agenesis of the corpus collosum demonstrated a de novo Xp22.2 deletion which resulted in the removal of most of the OFD1 gene which is known to cause orofaciodigital syndrome, and is associated with absence of the corpus callosum is approximately 40% .
The diagnostic yield of this study was 10%. Only one of these mutations was a CNV detected by CMA, highlighting the utility of exome sequencing, and increasing the detection rate of prenatal genetic abnormalities over that achieved by karyotyping and CMA alone [6,23,31].
Nevertheless, our diagnostic rate is lower than that found in exome sequencing studies of rare postnatal diseases [55,64]. There are several possible reasons for this. Our estimate of 10%, being based on a relatively small sample size, has a broad confidence interval. Furthermore, it is likely that in some cases, mutations in the same gene will have different phenotypic manifestations between prenatal and postnatal stages of development . Also, in some cases we only had phenotypic data based on ultrasound scans. There are many phenotypes that cannot be identified from an ultrasound scan. Interpreting the clinical significance of the many unknown variants identified is generally the most challenging aspect of any exome sequencing study of rare disease [73,74]. For the reasons described, doing so in the context of prenatal phenotypic data is particularly difficult. However, as more exome sequencing is performed, databases of pathogenic mutations such as the DECIPHER database will be expanded , the diagnostic yield of exome sequencing, including in the prenatal context, is likely to increase. The ability to match SNVs to organ-specific anomalies, for example, the heart, would be particularly useful and may allow a “targeted” approach.
4. The Ethics of Prenatal Exome Sequencing as a Screening Tool
There is no technical reason why exome sequencing of fetal DNA obtained during pregnancy could not be used on structurally normal fetuses, as a screening tool rather than a diagnostic test. While this is not a proposal that is likely to be implemented in the near future, it is a responsibility of the prenatal genetic diagnostics community to begin to consider the relevant ethical issues .
The many thorny ethical issues surrounding exome sequencing in the clinical postnatal context have been extensively debated, chief among which are whether to report incidental findings, and how to report VOUS. Last year, the American College of Medical Genetics and Genomics (ACMG) recommended that mutations in a set of 57 known disease genes should always be reported where sequencing is used as a clinical test . Fetuses were excluded from the ACMG recommendations. They have since revised these recommendations, saying patients have a right to opt out of receiving information on incidental findings . The European Society of Human Genetics have adopted rather more conservative guidelines preferring a targeted approach to avoid discovering incidental findings , and the Deciphering Developmental Disorders project which is investigating the causes of rare genetic diseases in children in the UK is not returning incidental findings to participants under any circumstances . Some researchers and ethicists object to the ACMG recommendations on the grounds that the line between “actionable” and “non-actionable” conditions is far from clear, and the probabilistic nature of the link between genotype and phenotype will result in unnecessary distress for a proportion of families who receive information about mutations which will in fact never cause them to develop disease . Some have argued that routinely returning incidental findings regarding a list of genes amounts to genomic screening .
When considering prenatal sequencing as a screening tool, the ethical dilemmas are similar but amplified, partly due to the possibility of termination of the pregnancy. If prenatal sequencing were to be used as a screening tool, in some cases, it would identify a variant that causes a severe, distressing, and lethal phenotype and is highly penetrant, at an earlier stage than an ultrasound scan could have found structural abnormalities. An example of such a variant might be missense changes in FGFR3 that cause thanataphoric dysplasia [8,9]. In this scenario, earlier detection is undoubtedly better for families. It avoids potentially devastating news later in pregnancy, in the neonatal period, or even later in childhood when developmental delay is clinically apparent. If the families elect to terminate the pregnancy, distress is generally less severe at an early stage of pregnancy . For families who choose to continue with the pregnancy, early diagnosis may offer a more accurate prognosis, more time to prepare, and in some cases the option to start treatments earlier. Therefore, these families would definitely benefit from prenatal sequencing.
In other, less clear-cut cases, the disadvantages of prenatal sequencing as a screening tool may outweigh the advantages. Parents are potentially at risk of “truth dumping”, whereby a large quantity of information is given to parents and they are expected to interpret the information which professionals are unable to interpret with certainty, and then make a decision. Identification of “normal” genomic variation and VOUS is virtually inevitable during prenatal sequencing. For example, a predicted pathogenic variant may be identified in a known developmental disorder gene, but if it has never been reported before it may be very difficult to accurately predict the phenotype. The ethical issues of returning VOUS to families have been considered in the context of CNVs discovered by CMA. Some research suggests that receiving information on VOUS during pregnancy can be very stressful and distressing . Therefore, some researchers and clinicians think that they should not be reported to families, and that their detection should be limited in the first place by using targeted tests [26,85]. Others think that it is paternalistic to withhold this information . If VOUS were to be returned, it is imperative that families receive extensive genetic counselling pre- and post-test . These issues are still under debate, but it would be important for clinicians and researchers to come to a consensus on the issue of reporting VOUS, prior to any use of prenatal exome sequencing as a screening technique, because interpreting mutations identified by exome sequencing is generally more difficult than those identified by CMA, and there will be a higher number of VOUS identified.
Another question is whether to return to families information on mutations that are likely to cause late-onset disease, and/or have incomplete penetrance, such as a BRCA1 variant that confers an 80% risk of developing cancer later in life . Some argue that families have a right to this information to do with what they will, even if it will result in increased termination rates, and termination of some healthy fetuses . An alternative is to do more targeted sequencing based on the indication for the test, so as to avoid incidental diagnoses.
Additional problems include issues surrounding paternity, both in terms of needing correct information to aid the diagnosis of de novo mutations, but also decision making when couples disagree. It also reignites the perpetual ethical debate regarding the rights of the fetus itself. The potential to use exome sequencing to test for non-medical genetic markers and consequently create a “designer baby” is also a fear.
There are currently more questions than answers regarding the ethics of prenatal exome sequencing as a screening tool. Nevertheless, many pertinent issues have already been thoroughly discussed in the context of postnatal clinical sequencing, or interpretation of prenatal CMA results. While prenatal exome sequencing clearly poses additional specific ethical challenges, it is likely that with continued open debate amongst clinicians and researchers, along with sensitive and thorough genetic counselling to families, these can be overcome.
5. Next-Generation Sequencing: The Future of Prenatal Genetic Diagnostics
From a scientific perspective, it seems likely that next-generation sequencing is the future of prenatal genetic diagnostics. Nevertheless, many questions remain to be answered before prenatal next-generation sequencing could become widespread. These include issues of cost effectiveness, clinical utility, ethics, and interpretation of mutations. To address some of these, the Wellcome Trust and the Department of Health in the UK have awarded a Health Innovation Challenge Fund grant to the collaborative Prenatal Assessment of Genomes and Exomes (PAGE) project. This will involve the Wellcome Trust Sanger Institute, the University of Cambridge, the University of Birmingham, Birmingham Women’s Foundation Trust, University College London and Great Ormond Street Hospital (London, UK). One thousand fetuses with structural abnormalities, along with maternal and paternal samples, will undergo exome sequencing or whole genome sequencing. Qualitative work and an ethical review will also be performed to address the many issues this rapidly developing area is raising. The results of this study are expected to yield insights into the genetic causes of fetal abnormalities, and pave the way scientifically, clinically and socially for large-scale implementation of NGS in the UK’s prenatal arena.
In this review we have focused on exome sequencing, as it is currently more cost-efficient than whole-genome sequencing for clinical diagnostic purposes. However, for several reasons, we predict an eventual move towards whole-genome sequencing rather than exome sequencing for clinical diagnostic purposes, including in prenatal samples. First, there are many examples of non-coding mutations that can cause congenital abnormalities including pancreatic agenesis and malformations of the digits [88,89,90,91]. These variants would usually not be detected by exome sequencing. Additionally, while the costs of NGS are falling rapidly , if the costs of the exome capture step do not fall in line with this, at some point whole-genome sequencing may become more cost-effective than exome sequencing . Finally, a major reason why whole-genome sequencing is currently often avoided is that interpretation of non-coding variants is very difficult. However, with large-scale whole-genome projects being planned, this is also likely to start becoming easier .
Next Generation Sequencing and examination of exomes is a powerful tool. In fetuses with congenital malformations it is helpful when delineating prenatal prognosis to be able to exclude chromosomal anomalies. However, the use of these new genetic techniques potentially allows identification of causative single gene anomalies and equally may allow the exclusion of such risk and the reassurance to parents that the underlying aetiology of fetal structural anomalies is “de-novo”.
The PAGE study, undertaken in the UK from 2014 to 2016 will allow us to collect information on the use of such technology in prenatal diagnosis and to evaluate the potential for its use in clinical practice.
Matthew Hurles, Mark Kilby and Sarah Hillman are investigators of the PAGE study that is funded by the Wellcome Trust and Department of Health (UK) HICF innovative. Fiona Mackie is an NIHR funded Academic Clinical Fellow in the West Midlands.
Fiona Mackie performed the literature search and first draft of the manuscript. Keren Carss, Sarah Hillman, Matthew Hillman and Mark Kilby conducted the proof-of-concept study described in Section 3.2 and all contributed to amendments of the manuscript to produce the final version of the paper.
Conflicts of Interest
The PAGE project is funded to Mark Kilby, Matthew Hurles and Sarah Hillman by a Wellcome Trust/HICF grant.
- Springett, A.; Morris, J.K. Congenital Anomaly Statistics, England and Wales; British Isles Network of Congenital Anomaly Registers: London, UK, 2010. [Google Scholar]
- Vlastos, I.M.; Koudoumnakis, E.; Houlakis, M.; Nasika, M.; Griva, M.; Stylogianni, E. Cleft lip and palate treatment of 530 children over a decade in a single centre. Int. J. Pediatr. Otorhinolaryngol. 2009, 73, 993–997. [Google Scholar] [CrossRef]
- Schmidt, W.; Schroeder, T.M.; Buchinger, G.; Kubli, F. Genetics, pathoanatomy and prenatal diagnosis of Potter I syndrome and other urogenital tract diseases. Clin. Genet. 1982, 22, 105–127. [Google Scholar]
- Verity, C.; Firth, H.; French-Constant, C. Congenital abnormalities of the central nervous system. J. Neurol. Neurosurg. Psychiatry 2003, 74. [Google Scholar] [CrossRef]
- Cereda, A.; Carey, J.C. The trisomy 18 syndrome. Orphanet J. Rare Dis. 2012, 7. [Google Scholar] [CrossRef]
- Hillman, S.C.; McMullan, D.J.; Hall, G.; Togneri, F.S.; James, N.; Maher, E.J.; Meller, C.H.; Williams, D.; Wapner, R.J.; Maher, E.R.; et al. Use of prenatal chromosomal microarray: Prospective cohort study and systematic review and meta-analysis. Ultrasound Obstet. Gynecol. 2013, 41, 610–620. [Google Scholar]
- Skinner, M.A.; Safford, S.D.; Reeves, J.G.; Jackson, M.E.; Freemerman, A.J. Renal aplasia in humans is associated with RET mutations. Am. J. Hum. Genet. 2008, 82, 344–351. [Google Scholar] [CrossRef]
- Rousseau, F.; El Ghouzzi, V.; Delezoide, A.L.; Legeai-Mallet, L.; le Merrer, M.; Munnich, A.; Bonaventure, J. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum. Mol. Genet. 1996, 5, 509–512. [Google Scholar] [CrossRef]
- Carss, K.J.; Hillman, S.C.; Parthiban, V.; McMullan, D.J.; Maher, E.R.; Kilby, M.D.; Hurles, M.E. Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound. Hum. Mol. Genet. 2014, 23. [Google Scholar] [CrossRef]
- Firth, H.V.; Wright, C.F. The Deciphering Developmental Disorders (DDD) study. Dev. Med. Child Neurol. 2011, 53, 702–703. [Google Scholar] [CrossRef]
- Tabor, A.; Philip, J.; Madsen, M.; Bang, J.; Obel, E.B.; Norgaard-Pedersen, B. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet 1986, 1, 1287–1293. [Google Scholar]
- Smidt-Jensen, S.; Permin, M.; Philip, J.; Lundsteen, C.; Zachary, J.M.; Fowler, S.E.; Grünig, K. Randomised comparison of amniocentesis and transabdominal and transcervical chorionic villus sampling. Lancet 1992, 340, 1237–1244. [Google Scholar] [CrossRef]
- Group CCC-ACT. Multicentre randomised clinical trial of chorion villus sampling and amniocentesis. First report. Lancet 1989, 1, 1–6. [Google Scholar]
- Tabor, A.; Vestergaard, C.H.; Lidegaard, O. Fetal loss rate after chorionic villus sampling and amniocentesis: An 11-year national registry study. Ultrasound Obstet. Gynecol. 2009, 34, 19–24. [Google Scholar]
- Lo, Y.M.; Corbetta, N.; Chamberlain, P.F.; Rai, V.; Sargent, I.L.; Redman, C.W.; Wainscoat, J.S. Presence of fetal DNA in maternal plasma and serum. Lancet 1997, 350, 485–487. [Google Scholar]
- Caspersson, T.; Farber, S.; Foley, G.E.; Kudynowski, J.; Modest, E.J.; Simonsson, E.; Waqh, U.; Zech, L. Chemical differentiation along metaphase chromosomes. Exp. Cell Res. 1968, 49, 219–222. [Google Scholar] [CrossRef]
- Sumner, A.T.; Evans, H.J.; Buckland, RA. New technique for distinguishing between human chromosomes. Nat. New Biol. 1971, 232, 31–32. [Google Scholar] [CrossRef]
- Shaffer, L.G.; Bejjani, B.A. A cytogeneticist’s perspective on genomic microarrays. Hum. Reprod. Update 2004, 10, 221–226. [Google Scholar] [CrossRef]
- Driscoll, D.A.; Salvin, J.; Sellinger, B.; Budarf, M.L.; McDonald-McGinn, D.M.; Zackai, E.H.; Emanuel, B.S. Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: Implications for genetic counselling and prenatal diagnosis. J. Med. Genet. 1993, 30, 813–817. [Google Scholar] [CrossRef]
- Nickerson, E.; Greenberg, F.; Keating, M.T.; McCaskill, C.; Shaffer, L.G. Deletions of the elastin gene at 7q11.23 occur in approximately 90% of patients with Williams syndrome. Am. J. Hum. Genet. 1995, 56, 1156–1161. [Google Scholar]
- Ligon, A.H.; Kashork, C.D.; Richards, C.S.; Shaffer, L.G. Identification of female carriers for Duchenne and Becker muscular dystrophies using a FISH-based approach. Eur. J. Hum. Genet. 2000, 8, 293–298. [Google Scholar] [CrossRef]
- Brackley, K.J.; Kilby, M.D.; Morton, J.; Whittle, M.J.; Knight, S.J.; Flint, J. A case of recurrent congenital fetal anomalies associated with a familial subtelomeric translocation. Prenat. Diagn. 1999, 19, 570–574. [Google Scholar] [CrossRef]
- Wapner, R.J.; Martin, C.L.; Levy, B.; Ballif, B.C.; Eng, C.M.; Zachary, J.M.; Melissa Savage, M.S.; Lawrence, D.; Platt, M.D.; Daniel Saltzman, M.D.; et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N. Engl. J. Med. 2012, 367, 2175–2184. [Google Scholar] [CrossRef]
- Hillman, S.C.; Pretlove, S.; Coomarasamy, A.; McMullan, D.J.; Davison, E.V.; Maher, E.R.; Kilby, M.D. Additional information from array comparative genomic hybridization technology over conventional karyotyping in prenatal diagnosis: A systematic review and meta-analysis. Ultrasound Obstet. Gynecol. 2011, 37, 6–14. [Google Scholar] [CrossRef]
- Shaffer, L.G.; Dabell, M.P.; Rosenfeld, J.A.; Neill, N.J.; Ballif, B.C.; Coppinger, J.; Diwan, N.R.; Chong, K.; Shohat, M.; Chitayat, D. Referral patterns for microarray testing in prenatal diagnosis. Prenat. Diagn. 2012, 32, 344–350. [Google Scholar] [CrossRef]
- Vanakker, O.; Vilain, C.; Janssens, K.; Van der Aa, N.; Smits, G.; Bandelier, C.; Blaumeiser, B.; Bulk, S.; Caberq, J.H.; de Leener, A.; et al. Implementation of genomic arrays in prenatal diagnosis: The Belgian approach to meet the challenges. Eur. J. Med. Genet. 2014, 57, 151–156. [Google Scholar]
- Bodrug, S.E.; Roberson, J.R.; Weiss, L.; Ray, P.N.; Worton, R.G.; van Dyke, D.L. Prenatal identification of a girl with a t(X;4)(p21;q35) translocation: Molecular characterisation, paternal origin, and association with muscular dystrophy. J. Med. Genet. 1990, 27, 426–432. [Google Scholar]
- De Gregori, M.; Ciccone, R.; Magini, P.; Pramparo, T.; Gimelli, S.; Messa, J.; Novara, F.; Vetro, A.; Rossi, E.; Maraschio, P.; et al. Cryptic deletions are a common finding in “balanced” reciprocal and complex chromosome rearrangements: A study of 59 patients. J. Med. Genet. 2007, 44, 750–762. [Google Scholar] [CrossRef]
- Hillman, S.C.; McMullan, D.J.; Maher, E.R.; Kilby, M.D. The use of chromosomal microarray in prenatal diagnosis. Obstet. Gynaecol. 2013, 15, 80–84. [Google Scholar] [CrossRef]
- UKGTN. UK Genetic Testing Network arrayCGH Commissioning Workshop. Phg Foundation, London, UK, 2009. [Google Scholar]
- Valduga, M.; Philippe, C.; Bach Segura, P.; Thiebaugeorges, O.; Miton, A.; Beri, M.; Bonnet, C.; Nemos, C.; Foliquet, B.; Jonveaux, P. A retrospective study by oligonucleotide array-CGH analysis in 50 fetuses with multiple malformations. Prenat. Diagn. 2010, 30, 333–341. [Google Scholar]
- Clinical Genetics Clinical Reference Group; (National Health Service, England, UK). Personal communication, 2014.
- The American College of Obstetricians and Gynecologists Committee on Genetics Society for Maternal-Fetal Medicine. Committee Opinion No. 581: The use of chromosomal microarray analysis in prenatal diagnosis. Obstet. Gynecol. 2013, 122, 1374–1377. [Google Scholar] [CrossRef]
- Lo, Y.M.; Tein, M.S.; Lau, T.K.; Haines, C.J.; Leung, T.N.; Poon, P.M.; Wainscoat, J.S.; Johnson, P.J.; Chang, A.M.; Hjelm, N.M. Quantitative analysis of fetal DNA in maternal plasma and serum: Implications for noninvasive prenatal diagnosis. Am. J. Hum. Genet. 1998, 62, 768–775. [Google Scholar]
- Lun, F.M.; Chiu, R.W.; Allen Chan, K.C.; Yeung Leung, T.; Kin Lau, T.; Dennis Lo, Y.M. Microfluidics digital PCR reveals a higher than expected fraction of fetal DNA in maternal plasma. Clin. Chem. 2008, 54, 1664–1672. [Google Scholar]
- Palomaki, G.E.; Deciu, C.; Kloza, E.M.; Lambert-Messerlian, G.M.; Haddow, J.E.; Neveux, L.M.; Ehrich, M.; van den Boom, D.; Bombard, A.T.; Grody, W.W.; et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: An international collaborative study. Genet. Med. 2012, 14, 296–305. [Google Scholar] [CrossRef]
- Fan, H.C.; Blumenfeld, Y.J.; Chitkara, U.; Hudgins, L.; Quake, S.R. Analysis of the size distributions of fetal and maternal cell-free DNA by paired-end sequencing. Clin. Chem. 2010, 56, 1279–1286. [Google Scholar] [CrossRef]
- Nicolaides, K.H.; Syngelaki, A.; Gil, M.; Atanasova, V.; Markova, D. Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y. Prenat. Diagn. 2013, 33, 575–579. [Google Scholar] [CrossRef]
- Samango-Sprouse, C.; Banjevic, M.; Ryan, A.; Sigurjonsson, S.; Zimmermann, B.; Hill, M.; Hall, M.P.; Westemeyer, M.; Saucier, J.; Demko, Z.; et al. SNP-based non-invasive prenatal testing detects sex chromosome aneuploidies with high accuracy. Prenat. Diagn. 2013, 33, 643–649. [Google Scholar] [CrossRef]
- Hooks, J.; Wolfberg, A.J.; Wang, E.T.; Struble, C.A.; Zahn, J.; Juneau, K.; Mohseni, M.; Huang, S.; Bogard, P.; Song, K.; et al. Non-invasive risk assessment of fetal sex chromosome aneuploidy through directed analysis and incorporation of fetal fraction. Prenat. Diagn. 2014, 34, 496–499. [Google Scholar] [CrossRef]
- Jiang, F.; Ren, J.; Chen, F.; Zhou, Y.; Xie, J.; Dan, S.; Su, Y.; Xie, J.H.; Yin, B.M.; Su, W.; et al. Noninvasive Fetal Trisomy (NIFTY) test: An advanced noninvasive prenatal diagnosis methodology for fetal autosomal and sex chromosomal aneuploidies. BMC Med. Genomics 2012, 5. [Google Scholar] [CrossRef]
- Lau, T.K.; Jiang, F.M.; Stevenson, R.J.; Lo, T.K.; Chan, L.W.; Chan, M.K.; Lo, P.S.; Wang, W.; Zhang, H.Y.; Chen, F.; et al. Secondary findings from non-invasive prenatal testing for common fetal aneuploidies by whole genome sequencing as a clinical service. Prenat. Diagn. 2013, 33, 602–608. [Google Scholar] [CrossRef]
- Ge, H.; Huang, X.; Li, X.; Chen, S.; Zheng, J.; Jiang, H.; Zhang, C.; Pan, X.; Chen, F.; Chen, N.; et al. Noninvasive prenatal detection for pathogenic CNVs: The application in alpha-thalassemia. PLoS One 2013, 8, e67464. [Google Scholar]
- Wright, C.F.; Wei, Y.; Higgins, J.P.; Sagoo, G.S. Non-invasive prenatal diagnostic test accuracy for fetal sex using cell-free DNA a review and meta-analysis. BMC Res. Notes 2012, 5. [Google Scholar] [CrossRef]
- Moise, K.J., Jr.; Boring, N.H.; O’Shaughnessy, R.; Simpson, L.L.; Wolfe, H.M.; Baxter, J.K.; Polzin, W.; Eddleman, K.A.; Hassan, S.S.; Skupski, D.; et al. Circulating cell-free fetal DNA for the detection of RHD status and sex using reflex fetal identifiers. Prenat. Diagn. 2013, 33, 95–101. [Google Scholar] [CrossRef]
- Lim, J.H.; Kim, M.J.; Kim, S.Y.; Kim, H.O.; Song, M.J.; Kim, M.H.; Park, S.Y.; Yang, J.H.; Ryu, H.M. Non-invasive prenatal detection of achondroplasia using circulating fetal DNA in maternal plasma. J. Assist. Reprod. Genet. 2011, 28, 167–172. [Google Scholar] [CrossRef]
- Bustamante-Aragones, A.; Gallego-Merlo, J.; Trujillo-Tiebas, M.J.; de Alba, M.R.; Gonzalez-Gonzalez, C.; Glover, G.; Diego-Alvarez, D.; Ayuso, C.; Ramos, C. New strategy for the prenatal detection/exclusion of paternal cystic fibrosis mutations in maternal plasma. J. Cyst. Fibros. 2008, 7, 505–510. [Google Scholar]
- Lench, N.; Barrett, A.; Fielding, S.; McKay, F.; Hill, M.; Jenkins, L.; White, H.; Chitty, L.S. The clinical implementation of non-invasive prenatal diagnosis for single-gene disorders: Challenges and progress made. Prenat. Diagn. 2013, 33, 555–562. [Google Scholar] [CrossRef]
- Agarwal, A.; Sayres, L.C.; Cho, M.K.; Cook-Deegan, R.; Chandrasekharan, S. Commercial landscape of noninvasive prenatal testing in the United States. Prenat. Diagn. 2013, 33, 521–531. [Google Scholar] [CrossRef]
- Song, Y.; Liu, C.; Qi, H.; Zhang, Y.; Bian, X.; Liu, J. Noninvasive prenatal testing of fetal aneuploidies by massively parallel sequencing in a prospective Chinese population. Prenat. Diagn. 2013, 33, 700–706. [Google Scholar]
- Hill, M.; Karunaratna, M.; Lewis, C.; Forya, F.; Chitty, L. Views and preferences for the implementation of non-invasive prenatal diagnosis for single gene disorders from health professionals in the United Kingdom. Am. J. Med. Genet. Part A 2013, 161, 1612–1618. [Google Scholar] [CrossRef]
- Fan, H.C.; Gu, W.; Wang, J.; Blumenfeld, Y.J.; El-Sayed, Y.Y.; Quake, S.R. Non-invasive prenatal measurement of the fetal genome. Nature 2012, 487, 320–324. [Google Scholar] [CrossRef]
- Kitzman, J.O.; Snyder, M.W.; Ventura, M.; Lewis, A.P.; Qiu, R.; Simmons, L.E.; Gammill, H.S.; Rubens, C.E.; Santillan, D.A.; Murray, J.C.; et al. Noninvasive whole-genome sequencing of a human fetus. Sci. Transl. Med. 2012, 4. [Google Scholar] [CrossRef]
- Veltman, J.A.; Brunner, H.G. De novo mutations in human genetic disease. Nat. Rev. Genet. 2012, 13, 565–575. [Google Scholar]
- Yang, Y.; Muzny, D.M.; Reid, J.G.; Bainbridge, M.N.; Willis, A.; Ward, P.A.; Braxton, A.; Beuten, J.; Xia, F.; Niu, Z.; et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N. Engl. J. Med. 2013, 369, 1502–1511. [Google Scholar]
- O’Roak, B.J.; Deriziotis, P.; Lee, C.; Vives, L.; Schwartz, J.J.; Girirajan, S.; Karakoc, E.; MacKenzie, A.P.; Ng, S.B.; Baker, C.B.; et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet. 2011, 43, 585–589. [Google Scholar]
- De Ligt, J.; Willemsen, M.H.; van Bon, B.W.; Kleefstra, T.; Yntema, H.G.; Kroes, T.; Anneke, T.; Vulto-van Silfhout, M.D.; David, A.; Koolen, M.D.; et al. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 2012, 367, 1921–1929. [Google Scholar] [CrossRef]
- Zaidi, S.; Choi, M.; Wakimoto, H.; Ma, L.; Jiang, J.; Overton, J.D.; Romano-Adesman, A.; Bjornson, R.D.; Breitbart, R.E.; Brown, K.K.; et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature 2013, 498, 220–223. [Google Scholar] [CrossRef]
- Ng, S.B.; Turner, E.H.; Robertson, P.D.; Flygare, S.D.; Bigham, A.W.; Lee, C.; Shaffer, T.; Wong, M.; Bhattacharjee, A.; Eichler, E.E.; et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 2009, 461, 272–276. [Google Scholar] [CrossRef]
- Bainbridge, M.N.; Wang, M.; Burgess, D.L.; Kovar, C.; Rodesch, M.J.; D’Ascenzo, M.; Kitzman, J.; Wu, Y.Q.; Newsham, I.; Richmond, T.A.; et al. Whole exome capture in solution with 3 Gbp of data. Genome Biol. 2010, 11. [Google Scholar] [CrossRef]
- Stenson, P.D.; Ball, E.V.; Howells, K.; Phillips, A.D.; Mort, M.; Cooper, D.N. The Human Gene Mutation Database: Providing a comprehensive central mutation database for molecular diagnostics and personalized genomics. Hum. Genomics 2009, 4, 69–72. [Google Scholar]
- Ng, S.B.; Buckingham, K.J.; Lee, C.; Bigham, A.W.; Tabor, H.K.; Dent, K.M.; Huff, C.D.; Shannon, P.T.; Jabs, E.W.; Nickerson, D.A.; et al. Exome sequencing identifies the cause of a mendelian disorder. Nat. Genet. 2010, 42, 30–35. [Google Scholar] [CrossRef]
- Wang, Z.; Liu, X.; Yang, B.Z.; Gelernter, J. The role and challenges of exome sequencing in studies of human diseases. Front. Genet. 2013, 4. [Google Scholar] [CrossRef]
- Gahl, W.A.; Markello, T.C.; Toro, C.; Fajardo, K.F.; Sincan, M.; Gill, F.; Carlson-Donohoe, H.; Gropman, A.; Pierson, T.M.; Golas, G.; et al. The National Institutes of Health Undiagnosed Diseases Program: Insights into rare diseases. Genet. Med. 2012, 14, 51–59. [Google Scholar] [CrossRef]
- Dan, S.; Chen, F.; Choy, K.W.; Jiang, F.; Lin, J.; Xuan, Z.; Wang, W.; Chen, S.; Li, X.; Jiang, H.; et al. Prenatal detection of aneuploidy and imbalanced chromosomal arrangements by massively parallel sequencing. PLoS One 2012, 7, e27835. [Google Scholar]
- Talkowski, M.E.; Ordulu, Z.; Pillalamarri, V.; Benson, C.B.; Blumenthal, I.; Connolly, S.; Hanscom, C.; Hussain, N.; Pereira, S.; Picker, J.; et al. Clinical diagnosis by whole-genome sequencing of a prenatal sample. N. Engl. J. Med. 2012, 367, 2226–2232. [Google Scholar] [CrossRef]
- Filges, I.; Nosova, E.; Bruder, E.; Tercanli, S.; Townsend, K.; Gibson, W.; Röthlisberger, B.; Heinimann, K.; Hall, J.; Gregory-Evans, C.; et al. Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype. Clin. Genet. 2013. [Google Scholar] [CrossRef]
- CoNVex: Copy number variants from exomes. Available online: Available online: ftp://ftp.sanger.ac.uk/pub/users/pv1/CoNVex/ (accessed on 1 February 2013).
- Rauch, A.; Wieczorek, D.; Graf, E.; Wieland, T.; Endele, S.; Schwarzmayr, T. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: An exome sequencing study. Lancet 2012, 380, 1674–1682. [Google Scholar] [CrossRef]
- Awadalla, P.; Gauthier, J.; Myers, R.A.; Casals, F.; Hamdan, F.F.; Griffing, A.R.; Côté, M.; Henrion, E.; Spiegelman, D.; Tarabeux, J.; et al. Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. Am. J. Hum. Genet. 2010, 87, 316–324. [Google Scholar] [CrossRef]
- Bischoff, I.J.; Zeschnigk, C.; Horn, D.; Wellek, B.; Riess, A.; Wessels, M.; Willems, P.; Jensen, P.; Busche, A.; Bekkebraten, J.; et al. Novel mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciogdigital syndrome: A study of the extensive clinical variability. Hum. Mutat. 2013, 34, 237–247. [Google Scholar] [CrossRef]
- Mefford, H.C.; Clauin, S.; Sharp, A.J.; Moller, R.S.; Ullmann, R.; Kapur, R.; Pinkel, D.; Cooper, G.M.; Ventura, M.; Ropers, H.H.; et al. Recurrent reciprocal genomic rearrangements of 17q12 are associated with renal disease, diabetes, and epilepsy. Am. J. Hum. Genet. 2007, 81, 1057–1069. [Google Scholar] [CrossRef]
- Stanley, C.M.; Sunyaev, S.R.; Greenblatt, M.S.; Oetting, W.S. Clinically relevant variants—Identifying, collecting, interpreting, and disseminating: The 2013 annual scientific meeting of the human genome variation society. Hum. Mutat. 2014, 35, 505–510. [Google Scholar] [CrossRef]
- Isakov, O.; Perrone, M.; Shomron, N. Exome sequencing analysis: A guide to disease variant detection. Methods Mol. Biol. 2013, 1038, 137–158. [Google Scholar]
- Bragin, E.; Chatzimichali, E.A.; Wright, C.F.; Hurles, M.E.; Firth, H.V.; Bevan, A.P.; Swaminathan, G.J. Decipher: Database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation. Nucl. Acid. Res. 2014, 42. [Google Scholar] [CrossRef]
- Yurkiewicz, I.R.; Korf, B.R.; Lehmann, L.S. Prenatal whole-genome sequencing—Is the quest to know a fetus’s future ethical? N. Engl. J. Med. 2014, 370, 195–197. [Google Scholar] [CrossRef]
- Green, R.C.; Berg, J.S.; Grody, W.W.; Kalia, S.S.; Korf, B.R.; Martin, C.L.; Amy McGuire, J.D.; Nussbaum, R.L.; O’Daniel, J.M.; Ormond, K.E.; et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet. Med. 2013, 15, 565–574. [Google Scholar] [CrossRef]
- American College of Medical Genetics and Genomics. ACMG Updates Recommendation on “Opt Out” for Genome Sequencing Return of Results 2014. Available online: Available online: https://www.acmg.net/docs/Release_ACMGUpdatesRecommendations_final.pdf (accessed on 10 April 2014).
- Van El, C.G.; Cornel, M.C.; Borry, P.; Hastings, R.J.; Fellmann, F.; Hodgson, S.V.; Howard, H.C.; Cambon-Thomsen, A.; Knoppers, B.M.; Meijers-Heijboer, H.; et al. Whole-genome sequencing in health care. Recommendations of the European Society of Human Genetics. Eur. J. Hum. Genet. 2013, 21, S1–S5. [Google Scholar]
- Middleton, A.; Parker, M.; Wright, C.F.; Bragin, E.; Hurles, M.E.; Study, D.D.D. Empirical research on the ethics of genomic research. Am. J. Med. Genet. Part A 2013, 161A, 2099–2101. [Google Scholar]
- Holtzman, N.A. ACMG recommendations on incidental findings are flawed scientifically and ethically. Genet. Med. 2013, 15, 750–751. [Google Scholar] [CrossRef]
- Wright, C.F.; Middleton, A.; Burton, H.; Cunningham, F.; Humphries, S.E.; Hurst, J.; Birney, E.; Firth, H. Policy challenges of clinical genome sequencing. BMJ 2013, 347. [Google Scholar] [CrossRef]
- Hern, W.M. Fetal diagnostic indications for second and third trimester outpatient pregnancy termination. Prenat. Diagn. 2014, 34, 438–444. [Google Scholar] [CrossRef]
- Bernhardt, B.A.; Soucier, D.; Hanson, K.; Savage, M.S.; Jackson, L.; Wapner, R.J. Women’s experiences receiving abnormal prenatal chromosomal microarray testing results. Genet. Med. 2013, 15, 139–145. [Google Scholar] [CrossRef]
- De Jong, A.; Dondorp, W.J.; Macville, M.V.; de Die-Smulders, C.E.; van Lith, J.M.; de Wert, G.M. Microarrays as a diagnostic tool in prenatal screening strategies: Ethical reflection. Hum. Genet. 2014, 133, 163–172. [Google Scholar] [CrossRef]
- McGillivray, G.; Rosenfeld, J.A.; McKinlay Gardner, R.J.; Gillam, L.H. Genetic counselling and ethical issues with chromosome microarray analysis in prenatal testing. Prenat. Diagn. 2012, 32, 389–395. [Google Scholar] [CrossRef]
- Ford, D.; Easton, D.F.; Stratton, M.; Narod, S.; Goldgar, D.; Devilee, P.; Bishop, D.T.; Weber, B.; Lenoir, G.; Chang-Claude, J.; et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am. J. Hum. Genet. 1998, 62, 676–689. [Google Scholar] [CrossRef]
- Weedon, M.N.; Cebola, I.; Patch, A.M.; Flanagan, S.E.; de Franco, E.; Caswell, R.; Rodríguez-Seguí, S.A.; Shaw-Smith, C.; Cho, C.H.H.; Allen, H.L.; et al. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nat. Genet. 2014, 46, 61–64. [Google Scholar]
- Benko, S.; Gordon, C.T.; Mallet, D.; Sreenivasan, R.; Thauvin-Robinet, C.; Brendehaug, A.; Thomas, S.; Bruland, O.; David, M.; Nicolino, M.; et al. Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development. J. Med. Genet. 2011, 48, 825–830. [Google Scholar] [CrossRef]
- Dathe, K.; Kjaer, K.W.; Brehm, A.; Meinecke, P.; Nurnberg, P.; Neto, J.C.; Brunoni, D.; Tommerup, N.; Ott, C.E.; Klopocki, E.; et al. Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2. Am. J. Hum. Genet. 2009, 84, 483–492. [Google Scholar] [CrossRef]
- Lettice, L.A.; Heaney, S.J.; Purdie, L.A.; Li, L.; de Beer, P.; Oostra, B.A.; Goode, D.; Elgar, G.; Hill, R.E.; de Graaff, E.; et al. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum. Mol. Genet. 2003, 12, 1725–1735. [Google Scholar] [CrossRef]
- Wetterstrand, K.A. DNA sequencing costs: Data from the NHGRI Genome Sequencing Program (GSP). National Human Genome Research Institute 2013. Available online: Available online: https://www.genome.gov/sequencingcosts (accessed on 7 April 2014).
- Biesecker, L.G.; Shianna, K.V.; Mullikin, J.C. Exome sequencing: The expert view. Gen. Biol. 2011, 12. [Google Scholar]
- Prime Minister’s Office. Press release: DNA tests to revolutionise fight against cancer and help 100,000 NHS patients 2012. Available online: Available online: https://www.gov.uk/government/news/dna-tests-to-revolutionise-fight-against-cancer-and-help-100000-nhs-patients (accessed on 7 April 2014).
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text:
Summarize, and explain how the changing attitudes of the times were expressed through these various political events and movements such as civil rights.
Resources: Fiero, Gloria K. (2006). Modernism, Globalism, and the Information Age. New York, NY: McGraw Hill© BrainMass Inc. brainmass.com June 3, 2020, 11:15 pm ad1c9bdddf
Political Movements in the 20th Century
The period of 20th century is the signal period in which the progressive moment in the political era has begun (Fiero, 2006). The political system has become completely changed in comparison to 19th century. In 19th century, people lived in the world of empires and they followed the rules and regulations of the king (Gardner, Kleiner & Mamiya, 2005). On the other hand in the 20th century, the perspective of the society had been changed and various political movements had been taken place in the society that was related to the civil rights of the human being (Fiero, 2006).
This century was predicted as the end of the biggest empires and rulers such as Russian, Chinese or Turkish, Austro-Hungarian, British, etc. (Gardner, Kleiner & Mamiya, 2005). These political changes had been started revolution in the society and gave birth to the democracy, which was the biggest step to develop civilization and independence in the world almost in all the societies.
In 20th century, there was a decline in the monarchy and colonialism in the developed countries and democracy had taken birth among all the societies (Fiero, 2006). In this decade the biggest political movement in the society is related to the freedom and civil rights. But it has been shown in the various researches in 2000 that more than 40% people are still living in those countries that were not free. Almost 33% of people ...
The solution examines political movements in the 20th century.

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