106 research outputs found
Phenotypic Characterisation of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically with Pulmonary Arterial Hypertension
- Author
- Bleda M
- Bogaard H
- Church C
- Coghlan G
- Condliffe R
- Corris PA
- DorfmĂŒller P
- Gibbs S
- Girerd B
- GrÀf S
- Hadinnapola C
- Haimel M
- Hernandez-Sanchez J
- Holden S
- Humbert M
- Kiely DG
- Lawrie A
- Machado R
- MacKenzie Ross R
- Martin J
- Moledina S
- Montani D
- Morrell NW
- Newnham M
- NIHR BioResourceâRare Diseases Consortium
- Noordegraaf AV
- Peacock A
- Pepke-Zaba J
- Preston SD
- Rayner-Matthews P
- Screaton N
- Shamardina O
- Soubrier F
- Southgate L
- Southwood M
- Suntharalingam J
- Swift A
- Toshner M
- Treacy C
- Trembath R
- Wharton J
- Wilkins MR
- Wort SJ
- Yates K
- Publication venue
- Circulation
- Publication date
- 25/08/2017
- Field of study
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis (PVOD/PCH). Here, we determined the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole genome sequencing was performed on DNA from patients with idiopathic and heritable PAH, as well as PVOD/PCH recruited to the NIHR BioResource - Rare Diseases Study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of < 1:10,000 in control data sets and predicted to be deleterious (by CADD, PolyPhen-2 and SIFT predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred and sixty-four patients with idiopathic or heritable PAH and 16 with PVOD/PCH were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of PVOD/PCH. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (KCO: 33 [IQR: 30 - 35] % predicted) and younger age at diagnosis (29 [23 - 38] years) as well as more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest, compared to PAH patients without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. PAH patients with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as idiopathic and heritable PAH. These patients cannot be identified reliably by CT, but a low KCO and a young age of diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.The National Institute of Health Research (NIHR) BioResource for Rare Diseases provided funding for sequencing and analysis. The study was supported by a British Heart Foundation Special Project Grant and a Medical Research Council (UK) Experimental Challenge Award
De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures.
- Author
- Afzal M
- Aitman T
- Alachkar H
- Alavijeh OS
- Ali S
- Ali S
- Allen L
- Allsup D
- Ambegaonkar G
- Ancliff P
- Anderson J
- Antrobus R
- Armstrong R
- Arno G
- Arumugakani G
- Ashford S
- Astle W
- Attwood A
- Austin S
- Babbs C
- Bacchelli C
- Bakchoul T
- Bariana TK
- Baxendale H
- Bennett D
- Bethune C
- Bibi S
- Bitner-Glindzicz M
- Bleda M
- Boggard HJ
- Bolton-Maggs P
- Booth C
- Boycott KM
- Boycott KM
- Bradley JR
- Brady A
- Brown M
- Browning M
- Brudno M
- Bryson C
- Bulman D
- Burns S
- Calleja P
- Canham N
- Carmichael J
- Carss KJ
- Carss KJ
- Caulfield M
- Chalmers E
- Chambers J
- Chandra A
- Charles P
- Chinnery P
- Chitre M
- Chong S
- Church C
- Clement E
- Clements-Brod N
- Clowes V
- Coghlan G
- Colby E
- Collins J
- Collins P
- Cook HT
- Cookson V
- Cooper N
- Corris PA
- Creaser-Myers A
- Dacosta R
- Daugherty L
- Davies S
- Davis J
- De Vries M
- Deegan P
- Deevi SVV
- Deshpande C
- Devlin L
- Dewhurst E
- Dixon P
- Doffinger R
- Dolling H
- Dormand N
- Drewe E
- Duarte ST
- Dyack S
- Dyment D
- Edgar D
- Egner W
- Emmerson I
- Erber WN
- Erwood M
- Estiu C
- Everington T
- Eyries M
- Favier R
- Firth H
- Fletcher D
- Flinter F
- Frary A
- French C
- Freson K
- Furie B
- Furnell A
- Gale D
- Gall H
- Gardham A
- Gattens M
- Gebhart J
- Ghali N
- Ghataorhe PK
- Ghio S
- Ghofrani A
- Ghurye R
- Gibbs JSR
- Gilmour K
- Ginsberg L
- Girerd B
- Gissen P
- Goddard S
- Gomez K
- Gordins P
- Gosal D
- Greene D
- Greenhalgh A
- Greinacher A
- Gresele P
- Grigoriadou S
- Grozeva D
- GrÀf S
- Hackett S
- Hadden R
- Hadinnapola C
- Hague B
- Hague R
- Haimel M
- Halmagyi C
- Hammerton T
- Harper L
- Hart D
- Hartley T
- Hayman G
- Heemskerk JWM
- Henderson R
- Hensiek A
- Henskens Y
- Herwadkar A
- Holden S
- Holder M
- Holder S
- Horvath R
- Houweling AC
- Hu F
- Hudson G
- Huissoon A
- Humbert M
- Hurst J
- InâT Veld AH
- Ito Y
- James R
- Johnson S
- Jolles S
- Josifova D
- Kazmi R
- Keeling D
- Kelleher P
- Kelly AM
- Kennedy F
- Keren B
- Kernohan KD
- Kiely DG
- Kingston N
- Kovacs G
- Koziell A
- Krishnakumar D
- Kuijpers TW
- Kumararatne D
- Kurian MA
- Kurian MA
- Laffan MA
- Lambert MP
- Lango-Allen H
- Lawrie A
- Layton M
- Lear S
- Lees M
- Lentaigne C
- Levine AP
- Liesner R
- Linger R
- Longhurst H
- Lorenzo L
- Louka E
- Machado R
- Mackenzie A
- Maclaren R
- Mahdi-Rogers M
- Maher E
- Maimaris J
- Majewski J
- Makris M
- Mangles S
- Manson A
- Manzur A
- Mapeta R
- Marey I
- Markus HS
- Marschall H-U
- Marshall A
- Martin JM
- Masati L
- Mathias M
- Matser V
- Matthews E
- Maw A
- McCarthy M
- McDermott E
- McGowan S
- McJannet C
- Meacham S
- Mead A
- Meehan S
- Megy K
- Mehta S
- Mendonça C
- Michaelides M
- Millar CM
- Moledina S
- Montani D
- Moore A
- Morrell NW
- Mumford A
- Murng S
- Murphy E
- Nava C
- Nejentsev S
- Noorani S
- Noordegraaf AV
- Nurden P
- Oksenhendler E
- Ormondroyd L
- Othman S
- Ouwehand WH
- Papadia S
- Park S-M
- Parker A
- Pasi J
- Patch C
- Paterson J
- Payne J
- Peacock AJ
- Peerlinck K
- Penkett CJ
- Pepke-Zaba J
- Perry DJ
- Pfundt R
- Pollock V
- Polwarth G
- Ponsford M
- Qasim W
- Quinti I
- Ranganathan L
- Rankin J
- Rankin S
- Raymond FL
- Raymond FL
- Rayner-Matthews P
- Rehnstrom K
- Reid E
- Reilly M
- Renton T
- Revel-Vilk S
- Rhodes CJ
- Rice A
- Richards M
- Richardson S
- Richter A
- Roberts I
- Rondina M
- Ross RVM
- Rosser E
- Roughley C
- Roy N
- Rue-Albrecht K
- Saleem M
- Samarghitean C
- Sanchis-Juan A
- Sanchis-Juan A
- Sandford R
- Santra S
- Sargur R
- Savic S
- Scelsi L
- Schotte G
- Schulman S
- Schulze H
- Scott R
- Scully M
- Seneviratne S
- Sewell C
- Shamardina O
- Shipley D
- Simeoni I
- Simpson M
- Sivapalaratnam S
- Smith KGC
- Sohal A
- Soubrier F
- Southgate L
- Staines S
- Staples E
- Stark H
- Stauss H
- Stein P
- Stephens J
- Stirrups K
- Stock S
- Stubbs M
- Suntharalingam J
- Tait RC
- Talks K
- Tan R
- Tan Y
- Thachil J
- Thaventhiran J
- Themistocleous A
- Thomas E
- Thomas M
- Thompson D
- Thrasher A
- Tischkowitz M
- Titterton C
- Toh C-H
- Toshner M
- Treacy CM
- Trembath R
- Tuna S
- Turek W
- Turro E
- Vale T
- Van Bokhoven H
- Van Essen A
- Van Geet C
- Van Ravenswaaij-Arts C
- Van Zuydam N
- Veltman M
- Vogt J
- Von Ziegenweldt J
- Wakeling E
- Walker S
- Walker S
- Wanjiku I
- Warner TQ
- Wassmer E
- Watkins H
- Watson H
- Watt C
- Webster A
- Wei W
- Welch S
- Westbury S
- Wharton J
- Whitehorn D
- Whitworth J
- Wilkins M
- Willcocks L
- Williamson C
- Wong EKS
- Woods G
- Wort SJ
- Yates K
- Yeatman N
- Yong P
- Young T
- Yu Wai Man P
- Yu P
- Publication venue
- 'Elsevier BV'
- Publication date
- 01/01/2018
- Field of study
Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability
Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.
- Author
- Ab Majid MA
- Ab Rahman AS
- Ab Rahman R
- Abayasinghe C
- Abbott T
- Abdullah NH
- Abdur-Rahman L
- Abeloos J
- Abernethy C
- Abidin UN
- Abrunhosa A
- Absar M
- Adam S
- Adams D
- Adams G
- Adamson M
- Adekola O
- Adelaja Y
- Ademola A
- Adenekan A
- Adenike O
- Adeolu AA
- Adetoye A
- Adewale B
- Adigun T
- Adolfsson A
- Aflori L
- Africander C
- Afshari A
- Agarwal V
- Agodirin O
- Aguero Vera M
- Aguzzoli C
- Ahmad A
- Ahmad N
- Ahmad T
- Ahmad T
- Ahmad Y
- Ahmed A
- Ahmed J
- Ai Y
- Aignatoaie M
- Aimoniotou-Georgiou E
- Akanmu O
- Akerman N
- Akinwale M
- Akring I
- Al 'Amri K
- Al Anizi M
- Al hussaini S
- Al-Soudaine Y
- Aladin H
- Alagbe-Briggs O
- Alaman Laguarda G
- Albaj S
- Alcock D
- Alcock L
- Aldecoa C
- Aldecoa C
- Aleixo FB
- Alexander H
- Alexander M
- Alexander-Sefre F
- Alherz F
- Ali H
- Ali M
- Ali S
- Alias A
- Alias AH
- Alias RLR
- Alit MA
- Allen S
- Allen SJ
- Allison J
- Alloj C
- Allorto NL
- Allsop J
- Almeida W
- Alonso E
- Alphonsus C
- Alvares D
- Alves MJ
- Amador JCB
- Ameer Y
- Amendola CP
- Ami N
- Amstrup-Hansen L
- Anagnou A
- Andersen C
- Anderson C
- Anderson C
- Anderson F
- Anderson P
- Andreadaki E
- Andreou A
- Andreou P
- Andrew A
- Andrews E
- Angermair S
- Angus K
- Anillo V
- Antal O
- Antill P
- Antoniadou E
- Antonina W
- Apagaki E
- Apostolou K
- Applewhaite C
- Aquino LPG
- Ar P
- Arawwawala D
- Ardern D
- Argue R
- Arkalaki E
- Armaganidis A
- Armstrong J
- Armstrong R
- Arnaoutoglou C
- Arnaoutoglou E
- Arnold G
- Arrandale L
- Arrich J
- Arrigo M
- Arshad H
- Arshad MA
- Arumugam S
- Arustei M
- Arvaniti K
- Arya A
- Arya S
- Asimakos A
- Asudo F
- Athanasakis E
- Atiku M
- Attrill E
- Attwood C
- Auer P
- Avidan M
- Avila Sanchez FJ
- Avila EJD
- Avis J
- Awad H
- Axioti E
- Ayyaz H
- Azam UAA
- Azambuja P
- Azevedo C
- Aziz FZ
- Baas P
- Baghirzada L
- Bai H-P
- Bai Y
- Baillie S
- Baines D
- Baio TH
- Bairaktari A
- Baker G
- Baker K-A
- Baker P
- Balain B
- Balaji P
- Balajonda N
- Balanescu A
- Balasubramaniam M
- Baldisserotto S
- Baldwin J
- Baldwin M
- Balfoussia D
- Bali C
- Bandeira ME
- Banerjee R
- Bankewitz C
- Banner-Goodspeed V
- Bao Q
- Barcraft-Barnes H
- Barneto L
- Barnett A
- Baroselli A
- Barraclough J
- Barras J-P
- Barrett S
- Barrett WJ
- Basanth S
- Batchelor N
- Bateman B
- Bates A
- Bates S
- Batista HD
- Bauchmuller K
- Bauer M
- Baumgarten G
- Baxter L
- Beaton C
- Beattie S
- Beavis V
- Bechan S
- Bejia T
- Belciu I
- Belda MT
- Bell G
- Bell R
- Bell S
- Bellandi M
- Bello J
- Beloeil H
- Belskiy V
- Ben-Menachem E
- Benavent P
- Benevento A
- Bengeri S
- Bennett C
- Bennett M
- Bennett R
- Bennett V
- Bentley C
- Beretta L
- Berg A
- Bergin C
- Bernard A
- Berntsen E
- Bertram W
- Bester D
- Bester M
- Bettega F
- Bettinelli A
- Bhardwaj N
- Bhatia K
- Bhula C
- Bi Y
- Biais M
- Biccard BM
- Bidd H
- Bidgoli J
- Biffen A
- Bignami E
- Bilolikar A
- Bin Mustapha MT
- Birch J
- Bishop DG
- Biyase T
- Bizios C
- Blackwell C
- Blackwood D
- Blaj M
- Blakemore SP
- Bland M
- Blunt M
- Blyth K
- Bocchino S
- Bodansky D
- Bodger P
- Boer C
- Boereboom C
- Boggiano V
- Bogner G
- Bolaji B
- Bolton D
- Boone M
- Boschi L
- Boshier P
- Botes M
- Botis I
- Bottini C
- Bottrill F
- Bouchez S
- Boulton K
- Bouris V
- Bourner L
- Boutsikos G
- Bouwman A
- Bouwman RA
- Bowrey S
- Boxall L
- Boyd C
- Bradburn M
- Bradley J
- Branagan G
- Branco T
- Brand B
- Brandsborg B
- Breitenstein S
- Brennan A
- Brennan E
- Brenner L
- Brincat M
- Briscoe R
- Bristogiannis S
- Brooke J
- Brookes J
- Brookes M
- Brooks C
- Broomby R
- Brotto AF
- Brown A
- Brown CW
- Brown G
- Brown J
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- Browning J
- Bruma D
- Brunete T
- Brunswicker A
- Bryant H
- Bua E
- Buccimazza I
- Buckley S
- Buerkle C
- Buhre W
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- Bunwarie B
- Burns K
- Burrows L
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- Burston B
- Burtenshaw A
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- Busuioc M
- Butryn I
- Butt G
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- Cabezuelo E
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- Cabral TDN
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- Calderwood C
- Callaghan M
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- Camsooksai J
- Cancho D
- Candido K
- Cang J
- Cannavo M
- Cao J
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- Cardosa J
- Cardoso G
- Cardy J
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- Carp CP
- Carr A
- Carrera R
- Carroll C
- Carroll J
- Caser E
- Castano Moreira B
- Castano B
- Castle G
- Cavanagh S
- Cawthorn L
- Cernea DD
- Chaddock M
- Chaloulis P
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- Chan HMH
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- Chan P
- Chan V
- Chan WK
- Chan WKJ
- Chan YL
- Chande S
- Chandler B
- Chandra S
- Chandrasekharan S
- Chang YH
- Chaniotaki F
- Charitos E
- Charlalampidoy A
- Charles R
- Chatterjee D
- Chatterjee J
- Chatzimichali CA
- Chau S
- Chazova E
- Cheah C
- Cheah S
- Cheeseman M
- Cheing Y
- Chen C
- Chen C
- Chen F
- Chen F
- Chen H
- Chen J
- Chen J
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- Chen L-L
- Chen P
- Chen Q
- Chen R
- Chen S
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- Chen Y
- Chen Y
- Chen Y
- Chen Y
- Chen Z
- Cheng B
- Cheng KH
- Cheng Z
- Cheong E
- Cherian R
- Cherrett V
- Chetty RR
- Chew M
- Chhabra A
- Chicken D-W
- Chilinciuc I
- Chin II
- Chirkut S
- Chisbert Cuenca V
- Chlorou D
- Choi H-MD
- Choi S
- Chow L
- Christian R
- Christiansen IC
- Christmas N
- Christodoulidis G
- Christodoulopoulou T
- Christofaki M
- Christoforidis D
- Chronis C
- Chu HM
- Chu S
- Chua P
- Chukkambotla S
- Chung CKE
- Cifra E
- Ciobanu C
- Ciobotaru OR
- Cirstea E
- Clark R
- Clarkson A
- Clarkson R
- Claxton A
- Clemmons K
- Cloro LM
- Clyde A
- Cobzaru I
- Codita A
- Colangelo A
- Colangelo C
- Colling K
- Collins H
- Collins M
- Collins N
- Colvin C
- Commey T
- Comptaer N
- Conde C
- Conradie A
- Constantin K
- Cook T
- Cooper L
- Cooper L
- Cooper M
- Cooper R
- Cooper S
- Copaciu E
- Cope J
- Copetti E
- Copley E
- Copotoiu SM
- Coppens M
- Corneci D
- Cornell J
- Cornish J
- Correia da Silva RFM
- Corti D
- Costanzo E
- Costelloe H
- Cotter R
- Cotterell S
- Cotterill D
- Coughlan E
- Coulter I
- Coulter S
- Coutinho F
- Cowton A
- Cox H
- Cozar OI
- Craig J
- Craven R
- Craw N
- Craw S
- Creary T
- Cripps H
- Critchley R
- Cronje L
- Cruickshank R
- Cruikshanks A
- Cruz S
- Cueva A
- Cunha P
- Curley G
- Currow H
- Czepanski C
- Czeslick E
- D'Andrea R
- da Costa Fischer BF
- Dafnios N
- Dai H
- Dai Q
- Dai Q
- Dai SY
- Daikou P
- Dalamagka M
- Dalampini E
- Dali-Kemmery L
- Dalton E
- Damant R
- Daniel C
- Daniel GD
- Daniel H
- Daniel H
- Daniel S
- Dankl D
- Darko J
- Darwish S
- Das S
- Dasrath A
- Datson A
- Daubeny T
- Daugaard M
- Davari M
- Dave T
- Davies C
- Davies H
- Davies K
- Davies K
- Davies L
- Davies Z
- Davis E
- Davis F
- Davis S
- Daya B
- De Andres Ibanez JA
- de Araujo DM
- De Baerdemaeker L
- de Beer J
- de Boer HD
- De Bruyne A
- de Campos Ferreira MF
- de Fretes J
- de Gasperi J
- De Hert S
- De Jongh K
- De Kegel D
- De Meyer JN
- De Oliveira MC
- de Rudnicki S
- de Swardt M
- de Vasconcellos K
- de Villiers M
- de Wet J
- Deacon M
- Deblaere I
- Dedemadi G
- Deen T
- Deepak S
- Deighton K
- Deja M
- Delgado Garcia DR
- Delgado Navarro C
- Della Rocca G
- Dempsey G
- Dempster A
- den Hoedt M
- Denham S
- Dent K
- Dermitzaki D
- Desbordes J
- Despotidis V
- Diaconescu C
- Dias F
- Dias S
- Dickson J
- Ditai J
- Divatia J
- Dixon L
- do Nascimento Junior P
- Dobson G
- Docherty P
- Dodiyi-Manuel A
- Dodsworth K
- Dolan R
- Dong B
- Donohue R
- Donovan A
- Douglas J
- Doumos R
- Downes C
- Doyle D
- Dragnea D
- Dragoescu NA
- Drake M
- Drimala M
- Drinkwater Z
- Drummond L
- Du F
- Du F
- Du X
- Duarte C
- Dube NZ
- Duca A
- Dudgeon L
- Dudson R
- Duenser M
- Dumitrascu CO
- Dumitrescu A
- Dunay A
- Dunk N
- Durant E
- Durodola A
- Dursin AN
- Durst A
- Duttchen K
- Dutu M
- Dwyer H
- Dylst D
- Dzhamullaev P
- Dzulkipli N
- Echem R
- Edmond H
- Edwards J
- Edwards M
- Edwards M
- Efthymiadi A
- Egan T
- Eggleston C
- Eichwalder A
- Eikman J
- Ekelund K
- el Manser D
- El-Sayed A
- Elabib A
- Elena G
- Elferink-Vonk R
- Elgasim M
- Ellis J
- Ellis K
- Elna C
- Emma T
- Endersby S
- Eneje P
- Eng K
- English D
- English R
- Epodoi J
- Eskildsen KZ
- Esteves S
- Ethgen S
- Evans A
- Evans C
- Everingham K
- Ewe R
- Ezekiel E
- Ezike H
- Fagerlund MJ
- Faina L
- Falk E
- Fan H
- Fan L
- Fan Y
- Fanfani LC
- Faponle F
- Faria e Maia D
- Faria F
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- Publication venue
- 'Oxford University Press (OUP)'
- Publication date
- 01/01/2016
- Field of study
BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44Â 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700
Measurement of the inclusive and differential Higgs boson production cross sections in the decay mode to a pair of Ï Leptons in pp collisions at sqrt[s]=13ââTeV
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- Wickramarathna DDC
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- Zorbilmez C
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- Zuo X
- Zuolo D
- Zygala L
- Ălvarez FernĂĄndez A
- Ăzçelik Ă
- Publication venue
- 'American Physical Society (APS)'
- Publication date
- 01/01/2022
- Field of study
Measurements of the inclusive and differential fiducial cross sections of the Higgs boson are presented, using the Ï lepton decay channel. The differential cross sections are measured as functions of the Higgs boson transverse momentum, jet multiplicity, and transverse momentum of the leading jet in the event, if any. The analysis is performed using proton-proton collision data collected with the CMS detector at the LHC at a center-of-mass energy of 13ââTeV and corresponding to an integrated luminosity of 138ââfb^{-1}. These are the first differential measurements of the Higgs boson cross section in the final state of two Ï leptons. In final states with a large jet multiplicity or with a Lorentz-boosted Higgs boson, these measurements constitute a significant improvement over measurements performed in other final states
Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis
- Author
- Abrea I
- Adlard J
- Ahmad F
- Ahmad S
- Ahmed M
- Ahmed S
- Aitman T
- Alachkar H
- Allahua M
- Allen HL
- Allsup D
- Almeida-King J
- Almeida-Peters S
- Aman J
- Amouyel P
- Ancliff P
- Anderson A
- Andrews M
- Antrobus R
- Archer SL
- Argula R
- Arkon A
- Armstrong R
- Arno G
- Arora A
- Ashford S
- Astle W
- Aston V
- Attwood A
- Austin ED
- Ayesh W
- Babbs C
- Badesch D
- Bakchoul T
- Bakshi S
- Bariana T
- Barnett C
- Barve M
- Barwell J
- Batai K
- Beckmann J
- Bennett D
- Bentley D
- Benza R
- Bhatt N
- Bierzynska A
- Bindu J
- Birru H
- Biss T
- Blake R
- Bleda M
- Boekwig D
- Bogaard H
- Bogaard HJ
- Bourne C
- Boyce S
- Bradley J
- Brady D
- Breen G
- Brennan P
- Brewer C
- Broach D
- Brod NC
- Brody L
- Brown M
- Browning M
- Bruno J
- Buchan R
- Buckland M
- Bueser T
- Burger CD
- Burns S
- Burren O
- Calleja P
- Carr-White G
- Carss K
- Casanova N
- Casey R
- Caskey E
- Caulfield M
- Cebola I
- Chakinala M
- Chambers J
- Chambers J
- Cheng F
- Chinnery PF
- Christian M
- Church C
- Coghlan G
- Coghlan JG
- Colby E
- Cole T
- Collins J
- Collins P
- Colombo C
- Condliffe R
- Cook S
- Cook T
- Cooper N
- Cope M
- Cordell S
- Correa P
- Corris P
- Corris PA
- Crisp-Hihn A
- Curry N
- Danesino C
- Daniels M
- Daugherty L
- Davis A
- Davis J
- Debette S
- Deevi SVV
- del Junco H
- DeMartino J
- Dent T
- Desai AA
- Devereux J
- Dewhurst E
- Dillon L
- Dixon P
- Do R
- Dotson A
- Downes K
- Drake J
- Drazyk A
- Drewe E
- Durst L
- Dutt T
- Edgar D
- Edwards K
- Egner W
- Elliott CG
- Elwing J
- Erber W
- Erwood M
- Estiu MC
- Evans DG
- Evans G
- Everington T
- Eyries M
- Eyries M
- Farber H
- Favier R
- Feliz N
- Ferrer J
- Fletcher D
- Fortin T
- Fox J
- Franke A
- Frantz RP
- Franzo M
- Frary A
- French C
- Freson K
- Frontini M
- Frost A
- Gale D
- Gall H
- Garcia JGN
- Geoghegan C
- Gerighty T
- Germain M
- Ghio S
- Ghofrani H-A
- Gibbs JSR
- Gibbs S
- Gilmour K
- Girerd B
- Goddard S
- Gomez K
- Gordins P
- Gosal D
- Graf S
- Grassi L
- Greene D
- Greenhalgh L
- Greinacher A
- Gresele P
- Griffiths P
- Grigoriadou S
- Grocock R
- Grozeva D
- Gruhlke P
- Gygi A
- Hackett S
- Hadinnapola C
- Hague W
- Haimel M
- Hall M
- Hannon K
- Hanscombe KB
- Hanson H
- Harbaum L
- Harkness K
- Harley J
- Harper A
- Harrington B
- Harris C
- Hart D
- Hassan A
- Hawke L
- Hawkes N
- Hayman G
- He H
- Henderson A
- Heuerman S
- Hill NS
- Hirsch R
- Hoffmann J
- Holy R
- Horvath R
- Houweling A
- Houweling AC
- Howard L
- Howard LS
- Hu F
- Hudson G
- Hughes J
- Huissoon A
- Humbert M
- Humphray S
- Hunter S
- Hurles M
- Iem T
- Igenoza T
- Ingledue R
- Ivy D
- Izatt L
- Jackson E
- James R
- Johnson S
- Jolles S
- Jolley J
- Jurkute N
- Kaakinen M
- Karnekar R
- Karnes JH
- Kasanicki M
- Kazkaz H
- Kazmi R
- Kelleher P
- Kennedy K
- Kiely D
- Kiely DG
- Kingston N
- Kittles R
- Klima R
- Klinger J
- Knight J
- Kostadima M
- Kovacs G
- Koziell A
- Kreuzhuber R
- Kuijpers T
- Kumar A
- Kumararatne D
- Kurian M
- Laffan M
- Lahm T
- Lalloo F
- Lambert M
- Larimore D
- Laudes M
- Lawrie A
- Layton M
- Lee J
- Lemma M
- Lentaigne C
- Levine A
- Lewis K
- Light A
- Linger R
- Longhurst H
- Louka E
- Lovato E
- Lutz K
- MacDonald C
- Machado RD
- Madan B
- Maher E
- Maimaris J
- Malur A
- Mangles S
- Mapeta R
- Marchbank K
- Marks J
- Marks S
- Markus HS
- Marschall H-U
- Marshall A
- Marsolo K
- Martin J
- Martin LJ
- Mathias M
- Matthews E
- Maxwell H
- McAlinden P
- McCarthy M
- McClain K
- Mcgaha T
- Meacham S
- Mead A
- Megy K
- Mehta S
- Mendibles L
- Michaelides M
- Millar C
- Miller-Reed K
- Moledina S
- Montani D
- Moore T
- Morrell N
- Morrell NW
- Mozere M
- Muir K
- Mumford A
- Nathan SD
- Newnham M
- Nichols WC
- Noordegraaf AV
- Norwood T
- O'Sullivan J
- Obaji S
- Okoli S
- Olanipekun L
- Olschewski A
- Olschewski H
- Ong KR
- Ormiston M
- Ormondroyd E
- Oudiz RJ
- Ouwehand W
- Ouwehand WH
- Paciotti G
- Palmer J
- Palmisciano A
- Papadia S
- Park S-M
- Parry D
- Paterson J
- Pauciulo MW
- Peacock A
- Peacock AJ
- Peden J
- Peerlinck K
- Peichel G
- Penkett C
- Pepke-Zaba J
- Petersen R
- Pisarcik J
- Prokopenko I
- Pyle A
- Rankin S
- Rao A
- Raymond FL
- Rayner-Matthews P
- Rees C
- Rehman Z
- Rendon A
- Renton T
- Reponen A
- Rhodes CJ
- Rice A
- Richardson S
- Richter A
- Roads T
- Robbins I
- Roberts I
- Roden DM
- Rohwer K
- Rosenzweig EB
- Ross RM
- Ross RVM
- Roughley C
- Rowley C
- Roy N
- Sadeghi-Alavijeh O
- Saleem M
- Samani N
- Sanchis-Juan A
- Santiago J
- Sargur R
- Satchell S
- Savic S
- Saydain G
- Scelsi L
- Schiltz K
- Schilz R
- Schulman S
- Scovel P
- Scully M
- Searle C
- Seeger W
- Sewell C
- Seyres D
- Shaffer CM
- Shapiro S
- Sharmardina O
- Shtoyerman R
- Sibson K
- Side L
- Simeoni I
- Simms RW
- Simon M
- Simpson M
- Singleton D
- Sitbon O
- Sivapalaratnam S
- Skytte A-B
- Smith K
- Smith KGC
- Snape K
- Soubrier F
- Southgate L
- Spears J
- Staines S
- Staples E
- Stark H
- Stephens J
- Stirrups K
- Stock S
- Stratoberdha M
- Stratton E
- Suntharalingam J
- Swietlik E
- Swietlik EM
- Szuberla S
- Tait RC
- Talks K
- Tan R
- Tang H
- Tavlarides A
- Tchourbanov AY
- Thaventhiran J
- Themistocleous A
- Thenappan T
- Theuer A
- Thomas M
- Thomson K
- Thrasher A
- Thys C
- Tischkowitz M
- Titterton C
- Toh C-H
- Tomer D
- Torres F
- Toshner M
- Toshner MR
- Traylor M
- Treacy C
- Treacy CM
- Tregouet D-A
- Trembath R
- Trembath RC
- Tuna S
- Turek W
- Turk E
- Turro E
- Ulrich A
- Urban T
- Vale T
- Van Geet C
- Van Zuydam N
- Vang B
- Vazquez-Lopez M
- Visnaw K
- Von Ziegenweidt J
- Waisfisz Q
- Waisfisz Q
- Walker S
- Walsworth AK
- Walter RE
- Warden A
- Ware J
- Watkins H
- Watt C
- Webster A
- Wei W
- Welch S
- Wessels J
- Westbury S
- Westwood J-P
- Wharton J
- White RJ
- Whitehorn D
- Whitman R
- Whitworth J
- Wilkins MR
- Williams A
- Williamson C
- Wilson O
- Wilt J
- Winslow C
- Wong E
- Wood N
- Wood Y
- Woods G
- Woodward E
- Wort S
- Wort SJ
- Worth A
- Yates K
- Yong P
- Young T
- Yu P
- Yu-Wai-Man P
- Yung D
- Ziemak C
- Publication venue
- ELSEVIER SCI LTD
- Publication date
- 01/03/2019
- Field of study
Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic
variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary
arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.
Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial
hypertension. These GWAS used data from four international case-control studies across 11744 individuals with
European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and
the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching
genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants
at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and
tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.
Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55â2·08], p=5·13Ă10â
Âčâ”) and a second locus in
HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42â1·71],
p=7·65Ă10â
ÂČâ°) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus
had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25â1·48],
p=1·69Ă10â
ÂčÂČ; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene
regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined
haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The
HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in
patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI
12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02â8·05]), despite similar baseline disease severity.
Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in
HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more
common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed
to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA
typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.
Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA,
ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and
RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR
Germline selection shapes human mitochondrial DNA diversity.
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- Publication venue
- Science
- Publication date
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- Field of study
Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.NIHR, Wellcome Trust, MRC, Genomics Englan
Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data (vol 8, 1300, 2018)
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- NATURE PUBLISHING GROUP
- Publication date
- 03/09/2018
- Field of study
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- Ălvarez FernĂĄndez A
- Ăzçelik Ă
- Publication venue
- Springer Nature on behalf of SISSA
- Publication date
- 01/08/2022
- Field of study
A preprint version of the article is available at arXiv:2204.12945v2 [hep-ex], https://arxiv.org/abs/2204.12945v2 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/HIG-19-014 (CMS Public Pages). Report number: CMS-HIG-19-014, CERN-EP-2022-019.Results are presented from a search for the Higgs boson decay H â ZÎł, where Z â â+ââ with â = e or ÎŒ. The search is performed using a sample of proton-proton (pp) collision data at a center-of-mass energy of 13 TeV, recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 138 fb^{â1}. Events are assigned to mutually exclusive categories, which exploit differences in both event topology and kinematics of distinct Higgs production mechanisms to enhance signal sensitivity. The signal strength ÎŒ, defined as the product of the cross section and the branching fraction [Ï(pp â H)B(H â ZÎł)] relative to the standard model prediction, is extracted from a simultaneous fit to the â+ââÎł invariant mass distributions in all categories and is found to be ÎŒ = 2.4 ± 0.9 for a Higgs boson mass of 125.38 GeV. The statistical significance of the observed excess of events is 2.7 standard deviations. This measurement corresponds to Ï(pp â H)B(H â ZÎł) = 0.21 ± 0.08 pb. The observed (expected) upper limit at 95% confidence level on ÎŒ is 4.1 (1.8). The ratio of branching fractions B(H â ZÎł)/B(H â γγ) is measured to be 1.5 +0.7â0.6, which agrees with the standard model prediction of 0.69 ± 0.04 at the 1.5 standard deviation level.SCOAP3
A new calibration method for charm jet identification validated with proton-proton collision events at âs = 13 TeV
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- Ălvarez FernĂĄndez A
- Ăzçelik Ă
- Publication venue
- 'IOP Publishing'
- Publication date
- 01/01/2022
- Field of study
ArXiv ePrint: 2111.03027Copyright © 2022 CERN for the benefit of the CMS collaboration. Many measurements at the LHC require efficient identification of heavy-flavour jets, i.e. jets originating from bottom (b) or charm (c) quarks. An overview of the algorithms used to identify c jets is described and a novel method to calibrate them is presented. This new method adjusts the entire distributions of the outputs obtained when the algorithms are applied to jets of different flavours. It is based on an iterative approach exploiting three distinct control regions that are enriched with either b jets, c jets, or light-flavour and gluon jets. Results are presented in the form of correction factors evaluated using proton-proton collision data with an integrated luminosity of 41.5 fb-1 at âs = 13 TeV, collected by the CMS experiment in 2017. The closure of the method is tested by applying the measured correction factors on simulated data sets and checking the agreement between the adjusted simulation and collision data. Furthermore, a validation is performed by testing the method on pseudodata, which emulate various mismodelling conditions. The calibrated results enable the use of the full distributions of heavy-flavour identification algorithm outputs, e.g. as inputs to machine-learning models. Thus, they are expected to increase the sensitivity of future physics analyses.SCOAP
Observation of triple J/Ï meson production in proton-proton collisions
- Author
- Aarrestad TK
- Abbaneo D
- Abbiendi G
- Abbrescia M
- Abdelalim AA
- Abdullah WATW
- Abdullin S
- Abercrombie D
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- Afanasiev S
- Agapitos A
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- Aggleton R
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- Aguilar-Benitez M
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- Ahmad WH
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- Ăzçelik Ă
- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 19/01/2023
- Field of study
Data availability:
Tabulated results are provided in the HEPData record for this analysis71. Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS policy as stated in CMS data preservation, re-use and open access policy.Code availability:
The CMS core software is publically available at https://github.com/cms-sw/cmssw.Copyright . Protons consist of three valence quarks, two up-quarks and one down-quark, held together by gluons and a sea of quark-antiquark pairs. Collectively, quarks and gluons are referred to as partons. In a proton-proton collision, typically only one parton of each proton undergoes a hard scattering â referred to as single-parton scattering â leaving the remainder of each proton only slightly disturbed. Here, we report the study of double- and triple-parton scatterings through the simultaneous production of three J/Ï mesons, which consist of a charm quark-antiquark pair, in proton-proton collisions recorded with the CMS experiment at the Large Hadron Collider. We observed this process â reconstructed through the decays of J/Ï mesons into pairs of oppositely charged muons â with a statistical significance above five standard deviations. We measured the inclusive fiducial cross-section to be 272+141â104(stat)±17(syst)fb, and compared it to theoretical expectations for triple-J/Ï meson production in single-, double- and triple-parton scattering scenarios. Assuming factorization of multiple hard-scattering probabilities in terms of single-parton scattering cross-sections, double- and triple-parton scattering are the dominant contributions for the measured process.SCOAP3.Change history:
27 February 2023A Correction to this paper has been published: https://doi.org/10.1038/s41567-023-01992-
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