Great Ormond Street Hospital for Children NHS Foundation Trust

AUTORES: Daniel J Klionsky1745,1749*, Kotb Abdelmohsen840, Akihisa Abe1237, Md Joynal Abedin1762, Hagai Abeliovich425,
\nAbraham Acevedo Arozena789, Hiroaki Adachi1800, Christopher M Adams1669, Peter D Adams57, Khosrow Adeli1981,
\nPeter J Adhihetty1625, Sharon G Adler700, Galila Agam67, Rajesh Agarwal1587, Manish K Aghi1537, Maria Agnello1826,
\nPatrizia Agostinis664, Patricia V Aguilar1960, Julio Aguirre-Ghiso784,786, Edoardo M Airoldi89,422, Slimane Ait-Si-Ali1376,
\nTakahiko Akematsu2010, Emmanuel T Akporiaye1097, Mohamed Al-Rubeai1394, Guillermo M Albaiceta1294,
\nChris Albanese363, Diego Albani561, Matthew L Albert517, Jesus Aldudo128, Hana Alg€ul1164, Mehrdad Alirezaei1198,
\nIraide Alloza642,888, Alexandru Almasan206, Maylin Almonte-Beceril524, Emad S Alnemri1212, Covadonga Alonso544,
\nNihal Altan-Bonnet848, Dario C Altieri1205, Silvia Alvarez1497, Lydia Alvarez-Erviti1395, Sandro Alves107,
\nGiuseppina Amadoro860, Atsuo Amano930, Consuelo Amantini1554, Santiago Ambrosio1458, Ivano Amelio756,
\nAmal O Amer918, Mohamed Amessou2089, Angelika Amon726, Zhenyi An1538, Frank A Anania291, Stig U Andersen6,
\nUsha P Andley2079, Catherine K Andreadi1690, Nathalie Andrieu-Abadie502, Alberto Anel2027, David K Ann58,
\nShailendra Anoopkumar-Dukie388, Manuela Antonioli832,858, Hiroshi Aoki1791, Nadezda Apostolova2007,
\nSaveria Aquila1500, Katia Aquilano1876, Koichi Araki292, Eli Arama2098, Agustin Aranda456, Jun Araya591,
\nAlexandre Arcaro1472, Esperanza Arias26, Hirokazu Arimoto1225, Aileen R Ariosa1749, Jane L Armstrong1930,
\nThierry Arnould1773, Ivica Arsov2120, Katsuhiko Asanuma675, Valerie Askanas1924, Eric Asselin1867, Ryuichiro Atarashi794,
\nSally S Atherton369, Julie D Atkin713, Laura D Attardi1131, Patrick Auberger1787, Georg Auburger379, Laure Aurelian1727,
\nRiccardo Autelli1992, Laura Avagliano1029,1755, Maria Laura Avantaggiati364, Limor Avrahami1166, Suresh Awale1986,
\nNeelam Azad404, Tiziana Bachetti568, Jonathan M Backer28, Dong-Hun Bae1933, Jae-sung Bae677, Ok-Nam Bae409,
\nSoo Han Bae2117, Eric H Baehrecke1729, Seung-Hoon Baek17, Stephen Baghdiguian1368,
\nAgnieszka Bagniewska-Zadworna2, Hua Bai90, Jie Bai667, Xue-Yuan Bai1133, Yannick Bailly884,
\nKithiganahalli Narayanaswamy Balaji473, Walter Balduini2002, Andrea Ballabio316, Rena Balzan1711, Rajkumar Banerjee239,
\nG abor B anhegyi1052, Haijun Bao2109, Benoit Barbeau1363, Maria D Barrachina2007, Esther Barreiro467, Bonnie Bartel997,
\nAlberto Bartolom e222, Diane C Bassham550, Maria Teresa Bassi1046, Robert C Bast Jr1273, Alakananda Basu1798,
\nMaria Teresa Batista1578, Henri Batoko1336, Maurizio Battino970, Kyle Bauckman2085, Bradley L Baumgarner1909,
\nK Ulrich Bayer1594, Rupert Beale1553, Jean-Fran¸cois Beaulieu1360, George R. Beck Jr48,294, Christoph Becker336,
\nJ David Beckham1595, Pierre-Andr e B edard749, Patrick J Bednarski301, Thomas J Begley1135, Christian Behl1419,
\nChristian Behrends757, Georg MN Behrens406, Kevin E Behrns1627, Eloy Bejarano26, Amine Belaid490,
\nFrancesca Belleudi1041, Giovanni B enard497, Guy Berchem706, Daniele Bergamaschi983, Matteo Bergami1401,
\nBen Berkhout1441, Laura Berliocchi714, Am elie Bernard1749, Monique Bernard1354, Francesca Bernassola1880,
\nAnne Bertolotti791, Amanda S Bess272, S ebastien Besteiro1351, Saverio Bettuzzi1828, Savita Bhalla913,
\nShalmoli Bhattacharyya973, Sujit K Bhutia838, Caroline Biagosch1159, Michele Wolfe Bianchi520,1378,1381,
\nMartine Biard-Piechaczyk210, Viktor Billes298, Claudia Bincoletto1314, Baris Bingol350, Sara W Bird1128, Marc Bitoun1112,
\nIvana Bjedov1258, Craig Blackstone843, Lionel Blanc1183, Guillermo A Blanco1496, Heidi Kiil Blomhoff1812,
\nEmilio Boada-Romero1297, Stefan B€ockler1464, Marianne Boes1423, Kathleen Boesze-Battaglia1835, Lawrence H Boise286,287,
\nAlessandra Bolino2063, Andrea Boman693, Paolo Bonaldo1823, Matteo Bordi897, J€urgen Bosch608, Luis M Botana1308,
\nJoelle Botti1375, German Bou1405, Marina Bouch e1038, Marion Bouchecareilh1331, Marie-Jos ee Boucher1901,
\nMichael E Boulton481, Sebastien G Bouret1926, Patricia Boya133, Micha€el Boyer-Guittaut1345, Peter V Bozhkov1141,
\nNathan Brady374, Vania MM Braga469, Claudio Brancolini1997, Gerhard H Braus353, Jos e M Bravo-San Pedro299,393,508,1374,
\nLisa A Brennan322, Emery H Bresnick2022, Patrick Brest490, Dave Bridges1939, Marie-Agn es Bringer124, Marisa Brini1822,
\nGlauber C Brito1311, Bertha Brodin631, Paul S Brookes1872, Eric J Brown352, Karen Brown1690, Hal E Broxmeyer480,
\nAlain Bruhat486,1339, Patricia Chakur Brum1893, John H Brumell446, Nicola Brunetti-Pierri315,1171,
\nRobert J Bryson-Richardson781, Shilpa Buch1777, Alastair M Buchan1819, Hikmet Budak1022, Dmitry V Bulavin118,505,1789,
\nScott J Bultman1792, Geert Bultynck665, Vladimir Bumbasirevic1470, Yan Burelle1356, Robert E Burke216,217,
\nMargit Burmeister1750, Peter B€utikofer1473, Laura Caberlotto1987, Ken Cadwell896, Monika Cahova112, Dongsheng Cai24,
\nJingjing Cai2099, Qian Cai1018, Sara Calatayud2007, Nadine Camougrand1343, Michelangelo Campanella1700,
\nGrant R Campbell1525, Matthew Campbell1249, Silvia Campello556,1876, Robin Candau1769, Isabella Caniggia1983,
\nLavinia Cantoni560, Lizhi Cao116, Allan B Caplan1656, Michele Caraglia1051, Claudio Cardinali1043, Sandra Morais Cardoso1579, Jennifer S Carew208, Laura A Carleton874, Cathleen R Carlin101, Silvia Carloni2002,
\nSven R Carlsson1267, Didac Carmona-Gutierrez1643, Leticia AM Carneiro312, Oliana Carnevali971, Serena Carra1318,
\nAlice Carrier120, Bernadette Carroll900, Caty Casas1324, Josefina Casas1116, Giuliana Cassinelli324, Perrine Castets1462,
\nSusana Castro-Obregon214, Gabriella Cavallini1841, Isabella Ceccherini568, Francesco Cecconi253,555,1884,
\nArthur I Cederbaum459, Valent ın Ce~na199,1281, Simone Cenci1323,2064, Claudia Cerella444, Davide Cervia1996,
\nSilvia Cetrullo1478, Hassan Chaachouay2028, Han-Jung Chae187, Andrei S Chagin634, Chee-Yin Chai626,628,
\nGopal Chakrabarti1502, Georgios Chamilos1601, Edmond YW Chan1142, Matthew TV Chan181, Dhyan Chandra1003,
\nPallavi Chandra548, Chih-Peng Chang818, Raymond Chuen-Chung Chang1653, Ta Yuan Chang345, John C Chatham1434,
\nSaurabh Chatterjee1910, Santosh Chauhan527, Yongsheng Che62, Michael E Cheetham1263, Rajkumar Cheluvappa1783,
\nChun-Jung Chen1153, Gang Chen598,1676, Guang-Chao Chen9, Guoqiang Chen1078, Hongzhuan Chen1077, Jeff W Chen1514,
\nJian-Kang Chen370,371, Min Chen249, Mingzhou Chen2104, Peiwen Chen1823, Qi Chen1674, Quan Chen172,
\nShang-Der Chen138, Si Chen325, Steve S-L Chen10, Wei Chen2125, Wei-Jung Chen829, Wen Qiang Chen979, Wenli Chen1113,
\nXiangmei Chen1133, Yau-Hung Chen1157, Ye-Guang Chen1250, Yin Chen1447, Yingyu Chen953,955, Yongshun Chen2135,
\nYu-Jen Chen712, Yue-Qin Chen1145, Yujie Chen1208, Zhen Chen339, Zhong Chen2123, Alan Cheng1702,
\nChristopher HK Cheng184, Hua Cheng1728, Heesun Cheong814, Sara Cherry1836, Jason Chesney1703,
\nChun Hei Antonio Cheung817, Eric Chevet1359, Hsiang Cheng Chi140, Sung-Gil Chi656, Fulvio Chiacchiera308,
\nHui-Ling Chiang958, Roberto Chiarelli1826, Mario Chiariello235,567,577, Marcello Chieppa835, Lih-Shen Chin290,
\nMario Chiong1285, Gigi NC Chiu878, Dong-Hyung Cho676, Ssang-Goo Cho650, William C Cho982, Yong-Yeon Cho105,
\nYoung-Seok Cho1064, Augustine MK Choi2095, Eui-Ju Choi656, Eun-Kyoung Choi387,400,685, Jayoung Choi1563,
\nMary E Choi2093, Seung-Il Choi2116, Tsui-Fen Chou412, Salem Chouaib395, Divaker Choubey1574, Vinay Choubey1936,
\nKuan-Chih Chow822, Kamal Chowdhury730, Charleen T Chu1856, Tsung-Hsien Chuang827, Taehoon Chun657,
\nHyewon Chung652, Taijoon Chung978, Yuen-Li Chung1194, Yong-Joon Chwae18, Valentina Cianfanelli254,
\nRoberto Ciarcia1775, Iwona A Ciechomska886, Maria Rosa Ciriolo1876, Mara Cirone1042, Sofie Claerhout1694,
\nMichael J Clague1698, Joan Cl aria1457, Peter GH Clarke1687, Robert Clarke361, Emilio Clementi1045,1398, C edric Cleyrat1781,
\nMiriam Cnop1366, Eliana M Coccia574, Tiziana Cocco1459, Patrice Codogno1375, J€orn Coers271, Ezra EW Cohen1533,
\nDavid Colecchia235,567,577, Luisa Coletto25, N uria S Coll123, Emma Colucci-Guyon516, Sergio Comincini1829,
\nMaria Condello578, Katherine L Cook2073, Graham H Coombs1929, Cynthia D Cooper2076, J Mark Cooper1395,
\nIsabelle Coppens601, Maria Tiziana Corasaniti1387, Marco Corazzari485,1884, Ramon Corbalan1566,
\nElisabeth Corcelle-Termeau251, Mario D Cordero1899, Cristina Corral-Ramos1289, Olga Corti507,1109, Andrea Cossarizza1767,
\nPaola Costelli1993, Safia Costes1518, Susan L Cotman721, Ana Coto-Montes946, Sandra Cottet566,1688, Eduardo Couve1301,
\nLori R Covey1015, L Ashley Cowart762, Jeffery S Cox1536, Fraser P Coxon1427, Carolyn B Coyne1846, Mark S Cragg1919,
\nRolf J Craven1679, Tiziana Crepaldi1995, Jose L Crespo1300, Alfredo Criollo1285, Valeria Crippa558, Maria Teresa Cruz1576,
\nAna Maria Cuervo26, Jose M Cuezva1277, Taixing Cui1907, Pedro R Cutillas987, Mark J Czaja27, Maria F Czyzyk-Krzeska1572,
\nRuben K Dagda2068, Uta Dahmen1404, Chunsun Dai800, Wenjie Dai1187, Yun Dai2059, Kevin N Dalby1940,
\nLuisa Dalla Valle1822, Guillaume Dalmasso1340, Marcello D’Amelio557, Markus Damme188, Arlette Darfeuille-Michaud1340,
\nCatherine Dargemont950, Victor M Darley-Usmar1433, Srinivasan Dasarathy205, Biplab Dasgupta202, Srikanta Dash1254,
\nCrispin R Dass242, Hazel Marie Davey8, Lester M Davids1560, David D avila227, Roger J Davis1731, Ted M Dawson604,
\nValina L Dawson606, Paula Daza1898, Jackie de Belleroche470, Paul de Figueiredo1180,1182,
\nRegina Celia Bressan Queiroz de Figueiredo135, Jos e de la Fuente1023, Luisa De Martino1775,
\nAntonella De Matteis1171, Guido RY De Meyer1443, Angelo De Milito631, Mauro De Santi2002,

Importance: In communities with high rates of coronavirus disease 2019, reports have emerged of children with an unusual syndrome of fever and inflammation. Objectives: To describe the clinical and laboratory characteristics of hospitalized children who met criteria for the pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS) and compare these characteristics with other pediatric inflammatory disorders. Design, Setting, and Participants: Case series of 58 children from 8 hospitals in England admitted between March 23 and May 16, 2020, with persistent fever and laboratory evidence of inflammation meeting published definitions for PIMS-TS. The final date of follow-up was May 22, 2020. Clinical and laboratory characteristics were abstracted by medical record review, and were compared with clinical characteristics of patients with Kawasaki disease (KD) (n = 1132), KD shock syndrome (n = 45), and toxic shock syndrome (n = 37) who had been admitted to hospitals in Europe and the US from 2002 to 2019. Exposures: Signs and symptoms and laboratory and imaging findings of children who met definitional criteria for PIMS-TS from the UK, the US, and World Health Organization. Main Outcomes and Measures: Clinical, laboratory, and imaging characteristics of children meeting definitional criteria for PIMS-TS, and comparison with the characteristics of other pediatric inflammatory disorders. Results: Fifty-eight children (median age, 9 years [interquartile range {IQR}, 5.7-14]; 20 girls [34%]) were identified who met the criteria for PIMS-TS. Results from SARS-CoV-2 polymerase chain reaction tests were positive in 15 of 58 patients (26%) and SARS-CoV-2 IgG test results were positive in 40 of 46 (87%). In total, 45 of 58 patients (78%) had evidence of current or prior SARS-CoV-2 infection. All children presented with fever and nonspecific symptoms, including vomiting (26/58 [45%]), abdominal pain (31/58 [53%]), and diarrhea (30/58 [52%]). Rash was present in 30 of 58 (52%), and conjunctival injection in 26 of 58 (45%) cases. Laboratory evaluation was consistent with marked inflammation, for example, C-reactive protein (229 mg/L [IQR, 156-338], assessed in 58 of 58) and ferritin (610 μg/L [IQR, 359-1280], assessed in 53 of 58). Of the 58 children, 29 developed shock (with biochemical evidence of myocardial dysfunction) and required inotropic support and fluid resuscitation (including 23/29 [79%] who received mechanical ventilation); 13 met the American Heart Association definition of KD, and 23 had fever and inflammation without features of shock or KD. Eight patients (14%) developed coronary artery dilatation or aneurysm. Comparison of PIMS-TS with KD and with KD shock syndrome showed differences in clinical and laboratory features, including older age (median age, 9 years [IQR, 5.7-14] vs 2.7 years [IQR, 1.4-4.7] and 3.8 years [IQR, 0.2-18], respectively), and greater elevation of inflammatory markers such as C-reactive protein (median, 229 mg/L [IQR 156-338] vs 67 mg/L [IQR, 40-150 mg/L] and 193 mg/L [IQR, 83-237], respectively). Conclusions and Relevance: In this case series of hospitalized children who met criteria for PIMS-TS, there was a wide spectrum of presenting signs and symptoms and disease severity, ranging from fever and inflammation to myocardial injury, shock, and development of coronary artery aneurysms. The comparison with patients with KD and KD shock syndrome provides insights into this syndrome, and suggests this disorder differs from other pediatric inflammatory entities.

The use of exosomes in clinical settings is progressively becoming a reality, as clinical trials testing exosomes for diagnostic and therapeutic applications are generating remarkable interest from the scientific community and investors. Exosomes are small extracellular vesicles secreted by all cell types playing intercellular communication roles in health and disease by transferring cellular cargoes such as functional proteins, metabolites and nucleic acids to recipient cells. An in-depth understanding of exosome biology is therefore essential to ensure clinical development of exosome based investigational therapeutic products. Here we summarise the most up-to-date knowkedge about the complex biological journey of exosomes from biogenesis and secretion, transport and uptake to their intracellular signalling. We delineate the major pathways and molecular players that influence each step of exosome physiology, highlighting the routes of interest, which will be of benefit to exosome manipulation and engineering. We highlight the main controversies in the field of exosome research: their adequate definition, characterisation and biogenesis at plasma membrane. We also delineate the most common identified pitfalls affecting exosome research and development. Unravelling exosome physiology is key to their ultimate progression towards clinical applications. Video Abstract.

Host-mediated lung inflammation is present 1 , and drives mortality 2 , in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development 3 . Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 10 -8 ) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 10 -8 ) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 10 -12 ) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 10 -8 ) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results. Low read depth sequencing of whole genomes and high read depth exomes of nearly 10,000 extensively phenotyped individuals are combined to help characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits; in addition to describing population structure and providing functional annotation of rare and low-frequency variants the authors use the data to estimate the benefits of sequencing for association studies. This paper, combining data and initial findings from the different arms of the UK10K project, describes insights from low-read-depth sequencing of whole genomes or high-read-depth exome sequencing of nearly 10,000 individuals sampled from a range of disease collections, as well as participants from healthy population based cohorts. The authors characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits. In addition to describing population structure and providing functional annotation of rare and low frequency variants, they use the data to estimate the benefits of sequencing for association studies.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

The KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD represents a selective update of the prior CKD-MBD Guideline published in 2009. This update, along with the 2009 publication, is intended to assist the practitioner caring for adults and children with chronic kidney disease (CKD), those on chronic dialysis therapy, or individuals with a kidney transplant. This review highlights key aspects of the 2017 CKD-MBD Guideline Update, with an emphasis on the rationale for the changes made to the original guideline document. Topic areas encompassing updated recommendations include diagnosis of bone abnormalities in CKD–mineral and bone disorder (MBD), treatment of CKD-MBD by targeting phosphate lowering and calcium maintenance, treatment of abnormalities in parathyroid hormone in CKD-MBD, treatment of bone abnormalities by antiresorptives and other osteoporosis therapies, and evaluation and treatment of kidney transplant bone disease. The KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD represents a selective update of the prior CKD-MBD Guideline published in 2009. This update, along with the 2009 publication, is intended to assist the practitioner caring for adults and children with chronic kidney disease (CKD), those on chronic dialysis therapy, or individuals with a kidney transplant. This review highlights key aspects of the 2017 CKD-MBD Guideline Update, with an emphasis on the rationale for the changes made to the original guideline document. Topic areas encompassing updated recommendations include diagnosis of bone abnormalities in CKD–mineral and bone disorder (MBD), treatment of CKD-MBD by targeting phosphate lowering and calcium maintenance, treatment of abnormalities in parathyroid hormone in CKD-MBD, treatment of bone abnormalities by antiresorptives and other osteoporosis therapies, and evaluation and treatment of kidney transplant bone disease. In 2009, Kidney Disease: Improving Global Outcomes (KDIGO) published the KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar At that time, the Work Group acknowledged the lack of high-quality evidence on which to base recommendations. Over the years that followed, multiple randomized controlled trials (RCTs) and prospective cohort studies examined some of the key issues underlying the assessment, development, progression, and treatment of CKD-MBD. KDIGO recognizes the need to reexamine the currency of its guidelines on a periodic basis, and therefore convened a Controversies Conference in 2013, titled “CKD-MBD: Back to the Future.”2Ketteler M. Elder G.J. Evenepoel P. et al.Revisiting KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference.Kidney Int. 2015; 87: 502-528Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar The conference participants concluded that most of the 2009 recommendations1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar were still applicable in current practice; however, a total of 12 recommendations were identified for revision, based on new data. As a result, a Work Group was convened to undertake a “selective update”3Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar of the 2009 KDIGO CKD-MBD Guideline (Table 1).1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar Notably, despite the availability of results from several new key clinical trials, large gaps of knowledge still remained. Accordingly, many of the “opinion-based” recommendation statements from the 2009 Guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar remain unchanged (see summary of KDIGO CKD-MBD recommendations).Table 1Comparison of the 2017 and 2009 KDIGO CKD-MBD Guideline recommendations2017 revised KDIGO CKD-MBD recommendations3Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar2009 KDIGO CKD-MBD recommendations1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google ScholarBrief rationale for updating3.2.1. 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To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. Δ(9) -Tetrahydrocannabinol (Δ(9) -THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Δ(9) -THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Δ(9) -THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the α3 and α1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Δ(9) -THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Hippocampal sclerosis (HS) is the most frequent histopathology encountered in patients with drug-resistant temporal lobe epilepsy (TLE). Over the past decades, various attempts have been made to classify specific patterns of hippocampal neuronal cell loss and correlate subtypes with postsurgical outcome. However, no international consensus about definitions and terminology has been achieved. A task force reviewed previous classification schemes and proposes a system based on semiquantitative hippocampal cell loss patterns that can be applied in any histopathology laboratory. Interobserver and intraobserver agreement studies reached consensus to classify three types in anatomically well-preserved hippocampal specimens: HS International League Against Epilepsy (ILAE) type 1 refers always to severe neuronal cell loss and gliosis predominantly in CA1 and CA4 regions, compared to CA1 predominant neuronal cell loss and gliosis (HS ILAE type 2), or CA4 predominant neuronal cell loss and gliosis (HS ILAE type 3). Surgical hippocampus specimens obtained from patients with TLE may also show normal content of neurons with reactive gliosis only (no-HS). HS ILAE type 1 is more often associated with a history of initial precipitating injuries before age 5 years, with early seizure onset, and favorable postsurgical seizure control. CA1 predominant HS ILAE type 2 and CA4 predominant HS ILAE type 3 have been studied less systematically so far, but some reports point to less favorable outcome, and to differences regarding epilepsy history, including age of seizure onset. The proposed international consensus classification will aid in the characterization of specific clinicopathologic syndromes, and explore variability in imaging and electrophysiology findings, and in postsurgical seizure control.

Messenger RNA encodes cellular function and phenotype. In the context of human cancer, it defines the identities of malignant cells and the diversity of tumor tissue. We studied 72,501 single-cell transcriptomes of human renal tumors and normal tissue from fetal, pediatric, and adult kidneys. We matched childhood Wilms tumor with specific fetal cell types, thus providing evidence for the hypothesis that Wilms tumor cells are aberrant fetal cells. In adult renal cell carcinoma, we identified a canonical cancer transcriptome that matched a little-known subtype of proximal convoluted tubular cell. Analyses of the tumor composition defined cancer-associated normal cells and delineated a complex vascular endothelial growth factor (VEGF) signaling circuit. Our findings reveal the precise cellular identities and compositions of human kidney tumors.

The International League Against Epilepsy (ILAE) Task Force on Nosology and Definitions proposes a classification and definition of epilepsy syndromes in the neonate and infant with seizure onset up to 2 years of age. The incidence of epilepsy is high in this age group and epilepsy is frequently associated with significant comorbidities and mortality. The licensing of syndrome specific antiseizure medications following randomized controlled trials and the development of precision, gene-related therapies are two of the drivers defining the electroclinical phenotypes of syndromes with onset in infancy. The principal aim of this proposal, consistent with the 2017 ILAE Classification of the Epilepsies, is to support epilepsy diagnosis and emphasize the importance of classifying epilepsy in an individual both by syndrome and etiology. For each syndrome, we report epidemiology, clinical course, seizure types, electroencephalography (EEG), neuroimaging, genetics, and differential diagnosis. Syndromes are separated into self-limited syndromes, where there is likely to be spontaneous remission and developmental and epileptic encephalopathies, diseases where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. The emerging class of etiology-specific epilepsy syndromes, where there is a specific etiology for the epilepsy that is associated with a clearly defined, relatively uniform, and distinct clinical phenotype in most affected individuals as well as consistent EEG, neuroimaging, and/or genetic correlates, is presented. The number of etiology-defined syndromes will continue to increase, and these newly described syndromes will in time be incorporated into this classification. The tables summarize mandatory features, cautionary alerts, and exclusionary features for the common syndromes. Guidance is given on the criteria for syndrome diagnosis in resource-limited regions where laboratory confirmation, including EEG, MRI, and genetic testing, might not be available.

SeCTion 4: WhaT iS The evidenCe for TranSmiSSion of nTm BeTWeen individualS? recommendation Adequate infection control policies need to be implemented in both inpatient and outpatient settings to minimise risks of person-to-person transmission of Mycobacterium abscessus in individuals with cystic fibrosis (CF). (Grade B) SeCTion 5: hoW Should The lung diSeaSe aTTriBuTaBle To nTm infeCTion Be defined? recommendation In the absence of robust evidence to support an alternative definition and due to the clinical and research benefits of having a uniform definition, use of the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) 2007 definition of non-tuberculous mycobacterial (NTM) pulmonary disease is recommended 1 (see Box 1). (Grade D) good practice point 3 The management of coexisting lung conditions/ infections should be optimised before ascribing clinical decline to NTM-pulmonary disease.

BACKGROUND: Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). OBJECTIVES: We sought to reclassify disorders with skin fragility, with a focus on EB, based on new clinical and molecular data. METHODS: This was a consensus expert review. RESULTS: In this latest consensus report, we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Other disorders with skin fragility, where blisters are a minor part of the clinical picture or are not seen because skin cleavage is very superficial, are classified as separate categories. These include peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility. Because of the common manifestation of skin fragility, these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. CONCLUSIONS: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB. What is already known about this topic? Epidermolysis bullosa (EB) is a group of genetic disorders with skin blistering. The last updated recommendations on diagnosis and classification were published in 2014. What does this study add? We introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors and natural history of EB are reviewed. Other disorders with skin fragility, e.g. peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility are classified as separate categories; these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Linked Comment: Pope. Br J Dermatol 2020; 183:603.

The guideline group was selected to be representative of UK-based aplastic anaemia (AA) medical experts. Recommendations are based on review of the literature using MEDLINE and PUBMED up to December 2014 under the heading: ‘aplastic anemia’. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria are specified in the BCSH guidance pack http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html and the GRADE working group website http://www.gradeworkinggroup.org The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with AA. The guidance may not be appropriate to every patient and in all cases individual patient circumstances may dictate an alternative approach. Review of the manuscript was performed by the British Committee for Standards in Haematology (BCSH) Haemato-Oncology Task Force, BCSH Executive Committee and then reviewed by a sounding board of the British Society for Haematology (BSH). This compromises 50 or more members of the BSH who have reviewed this guidance and commented on its content and applicability in the UK setting. It has also been reviewed by the Aplastic Anaemia Trust patient group but they do not necessarily approve or endorse the contents. Aplastic anaemia is a rare and heterogeneous disorder. It is defined as pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate or marrow fibrosis. To diagnose AA there must be at least two of the following (Camitta et al, 1975) haemoglobin concentration (Hb) <100 g/l, platelet count <50 × 109/l, neutrophil count <1·5 × 109/l. The majority (70-80%) of cases are idiopathic (Marsh et al, 2009). The remainder mainly consist of IBMFS. The incidence is 2-3 per million per year in Europe, but higher in East Asia (Montane et al, 2008). There is a biphasic distribution, with peaks at 10-25 years and over 60 years. AA not fulfilling the criteria for SAA or VSAA Patients commonly present with symptoms of anaemia and thrombocytopenia. Serious infection is not a frequent symptom early in the course of the disease. A preceding history of jaundice may suggest a post-hepatitic AA. Whilst the majority of cases are idiopathic, a careful drug, occupational exposure and family history should be obtained. Any putative drugs should be discontinued and the patient should not be re-challenged. If a possible drug association is suspected, this must be reported to the Medicines and MHRA using the Yellow Card Scheme (http://yellowcard.gov.uk). There is usually no hepatosplenomegaly or lymphadenopathy (except in infection). In young adults the presence of short stature, skin hyper/hypo pigmented areas and skeletal abnormalities, particularly affecting the thumb is suggestive of FA (Shimamura & Alter, 2010). The triad of nail dystrophy, reticular skin pigmentation and oral leucoplakia is characteristic of dyskeratosis congenita (DC) (Shimamura & Alter, 2010). The finding of peripheral lymphoedema may indicate a diagnosis of Emberger syndrome due to germline GATA2 mutation. See Table 1 for the summary of investigations for the diagnosis and further evaluation of AA; this table also summarizes the emerging diagnostics incorporating the latest molecular technologies that are likely to feature in the diagnosis and differential diagnosis within the next couple of years. Both a bone marrow aspirate and trephine biopsy are required for the diagnosis of AA, and the key bone marrow findings are summarized in Table 2. Karyotyping may fail in very hypocellular marrows with there being insufficient metaphases. In this situation perform FISH analysis for chromosomes 5, 7, 8 and 13 It was previously assumed that the presence of an abnormal cytogenetic clone indicated a diagnosis of MDS and not AA. However it is now evident that abnormal cytogenetic clones [such as del(13q), trisomy 8 and others], which may be transient, are present in up to 12% of patients with otherwise typical AA at diagnosis (Gupta et al, 2006; Afable et al, 2011b). Although monosomy 7 may indicate the likelihood of MDS in children, in adults monosomy 7 can also be seen in AA. Abnormal cytogenetic clones may arise during the course of the disease and the appearance of a new cytogenetic abnormality may provide evidence of clonal evolution (Maciejewski et al, 2002) The investigations in Table 1 should exclude non-AA causes of pancytopenia with a hypocellular bone marrow, which are listed in Table 3. A MDT meeting approach is recommended to collate relevant results and develop a treatment plan. Consideration should be given for seeking expert advice on the diagnosis and management of patients where there is uncertainty, or when an IBMFS is being considered. A number of inherited/genetic disorders are characterized by BMF/AA, usually in association with one or more somatic abnormality (Alter, 2007). The BMF typically presents in childhood but this can sometimes be in adulthood. The two syndromes frequently associated with generalized BMF/AA are FA and DC (Dokal, 2011; Soulier, 2011), which can sometimes present with AA alone as their initial manifestation. These syndromes are genetically heterogeneous; 16 FA genes and 10 DC genes have been identified. The FA genes are important in DNA repair, the DC genes in telomere maintenance. Based on the DNA repair defect a diagnostic test-‘chromosomal breakage test’ is available for FA. Patients with DC usually have very short telomeres and this measurement [using flow cytometric fluorescence in situ hybridization or multiplex quantitative polymerase chain reaction (PCR)] can be useful in the assessment of DC. Genetic testing for known DC genes (representing c. 60% of cases) is possible in specialized centres. In addition there are other genetic syndromes that are sometimes associated with AA/cytopenias. This includes Shwachman‒Diamond syndrome ‒ SDS (Dror et al, 2011) (mutations in SBDS), congenital amegakaryocytic thrombocytopenia ‒ CAMT (Ballmaier & Germeshausen, 2011) (mutations in MPL) and GATA2 deficiency (Emberger syndrome) (Horwitz, 2014) as well as genetically uncharacterized cases. Some cases of inherited AA first present in adulthood and it is important to recognize these as their management differs from that of idiopathic AA. Where there are sufficient characteristic abnormalities a diagnosis may be straightforward (e.g. mucocutaneous features in DC). Where the presentation is only with AA and with minimal non-haematological abnormalities, inherited BMF should be considered and testing for known BMF syndromes should be undertaken. Investigations for inherited forms of AA should be re-appraised in patients initially classified as “idiopathic AA” and who fail to respond to anti-thymocyte globulin (ATG). For most patients with AA, transfusion with red blood cells (RBC) is essential to maintain a safe blood count, improve symptoms of anaemia and maintain quality of life. The decision to transfuse RBC should be based on clinical symptoms (signs of anaemia), taking into consideration the patient's age and co-morbidities (cardiac, pulmonary or vascular). Although no specific pre-transfusion haemoglobin concentration (Hb) trigger can be recommended, it is important to maintain quality of life and avoid symptoms. A higher trigger may be needed for elderly patients and those with co-morbidities. Optimal use of RBC transfusion involves administration of enough red cells to maximize clinical outcome whilst avoiding unnecessary transfusions (Carson et al, 2012). Alloimmunization against red cell antigens and iron overload are the commonest risks associated with regular transfusion therapy. Provision of phenotype-matched blood (for Rh and Kell) should be considered to reduce the risk of alloimmunization. Regular platelet transfusion support may be required for AA patients. With the exception of one publication (Sagmeister et al, 1999), literature specific to platelet transfusion support in AA is lacking, and evidence is taken from studies addressing the need for platelet transfusion support in patients with reversible thrombocytopenia (Estcourt et al, 2012; Stanworth et al, 2013; Killick et al, 2014). It is recommended that prophylactic platelet transfusions should be given to stable AA patients on active therapy (where the treatment aims to reverse the severe thrombocytopenia) with a platelet count <10 × 109/l. For patients with sepsis, the platelet count should be kept >20 × 109/l. For thrombocytopenic patients requiring invasive procedures, platelet transfusions must be administered, aiming to achieve a platelet count in line with BCSH guidelines for the relevant procedures (British Committee for Standards in Haematology, 2003), and a pre-procedure platelet count should be checked. During treatment with ATG, worsening thrombocytopenia can occur. This is due to increased platelet consumption in the presence of cross-reacting antibodies in ATG binding to platelets. Although there are no studies to support the exact threshold for platelet transfusion support prior to ATG, most authors use a threshold of 20 × 109/l (Scheinberg et al, 2011; Scheinberg & Young, 2012). Regular support with RBC and platelet transfusions increases the risk of HLA and non-HLA (minor histocompatibility) alloimmunization, leading to poor platelet increments and increased risk of graft rejection after HSCT. Leucodepletion of cellular blood components may reduce, but not eliminate, alloimmunization (Killick et al, 1997; Desmarets et al, 2009). The possibility of HLA alloimmunization and provision of HLA-selected platelets should be considered for patients refractory to platelet transfusion, provided other causes of refractoriness have been excluded. In the absence of HLA antibodies and for patients failing to increment with HLA-matched platelets, investigation and matching for human platelet antigen antibodies should be considered. The use of irradiated granulocytes should be considered in patients with life-threatening infection related to severe neutropenia (Quillen et al, 2009), and anecdotally may be life saving. Data about the effectiveness of granulocyte concentrates are limited and usage is linked with a number of adverse events, such as transfusion-related acute lung injury, alloimmunization and febrile reactions. Irradiation of cellular blood components prevents transfusion-associated graft-versus-host disease (TA-GVHD). This is a rare complication of blood transfusion with 100% mortality. Irradiation may also reduce the risk of alloimmunization in AA, as reported from animal data (Bean et al, 1994). Following universal leucodepletion in the UK, the Committee on the of and no the use of blood components they have been for patients with and those should be considered To there has not been a from the British Society of blood and granulocyte components should be provided for Aplastic anaemia patients on regular RBC transfusion support develop iron but there on the clinical of iron In the of a is an adverse of outcome in cell et al, 2007). Although the most for assessment of iron or can and and is a useful its in AA has not been There are data iron therapy in AA. A was the Evaluation of with et al, 2010). This that with can be in patients with AA and can reduce the are required to those who are transfusion is with and the drug should be used with in AA patients who are taking is for use in but only as line therapy when is or is but not recommended in patients et al, For those to or after a is recommended for iron the of in AA (Marsh & In to patients in SAA neutropenia is and in a higher incidence of invasive infection and severe of to ATG in the two has and this has in with and of et al, Aplastic anaemia patients who are should be in when in In the UK it is to prophylactic and regular an as or and of content et al, two (e.g. and or (e.g. may be but the should be to A active or should be used as In the UK, against is not in patients with AA is not with or should be used during and after ATG therapy. During ATG of and is but and not need disease has only very been reported after ATG, most after It is not UK to with and guidelines for the management of febrile the assessment and management of are well and should and for and guidance et al, 2012). as per should be early for patients with as these patients have transfusions may be life in severe sepsis, such as invasive particularly for patients due to to (Quillen et al, 2009). such as and granulocyte are usually in blood in AA patients (Marsh et al, results are reported with the et al, also on of AA in the first line is the of ATG and ATG is no available (Marsh et al, & Scheinberg & Young, 2012). A from the of and a at and and with ATG to ATG for first line (Scheinberg et al, 2011; et al, 2012). There is no for use of with ATG et al, is used with ATG for the of of of There is no age for ATG, but there is increased in patients years with ATG et al, 2011) on of AA in the A course of ATG may be indicated for to respond or after a first course or the patient is for (Marsh et al, & Scheinberg & Young, For a ATG may be A course of ATG is an alternative but this may be associated with more and (Marsh et al, 2012). to ATG, ATG more and in more It is important to that patients prophylactic support when using The of ATG is for It is given as an over to the risk of a must be is to use an of the SAA data the first of the first is given over 1 ATG should be given a or other as it is to peripheral and also for of administration of other drugs and blood of ATG should be with 1 and platelet transfusions aiming to the platelet count × 109/l (Marsh et al, Scheinberg & Young, 2012). to should be given for febrile of the neutrophil commonly during ATG in careful to is is on the after ATG is at a of 1 for by over the should be as the is at a of to achieve blood levels of should be whilst the blood count to A of the drug every can be after at least a further of to reduce the risk of et al, of ATG are early acute pulmonary syndrome and and from the of ATG, most commonly with and is with a and it usually a of platelet transfusions are needed during the of due to platelet There is no for using with ATG as studies have that given for after ATG not improve or et al, to ATG defined in Table is after an of The to a first course of ATG is is 100% for age for for years and for years et al, In the to a first course of ATG is only with (Scheinberg et al, 2011; et al, 2012; Scheinberg & Young, 2012). For ATG results in higher to alone (Marsh et al, after ATG in up to of the risk of clonal evolution to is and in et al, Scheinberg & Young, 2012). previously or or of at least one cell line or of to a course of ATG from most studies is for refractory AA and for AA (Marsh et al, & Scheinberg & Young, 2012). for are summarized in Table It is recommended that expert advice be when the use of other and are not recommended in the treatment of AA Table There is a risk of AA following in those patients who have to The evidence is limited and based on as well as an that a is likely to be an important trigger in the of AA et al, et al, should be following when AA patients should be as recommended for all bone marrow The for are based on the guidelines et al, Patients should be in Society for and centres. from a is indicated for SAA in young and patients who have a data for patients to those years et al, co-morbidities should be to for of for patients years. is indicated for SAA after to respond to one course of There is no age but this should be on an individual patient and to co-morbidities at the The should be or based on HLA for and using a family or a may be other treatment after to respond to and in the absence of a and a et al, 2012; & should be for HLA the presence of which is associated with a very risk of graft There is clear guidance on the exact for alternative as this is or but new to alternative are being using In the rare situation where there is a should be considered in all patients of age as (Marsh & For all AA patients who may be HLA should be performed at of that can as as and the patient not only to HLA but also to and the of is that there is no to a course of ATG and the patient can then to the patient's is of with severe for to is usually at MDT approach is essential for the The aims of the up are to the diagnosis and clonal evolution assess co-morbidities the cell and and the transfusion of the and review of transfusion The of to use on patient age of for of ATG et al, et al, 2011) or (Marsh et al, 2011; et al, 2012). See Table For the is but is the of and 50 years. A analysis has that after are no to in that is not a of et al, 2013; et al, 2014). to AA early management and management of are summarized in Table The treatment of elderly patients with AA is more in patients. In the outcome is due to of the patients should be for co-morbidities and their specific should be as quality of life is an important outcome in this With to it is important to exclude as MDS is more AA in this age group diagnostic age per is not a to treatment in the very is considered the treatment of There is no for as first line therapy in patients can be considered in selected patients with a the least and most treatment should be consideration is a is such that those with life count × or a severe infection requiring should be more those with severe disease. with ATG and results in a more and alone in patients with (Marsh et al, patients and have a higher risk of acute and the risks and of treatment should be up for individual Patients must be as the risk of and with ATG is higher in the patients have an after ATG to patients et al, or Although the of alone is to the of ATG and in is not as patients may respond to line therapy with ATG and (Marsh et al, alone has the of being but patients must be for and may be used as a in AA, but medical very careful assessment in patients prior to this as a possible (Scheinberg et al, 2012). or can be considered in or to et al, et al, has may be a alternative for of is required as it can and blood Patients who are or who should be is a oral In an of an at patients with refractory SAA with et al, 2014). in of patients. The drug was well in most patients. levels may and there are about clonal monosomy 7, which further has been by the and in the for treatment of SAA refractory to It has as of been by the for SAA refractory to or patients who are and for HSCT. It should be used with for clonal or following a clinical It is that a bone marrow is performed prior to treatment to exclude an abnormal cytogenetic clone typical of particularly monosomy Although the or AA and is it a to and with a clinical AA can be for the first during in early or during but the disease may after or or after et al, is during in AA patients who have previously to ATG, those with et al, not trigger of the disease in patients who HSCT. et in previously with for AA. reported a complication in the two cases of and of AA in and a further needed transfusion during blood not from of AA during in particularly in of blood has to in and outcome et al, it is important to with the patient and family the risks to the and et al, It is essential that the patient be frequently initially but more frequently and to disease and with very with the and of a clone should with a The of should be on is the of treatment of AA in and the platelet count be 20 × 109/l with platelet The risk of alloimmunization and platelet refractoriness to be considered. is safe during & and is recommended for those ATG, or for AA during are not should be by flow et al, et al, 2010). of is a and quantitative for the of clones which in up to of AA the on the of the flow cytometric analysis used et al, et al, clones are most in the neutrophil and in AA and be by flow If the patient has a blood transfusion, a of red cells may be by flow in the granulocyte and the clinical of a clone in AA as by flow clones can in or the need for the is important is the presence of a clone associated with clinical or evidence of should be for as this is a feature of when the patient not have of associated with should be with the count, and Patients should be for at the diagnosis of AA. If for years and then to testing If the or for the first years and only reduce the the of the cells has The presence of a clone in the of AA not the of therapy for the There is evidence that the finding of a clone a to but this is not universal in all Patients with a clone ATG, should be for of AA may in patients in the presence of patients should be to one of the two specialized and to be for and for consideration for following MDT Patients be seen in of the two or in one of 10 Data from the to the that cell has an outcome in and to when indicated et al, 2012). the finding of a clone not or on the decision to the advice and in these guidelines is to be and at the of to the the British Committee for Standards in Haematology (BCSH) the for the content of these These guidelines are only to patients with AA. to and for their review of this The authors to the BCSH and the BSH sounding BCSH and the Aplastic Trust for their support in these the guidelines was the authors in and of the authors the of the authors have a of to the BCSH and Task which may be reviewed on In summary the following authors have the following of has from for at and from for at and has from has from for has from for at has from and has from has from and and have from for The of the authors have no of of the group the group new evidence available that the strength of the in this or it The be and from the BCSH guidelines website it If new are an be on the BCSH guidelines website at If are required due to in of evidence or evidence a new of the guidance be on the BCSH

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.

The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use “kidney“ rather than “renal” or “nephro-” when referring to kidney disease and kidney function; (ii) to use “kidney failure” with appropriate descriptions of presence or absence of symptoms, signs, and treatment, rather than “end-stage kidney disease”; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI), rather than alternative descriptions, to define and classify severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate (GFR), rather than “abnormal” or “reduced” kidney function to describe alterations in kidney structure and function. A proposed 5-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary, but they considered standardization of scientific nomenclature to be essential for improving communication. The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use “kidney“ rather than “renal” or “nephro-” when referring to kidney disease and kidney function; (ii) to use “kidney failure” with appropriate descriptions of presence or absence of symptoms, signs, and treatment, rather than “end-stage kidney disease”; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI), rather than alternative descriptions, to define and classify severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate (GFR), rather than “abnormal” or “reduced” kidney function to describe alterations in kidney structure and function. A proposed 5-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary, but they considered standardization of scientific nomenclature to be essential for improving communication. The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for effective communication by stakeholders in the kidney health community.1Plantinga L.C. Boulware L.E. Coresh J. et al.Patient awareness of chronic kidney disease: trends and predictors.Arch Intern Med. 2008; 168: 2268-2275Crossref PubMed Scopus (227) Google Scholar, 2Saran R. Robinson B. Abbott K.C. et al.US Renal Data System 2018 Annual Data Report: Epidemiology of Kidney Disease in the United States.Am J Kidney Dis. 2019; 73: A7-A8Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar, 3James S.L. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2018; 392: 1789-1858Abstract Full Text Full Text PDF PubMed Scopus (6082) Google Scholar, 4Global Burden of Disease 2017 Causes of Death CollaboratorsGlobal, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2018; 392: 1736-1788Abstract Full Text Full Text PDF PubMed Scopus (3582) Google Scholar Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. Two decades ago, a survey of hundreds of published articles and meeting abstracts reported a broad array of overlapping, confusing terms for chronic kidney disease (CKD) and advocated adoption of unambiguous terminology.5Hsu C.Y. Chertow G.M. Chronic renal confusion: insufficiency, failure, dysfunction, or disease.Am J Kidney Dis. 2000; 36: 415-418Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Nevertheless, terms flagged by that analysis as problematic, such as “chronic renal failure” and “pre-dialysis,” still appear in current-day publications. A coherent, shared nomenclature could influence communication at all levels, including not only greater appreciation of the burden of disease, but also improved understanding about how patients feel about their disease, more effective communication between kidney disease specialists and other clinicians, more straightforward comparison and integration of datasets, better recognition of gaps in knowledge for future research, and more comprehensive public health policies for acute and chronic kidney disease. The international organization Kidney Disease: Improving Global Outcomes (KDIGO) has developed guidelines promulgating definitions and classifications for acute kidney injury (AKI), acute kidney diseases and disorders (AKD), and CKD, and guidelines for their evaluation and management.6Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work GroupKDIGO clinical practice guideline for acute kidney injury.Kidney Int Suppl. 2012; 2: 1-138Abstract Full Text Full Text PDF Scopus (2007) Google Scholar,7Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1596) Google Scholar Developing consistent, patient-centered, and precise descriptions of kidney function and disease in the scientific literature is an important objective that KDIGO is now pursuing to align communication in clinical practice, research, and public health. Although some terms have been in use for decades, the increased exchange of information among stakeholders makes it timely to revisit nomenclature in order to ensure consistency. The goal is to facilitate communication within and across disciplines and between practitioner and patient communities, to ultimately improve outcomes through clarity and precision. In June 2019, KDIGO convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in English-language scientific articles to describe kidney function and disease, and developing a glossary that could be used by journals. Prior to the conference, KDIGO posted an announcement of the conference on its website, including the Scope of Work and requested public comment.8Kidney Disease: International Global OutcomesConsensus Conference on Nomenclature for Kidney Function & Disease.https://kdigo.org/conferences/nomenclature/Date Scholar at the conference of kidney kidney at general and other of clinical kidney health research, and Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines The on general of acute and chronic kidney disease and kidney measures, rather than specific kidney diseases and of function and The Scope of Work developed to the conference a of for of causes of kidney disease and measures, and for and were considered the of of the and and and the nomenclature to describe kidney function and on general of acute and chronic kidney disease and general kidney measures, rather than specific kidney diseases and specific of function and for “renal” or and definitions and other descriptions of disease and disease kidney and of “kidney with KDIGO guideline to that articles in the English-language literature should rather than “renal” or “nephro-” when referring to kidney disease and kidney failure” with appropriate descriptions of presence or absence of symptoms, signs, and rather than definition and classification of AKD and rather than alternative descriptions to define and classify severity of AKD and definition and classification of CKD rather than alternative descriptions to define and classify severity of kidney as albuminuria or decreased rather than “abnormal” or “reduced” kidney function to describe alterations in kidney structure and acute kidney diseases and acute kidney CKD, chronic kidney glomerular filtration Kidney Disease: Improving Global in a acute kidney diseases and acute kidney CKD, chronic kidney glomerular filtration Kidney Disease: Improving Global Prior KDIGO have been but is about the of terms used to describe kidney function and disease on have kidney disease. 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2: 1-138Abstract Full Text Full Text PDF Scopus (2007) Google Scholar,7Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1596) Google Scholar In the acute conference attendees with disease severity by and treatment, but they not consensus on use of the “kidney failure” rather than or use of “kidney for all of it be appropriate for to be in with the of the KDIGO Disease: International Global Conference on Acute Kidney 2019; Scholar Conference attendees that and of kidney or the be and and there or to was as for research, with the that it be in the future to classify kidney by the presence or absence of and The KDIGO Conference in Chronic Kidney Disease use of the for not to but to for of kidney et of the KDIGO Conference on in Chronic Kidney Disease: developing a to improving Full Text Full Text PDF PubMed Scopus Google Scholar also an that could be used of with was considered to be consistent with the attendees the that of this in nomenclature not the to in the United and that the KDIGO definition and classification for should be used rather than the definitions to the classification and the Acute Kidney Injury which were by the 2012 KDIGO guideline Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work GroupKDIGO clinical practice guideline for acute kidney injury.Kidney Int Suppl. 2012; 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BACKGROUND: Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). METHODS: In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. FINDINGS: The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4-11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses). INTERPRETATION: WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. FUNDING: UK Department of Health and Social Care and The Wellcome Trust.

Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle (five core enzymes, one activating enzyme and one mitochondrial ornithine/citrulline antiporter) with an estimated incidence of 1:8.000. Patients present with hyperammonemia either shortly after birth (~50%) or, later at any age, leading to death or to severe neurological handicap in many survivors. Despite the existence of effective therapy with alternative pathway therapy and liver transplantation, outcomes remain poor. This may be related to underrecognition and delayed diagnosis due to the nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim at providing a trans-European consensus to: guide practitioners, set standards of care and help awareness campaigns. To achieve these goals, the guidelines were developed using a Delphi methodology, by having professionals on UCDs across seven European countries to gather all the existing evidence, score it according to the SIGN evidence level system and draw a series of statements supported by an associated level of evidence. The guidelines were revised by external specialist consultants, unrelated authorities in the field of UCDs and practicing pediatricians in training. Although the evidence degree did hardly ever exceed level C (evidence from non-analytical studies like case reports and series), it was sufficient to guide practice on both acute and chronic presentations, address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Also, it identified knowledge voids that must be filled by future research. We believe these guidelines will help to: harmonise practice, set common standards and spread good practices with a positive impact on the outcomes of UCD patients.

During the first 24-48 hours of life, as normal neonates transition from intrauterine to extrauterine life, their plasma glucose (PG) concentrations are typically lower than later in life.1Cornblath M. Reisner S.H. Blood glucose in the neonate and its clinical significance.N Engl J Med. 1965; 273: 378-381Crossref PubMed Scopus (116) Google Scholar, 2Srinivasan G. Pildes R.S. Cattamanchi G. Voora S. Lilien L.D. Plasma glucose values in normal neonates: a new look.J Pediatr. 1986; 109: 114-117Abstract Full Text PDF PubMed Scopus (225) Google Scholar, 3Stanley C.A. Rozance P.J. Thornton P.S. De Leon D.D. Harris D. Haymond M.W. et al.Re-evaluating “transitional neonatal hypoglycemia”: mechanism and implications for management.J Pediatr. 2015; 166: 1520-1525Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Published guidelines for screening at-risk newborns and managing low PG concentrations in neonates focus on the immediate neonatal period, but do not address the diagnosis and management of disorders causing recurrent and prolonged hypoglycemia.4Canadian Paediatric SocietyScreening guidelines for newborns at risk for low blood glucose.Paediatr Child Health. 2004; 9: 723-740PubMed Google Scholar, 5Adamkin D.H. Postnatal glucose homeostasis in late-preterm and term infants.Pediatrics. 2011; 127: 575-579Crossref PubMed Scopus (424) Google Scholar, 6Wight N. Marinelli K.A. ABM clinical protocol 1: guidelines for glucose monitoring and treatment of hypoglycemia in breastfed neonates.Breastfeed Med. 2006; 1: 178-184Crossref PubMed Scopus (27) Google Scholar Distinguishing between transitional neonatal glucose regulation in normal newborns and hypoglycemia that persists or occurs for the first time beyond the first 3 days of life is important for prompt diagnosis and effective treatment to avoid serious consequences, including seizures and permanent brain injury.Moreover, the evaluation and management of pediatric hypoglycemia differ in several respects from that in adults, for whom guidelines were recently published.7Cryer P.E. Axelrod L. Grossman A.B. Heller S.R. Montori V.M. Seaquist E.R. et al.Evaluation and management of adult hypoglycemic disorders: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2009; 94: 709-728Crossref PubMed Scopus (704) Google Scholar First, persistent hypoglycemia most often results from a congenital or genetic defect in regulating secretion of insulin, deficiency of cortisol and/or growth hormone, or defects in the metabolism of glucose, glycogen, and fatty acids. Second, it may be difficult to identify and distinguish newborn infants with a persistent hypoglycemia disorder from those with transitional low glucose levels in the initial 48 hours of life, as detailed in the separate document on transitional neonatal hypoglycemia prepared by our committee.3Stanley C.A. Rozance P.J. Thornton P.S. De Leon D.D. Harris D. Haymond M.W. et al.Re-evaluating “transitional neonatal hypoglycemia”: mechanism and implications for management.J Pediatr. 2015; 166: 1520-1525Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Third, the first few months of life are the most vulnerable period for developmental disability, which occurs in ∼25%-50% of children with congenital hyperinsulinism. Early recognition and treatment are crucial for preventing these sequelae.8Menni F. de Lonlay P. Sevin C. Touati G. Peigne C. Barbier V. et al.Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia.Pediatrics. 2001; 107: 476-479Crossref PubMed Scopus (271) Google Scholar, 9Steinkrauss L. Lipman T.H. Hendell C.D. Gerdes M. Thornton P.S. Stanley C.A. Effects of hypoglycemia on developmental outcome in children with congenital hyperinsulinism.J Pediatr Nurs. 2005; 20: 109-118Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 10Meissner T. Wendel U. Burgard P. Schaetzle S. Mayatepek E. Long-term follow-up of 114 patients with congenital hyperinsulinism.Eur J Endocrinol. 2003; 149: 43-51Crossref PubMed Scopus (157) Google ScholarTo address these deficiencies, the Pediatric Endocrine Society convened an expert panel of pediatric endocrinologists and neonatologists to develop guidelines for managing hypoglycemia in neonates, infants, and children, but excluding children with diabetes. The goals of these guidelines are to help physicians recognize persistent hypoglycemia disorders, guide their expeditious diagnosis and effective treatment, and prevent brain damage in at-risk babies.MethodsEvidence Retrieval and RatingThe committee searched for existing evidence synthesis reports, systematic reviews, and meta-analyses. The committee also evaluated guidelines published by the Endocrine Society, American Academy of Pediatrics, Canadian Pediatric Society, and others, and reviewed their bibliographies.4Canadian Paediatric SocietyScreening guidelines for newborns at risk for low blood glucose.Paediatr Child Health. 2004; 9: 723-740PubMed Google Scholar, 5Adamkin D.H. Postnatal glucose homeostasis in late-preterm and term infants.Pediatrics. 2011; 127: 575-579Crossref PubMed Scopus (424) Google Scholar, 6Wight N. Marinelli K.A. ABM clinical protocol 1: guidelines for glucose monitoring and treatment of hypoglycemia in breastfed neonates.Breastfeed Med. 2006; 1: 178-184Crossref PubMed Scopus (27) Google Scholar, 7Cryer P.E. Axelrod L. Grossman A.B. Heller S.R. Montori V.M. Seaquist E.R. et al.Evaluation and management of adult hypoglycemic disorders: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2009; 94: 709-728Crossref PubMed Scopus (704) Google Scholar Committee members identified additional individual studies.The committee adopted the framework of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group,11Atkins D. Best D. Briss P.A. Eccles M. Falck-Ytter Y. Flottorp S. et al.Grading quality of evidence and strength of recommendations.BMJ. 2004; 328: 1490Crossref PubMed Google Scholar in which guideline developers rate their confidence in the evidence as very low (+000), low (++00), moderate (+++0), or high (++++). Randomized trials start as high, and observational studies start as low.11Atkins D. Best D. Briss P.A. Eccles M. Falck-Ytter Y. Flottorp S. et al.Grading quality of evidence and strength of recommendations.BMJ. 2004; 328: 1490Crossref PubMed Google ScholarGrading the Strength of RecommendationsThe guideline developers considered the quality of the evidence. They also considered the balance between benefits and harms, patients' values and preferences, cost and resource utilization, and other societal and contextual factors, such as availability of technology and health services and implementation barriers. The recommendations according to the GRADE framework are either strong (GRADE 1), stated as “we recommend,” or weak (GRADE 2), stated as “we suggest.”Section 1: Which Neonates, Infants, and Children to Evaluate for Hypoglycemia1.1For children who are able to communicate their symptoms, we recommend evaluation and management only of those in whom Whipple's triad (see below) is documented. GRADE 1++++.1.2For infants and younger children who are unable to reliably communicate symptoms, we suggest evaluation and management only of those whose PG concentrations are documented by laboratory quality assays to be below the normal threshold for neurogenic responses (<60 mg/dL [3.3 mmol/L]). GRADE 2+++0.1.3For those neonates who are suspected to be at high risk of having a persistent hypoglycemia disorder, we suggest evaluation when the infant is ≥48 hours of age so that the period of transitional glucose regulation has passed and persistent hypoglycemia may be excluded before discharge home. GRADE 2++00.Clinical Definition of HypoglycemiaClinical hypoglycemia is defined as a PG concentration low enough to cause symptoms and/or signs of impaired brain function.7Cryer P.E. Axelrod L. Grossman A.B. Heller S.R. Montori V.M. Seaquist E.R. et al.Evaluation and management of adult hypoglycemic disorders: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2009; 94: 709-728Crossref PubMed Scopus (704) Google Scholar Hypoglycemia may be difficult to recognize because the signs and symptoms are nonspecific, and a single low PG concentration may be an artifact. For these reasons, guidelines in adults emphasize the value of Whipple's triad for confirming hypoglycemia: symptoms and/or signs consistent with hypoglycemia, a documented low PG concentration, and relief of signs/symptoms when PG concentration is restored to normal. Young infants and children often cannot dependably recognize and/or communicate their symptoms, however; therefore, recognition of hypoglycemia may require confirmation by repeated measurements of PG concentration and formal testing. Nevertheless, suspected hypoglycemia should be treated promptly to avoid potential adverse consequences.Hypoglycemia cannot be defined as a specific PG concentration, because: (1) thresholds for specific brain responses to hypoglycemia occur across a range of PG concentrations, and these thresholds can be altered by the presence of alternative fuels, such as ketones, and by recent antecedent hypoglycemia; (2) it is not possible to identify a single PG value that causes brain injury, and the extent of injury is influenced by other factors, such as duration and degree of hypoglycemia; and (3) potential artifacts and technical factors that lead to inaccuracies in glucose determination may complicate the interpretation of any single PG value.Symptoms of HypoglycemiaThe symptoms of hypoglycemia reflect responses of the brain to glucose deprivation and have been well delineated in adults.12Cryer P.E. Hypoglycemia in diabetes: Pathophysiology, prevalence, and prevention.2nd ed. American Diabetes Association, Alexandria (VA)2013Google Scholar Neurogenic (autonomic) symptoms result from the perception of physiological changes caused by the sympathetic nervous discharge triggered by hypoglycemia; these include adrenergic responses (eg, palpitations, tremor, anxiety) and cholinergic responses (eg, sweating, hunger, paresthesias). Neuroglycopenic signs and symptoms, including confusion, coma, and seizures, are caused by brain dysfunction resulting from a deficient glucose supply to sustain brain energy metabolism. Awareness of hypoglycemia depends chiefly on perception of the central and peripheral effects of neurogenic (as opposed to neuroglycopenic) responses to hypoglycemia. Brain glucose utilization becomes limited at a PG concentration of approximately 55-65 mg/dL (3.0-3.6 mmol/L).12Cryer P.E. Hypoglycemia in diabetes: Pathophysiology, prevalence, and prevention.2nd ed. American Diabetes Association, Alexandria (VA)2013Google Scholar Neurogenic symptoms are perceived at a PG concentration <55 mg/dL (<3.0 mmol/L), which in older children and adults triggers a search for food or assistance, an important defense against hypoglycemia. Cognitive function is impaired (neuroglycopenia) at a PG concentration <50 mg/dL (<2.8 mmol/L).Glucose UtilizationThe adult brain accounts for more than one-half of total glucose consumption. Because of their disproportionately larger brain size relative to body mass, infants and young children have a 2- to 3-fold higher glucose utilization rate (4-6 mg/kg/min) per kilogram of body weight compared with adults.13Bier D.M. Leake R.D. Haymond M.W. Arnold K.J. Gruenke L.D. Sperling M.A. et al.Measurement of “true” glucose production rates in infancy and childhood with 6,6-dideuteroglucose.Diabetes. 1977; 26: 1016-1023Crossref PubMed Google Scholar Although the brain has an obligate requirement for glucose, it also can use plasma ketones and lactate as energy sources if the concentrations of these substances are sufficiently elevated.14Veneman T. Mitrakou A. Mokan M. Cryer P. Gerich J. Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans.Diabetes. 1994; 43: 1311-1317Crossref PubMed Scopus (142) Google Scholar However, in hypoketotic conditions, such as hyperinsulinism or fatty acid oxidation disorders, ketones and lactate are not available in sufficiently high concentrations to substitute for glucose, and the risk of brain energy failure is greater.Neuroendocrine Defenses against HypoglycemiaIn normal individuals, the maintenance of normal PG concentrations is highly protected. The first defense is suppression of insulin secretion when PG concentration falls below the normal postabsorptive mean of ∼85 mg/dL (4.9 mmol/L).15Cryer P.E. Hypoglycemia, functional brain failure, and brain death.J Clin Invest. 2007; 117: 868-870Crossref PubMed Scopus (223) Google Scholar A further reduction of PG to 65-70 mg/dL (3.6-3.9 mmol/L) elicits glucagon secretion and activation of the sympathoadrenal system (reflected by increased epinephrine concentration), which increases glucose release from liver glycogen stores to raise the PG concentration. At a PG concentration <65 mg/dL (3.6 mmol/L), levels of plasma cortisol and growth hormone, important for maintenance of glucose during prolonged fasting, increase as well. Because the brain has only a few minutes worth of stored fuel reserves in the form of glycogen,12Cryer P.E. Hypoglycemia in diabetes: Pathophysiology, prevalence, and prevention.2nd ed. American Diabetes Association, Alexandria (VA)2013Google Scholar interruption of glucose delivery can have devastating consequences. Whereas recovery from brief periods of hypoglycemia is usually complete, severe and prolonged hypoglycemia can cause permanent brain injury.8Menni F. de Lonlay P. Sevin C. Touati G. Peigne C. Barbier V. et al.Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia.Pediatrics. 2001; 107: 476-479Crossref PubMed Scopus (271) Google Scholar, 9Steinkrauss L. Lipman T.H. Hendell C.D. Gerdes M. Thornton P.S. Stanley C.A. Effects of hypoglycemia on developmental outcome in children with congenital hyperinsulinism.J Pediatr Nurs. 2005; 20: 109-118Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 10Meissner T. Wendel U. Burgard P. Schaetzle S. Mayatepek E. Long-term follow-up of 114 patients with congenital hyperinsulinism.Eur J Endocrinol. 2003; 149: 43-51Crossref PubMed Scopus (157) Google Scholar, 16Koivisto M. Blanco-Sequeiros M. Krause U. Neonatal symptomatic and asymptomatic hypoglycaemia: a follow-up study of 151 children.Dev Med Child Neurol. 1972; 14: 603-614Crossref PubMed Scopus (124) Google ScholarMetabolic Defenses against HypoglycemiaIn the postabsorptive phase, the liver supplies the brain and other tissues with glucose by releasing glucose from the breakdown of stored glycogen and by gluconeogenesis, principally from gluconeogenic amino acids, such as alanine, and recycled lactate. With longer fasting and further suppression of insulin secretion, glucose utilization is restricted to the brain and a few glycolytic tissues, such as erythrocytes. Adipose tissue lipolysis releases glycerol, a gluconeogenic substrate, and free fatty acids (FFAs) that can replace glucose as an energy substrate in skeletal and heart muscle, but not in brain. FFAs are also converted by the liver to beta-hydroxybutyrate (BOHB) and acetoacetate for use by the brain. BOHB is the predominant ketoacid, and its plasma level serves as a measure of ketogenesis. As ketoacid concentrations rise, they can partly support the brain's energy needs. The changes in fuel metabolism during fasting in normal neonates after 2-3 days of age and in infants and children do not differ substantially from those in adults, except that PG concentrations decrease more rapidly and hyperketonemia develops sooner, because of the energy needs of their relatively larger brains.17Chaussain J.L. Georges P. Calzada L. Job J.C. Glycemic response to 24-hour fast in normal children, III: influence of age.J Pediatr. 1977; 91: 711-714Abstract Full Text PDF PubMed Scopus (47) Google Scholar Measurement of BOHB, FFA, and lactate at the time of hypoglycemia provides important information for diagnosing the cause of hypoglycemia (Figure).Altered Hypoglycemia AwarenessPrevious exposure to an episode of hypoglycemia can blunt, and repeated episodes can eliminate, neurogenic responses to subsequent hypoglycemic episodes.18Cryer P.E. Diverse causes of hypoglycemia-associated autonomic failure in diabetes.N Engl J Med. 2004; 350: 2272-2279Crossref PubMed Scopus (314) Google Scholar This leads to reduced or absent awareness of hypoglycemia and impairs hepatic glucose release, perpetuating hypoglycemia. This combination of events has been termed hypoglycemia-associated autonomic failure (HAAF).18Cryer P.E. Diverse causes of hypoglycemia-associated autonomic failure in diabetes.N Engl J Med. 2004; 350: 2272-2279Crossref PubMed Scopus (314) Google Scholar HAAF can persist for >24 hours after a single episode of hypoglycemia or even longer after repeated episodes of hypoglycemia. A similar impairment in neuroendocrine responses to hypoglycemia also occurs during sleep and exercise.18Cryer P.E. Diverse causes of hypoglycemia-associated autonomic failure in diabetes.N Engl J Med. 2004; 350: 2272-2279Crossref PubMed Scopus (314) Google Scholar Thus, exposure to recurrent hypoglycemia can shift the usual glucose threshold for recognition of neurogenic symptoms of 55 mg/dL (3.0 mmol/L) to a lower level. Although previous exposure to hypoglycemia lowers the glucose threshold for neurogenic responses, the threshold for neuroglycopenic symptoms is not altered acutely; whether adaptation occurs with repeated exposure to hypoglycemia is unknown. Features of HAAF have been demonstrated in infants as young as age 10-13 weeks.19Hussain K. Bryan J. Christesen H.T. Brusgaard K. Aguilar-Bryan L. Serum glucagon counterregulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism.Diabetes. 2005; 54: 2946-2951Crossref PubMed Scopus (49) Google ScholarPotential Artifacts in Measurements of PG ConcentrationTo diagnose hypoglycemia, PG concentration should be measured using a clinical laboratory method.12Cryer P.E. Hypoglycemia in diabetes: Pathophysiology, prevalence, and prevention.2nd ed. American Diabetes Association, Alexandria (VA)2013Google Scholar Important considerations are that whole blood glucose values are ∼15% lower than PG concentrations, and that because of red cell glycolysis, delays in processing and assaying glucose can reduce the glucose concentration by up to 6 mg/dL/hour (0.3 mmol/L/hour). Point-of-care meters provide a convenient screening method for detecting hypoglycemia, but their accuracy is limited to approximately ±10-15 mg/dL (0.6-0.8 mmol/L) in the range of hypoglycemia. Therefore, before establishing a diagnosis of hypoglycemia in neonates, infants, and children, it is essential to confirm low PG concentration using a clinical laboratory method.Normal PG Concentrations in Neonates Aged >48 Hours, Infants, and ChildrenAfter the first 48 hours of life, PG concentration and the physiology of glucose homeostasis do not differ to any great extent with age. Mean PG concentration in the postabsorptive state in normal neonates after ∼2 days of age and in infants and children does not differ from that in adults (70-100 mg/dL [3.9-5.5 mmol/L])17Chaussain J.L. Georges P. Calzada L. Job J.C. Glycemic response to 24-hour fast in normal children, III: influence of age.J Pediatr. 1977; 91: 711-714Abstract Full Text PDF PubMed Scopus (47) Google Scholar, 20Bonnefont J.P. Specola N.B. Vassault A. Lombes A. Ogier H. de Klerk J.B. et al.The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states.Eur J Pediatr. 1990; 150: 80-85Crossref PubMed Scopus (119) Google Scholar, 21van Veen M.R. van Hasselt P.M. de Sain-van der Velden M.G. Verhoeven N. Hofstede F.C. de Koning T.J. et al.Metabolic profiles in children during fasting.Pediatrics. 2011; 127: e1021-e1027Crossref PubMed Scopus (55) Google Scholar; however, children under age 4 years may have a PG concentration <70 mg/dL (3.9 mmol/L) and hyperketonemia after overnight fasting because of limited fasting tolerance.17Chaussain J.L. Georges P. Calzada L. Job J.C. Glycemic response to 24-hour fast in normal children, III: influence of age.J Pediatr. 1977; 91: 711-714Abstract Full Text PDF PubMed Scopus (47) Google Scholar, 20Bonnefont J.P. Specola N.B. Vassault A. Lombes A. Ogier H. de Klerk J.B. et al.The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states.Eur J Pediatr. 1990; 150: 80-85Crossref PubMed Scopus (119) Google Scholar, 21van Veen M.R. van Hasselt P.M. de Sain-van der Velden M.G. Verhoeven N. Hofstede F.C. de Koning T.J. et al.Metabolic profiles in children during fasting.Pediatrics. 2011; 127: e1021-e1027Crossref PubMed Scopus (55) Google Scholar Other evidence that the normal PG concentration in children does not differ from that in adults include the following: (1) fasting hyperketonemia develops at a similar PG concentration in infants, children, and adults21van Veen M.R. van Hasselt P.M. de Sain-van der Velden M.G. Verhoeven N. Hofstede F.C. de Koning T.J. et al.Metabolic profiles in children during fasting.Pediatrics. 2011; 127: e1021-e1027Crossref PubMed Scopus (55) Google Scholar, 22Saudubray J.M. Marsac C. Limal J.M. Dumurgier E. Charpentier C. Ogier H. et al.Variation in plasma ketone bodies during a 24-hour fast in normal and in hypoglycemic children: relationship to age.J Pediatr. 1981; 98: 904-908Abstract Full Text PDF PubMed Scopus (45) Google Scholar (hyperketonemia does not occur during transitional neonatal hypoglycemia in normal newborns in the first 1-2 days of life3Stanley C.A. Rozance P.J. Thornton P.S. De Leon D.D. Harris D. Haymond M.W. et al.Re-evaluating “transitional neonatal hypoglycemia”: mechanism and implications for management.J Pediatr. 2015; 166: 1520-1525Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar); (2) plasma lactate rises as PG falls below ∼70 mg/dL (∼3.9 mmol/L) in children with glucose-6-phosphatase deficiency23Wolfsdorf J.I. Plotkin R.A. Laffel L.M. Crigler Jr., J.F. Continuous glucose for treatment of patients with type 1 glycogen-storage disease: comparison of the effects of dextrose and uncooked cornstarch on biochemical variables.Am J Clin Nutr. 1990; 52: Google Scholar; and (3) and are in patients with defects of fatty acid oxidation when PG to mg/dL Concentrations in Neonates Aged normal newborn infants, PG concentration after to levels below those in older infants and The interpretation and response to PG concentration during the first days of life have been Jr., R.D. and needs for and neonatal hypoglycemia: from the of Child and Pediatr. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar the brain of newborn infants has or to hypoglycemic injury is as M. of the brain to hypoglycemia J Endocrinol Metab. 2005; PubMed Scopus Google Scholar, brain 2001; Full Text PDF PubMed Scopus (124) Google Scholar As C.A. Rozance P.J. Thornton P.S. De Leon D.D. Harris D. Haymond M.W. et al.Re-evaluating “transitional neonatal hypoglycemia”: mechanism and implications for management.J Pediatr. 2015; 166: 1520-1525Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar the of available on transitional neonatal hypoglycemia in normal newborns hypoglycemia with responses to glucagon or epinephrine that it is a and form of hyperinsulinism in which the mean PG threshold for suppression of insulin secretion is mg/dL (3.0-3.6 mmol/L) after compared with mg/dL mmol/L) in older infants, children, and As the glucose secretion mechanism mean PG concentration in normal newborns increases and by hours of age is similar to those in older infants and M. Reisner S.H. Blood glucose in the neonate and its clinical significance.N Engl J Med. 1965; 273: 378-381Crossref PubMed Scopus (116) Google Scholar, 2Srinivasan G. Pildes R.S. Cattamanchi G. Voora S. Lilien L.D. Plasma glucose values in normal neonates: a new look.J Pediatr. 1986; 109: 114-117Abstract Full Text PDF PubMed Scopus (225) Google Scholar; therefore, the for normal neonates be beyond 2-3 days after Because of the in a suspected persistent hypoglycemia disorder from transitional neonatal glucose concentrations during the first 48 hours of life, we suggest 2-3 days after Aged >48 at for Hypoglycemia neonates can be identified by clinical as at high risk for severe hypoglycemia during the first 48 hours after M. Blanco-Sequeiros M. Krause U. Neonatal symptomatic and asymptomatic hypoglycaemia: a follow-up study of 151 children.Dev Med Child Neurol. 1972; 14: 603-614Crossref PubMed Scopus (124) Google Scholar, brain 2001; Full Text PDF PubMed Scopus (124) Google Scholar and a of those neonates are also at increased risk for persistent hypoglycemia beyond 48 hours of life in and infants with PubMed Scopus Google Scholar, D. V. D.M. et in for 1990; PubMed Scopus Google Scholar, A. A. to infants at risk of hypoglycemia before Pediatr. Full Text Full Text PDF PubMed Scopus Google Scholar, Thornton P.S. L. R.A. Stanley C.A. and insulin regulation in infants with a of prolonged neonatal hyperinsulinism.J Pediatr. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar include not only the infants with genetic hypoglycemia disorders, such as congenital hyperinsulinism or K. hypoglycaemia: genetic diagnosis and management.J Clin Pediatr Endocrinol. PubMed Scopus Google Scholar but also those with relatively more prolonged neonatal hyperinsulinism to as with intrauterine growth or in and infants with PubMed Scopus Google Scholar, D. V. D.M. et in for 1990; PubMed Scopus Google Scholar, Thornton P.S. L. R.A. Stanley C.A. and insulin regulation in infants with a of prolonged neonatal hyperinsulinism.J Pediatr. 2006; Full Text Full Text PDF PubMed Scopus Google and managing neonates at increased risk for a persistent hypoglycemia at increased risk of hypoglycemia and require glucose of for age delivery for or growth for or of of a genetic form of (eg, (eg, in whom to persistent hypoglycemia before hypoglycemia (eg, episode of symptomatic hypoglycemia or for dextrose to to PG concentration mg/dL up to 48 hours of age and mg/dL after 48 hours of of a genetic form of (eg, (eg, in a new provide a guide and in the of evidence in the committee a to the technical neonates with a risk of a genetic or other persistent form of

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.