Federico II University Hospital

The ESC/ESH Guidelines represent the views of the ESC and ESH and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating. The ESC and ESH are not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the ESC/ESH Guidelines and any other official

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,
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\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,
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\nThierry Arnould1773, Ivica Arsov2120, Katsuhiko Asanuma675, Valerie Askanas1924, Eric Asselin1867, Ryuichiro Atarashi794,
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\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,

Correction: Volume: 292 Pages: 160-162 DOI: 10.1016/j.atherosclerosis.2019.11.020 Published: JAN 2020

The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and, where appropriate and/or necessary, the patient's caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient's case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional's responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. During starvation, the cell expands both compartments to enhance degradation processes. We found that starvation activates a transcriptional program that controls major steps of the autophagic pathway, including autophagosome formation, autophagosome-lysosome fusion, and substrate degradation. The transcription factor EB (TFEB), a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Nuclear localization and activity of TFEB were regulated by serine phosphorylation mediated by the extracellular signal-regulated kinase 2, whose activity was tuned by the levels of extracellular nutrients. Thus, a mitogen-activated protein kinase-dependent mechanism regulates autophagy by controlling the biogenesis and partnership of two distinct cellular organelles.

Friedreich's ataxia (FRDA) is an autosomal recessive, degenerative disease that involves the central and peripheral nervous systems and the heart. A gene, X25, was identified in the critical region for the FRDA locus on chromosome 9q13. This gene encodes a 210-amino acid protein, frataxin, that has homologs in distant species such as Caenorhabditis elegans and yeast. A few FRDA patients were found to have point mutations in X25, but the majority were homozygous for an unstable GAA trinucleotide expansion in the first X25 intron.

Master Controller Cellular organelles allow the localized regulation of specialized processes. Under certain conditions, such as increased growth, organelles may be required to alter their function. Coordinated regulation of the gene networks required for mitochondrial and endoplasmic reticulum function has been observed. Now, Sardiello et al. (p. 473 ; published online 25 June) have discovered a gene network regulating the lysosome, the major organelle involved in the degradation of internalized macromolecules. Many lysosomal genes were regulated by a single transcription factor, TFEB. TFEB itself can be activated when the lysosome malfunctions and can regulate both the abundance of lysosomes found in the cell, as well as the ability to degrade complex molecules, including a mutant protein that accumulates in patients with Huntington's disease. These results may have implications for the treatment of human lysosomal storage disorders, which are characterized by the aberrant accumulation of macromolecules causing cellular dysfunction.

INTRODUCTION: The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association. METHODS: The Task Force identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document. RESULTS: The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC. CONCLUSIONS: The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendations to represent current, rational, and optimal medical practice.

Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477 [ClinicalTrials.gov]). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.

OBJECTIVE: To assess the relation between the level of habitual salt intake and stroke or total cardiovascular disease outcome. DESIGN: Systematic review and meta-analysis of prospective studies published 1966-2008. DATA SOURCES: Medline (1966-2008), Embase (from 1988), AMED (from 1985), CINAHL (from 1982), Psychinfo (from 1985), and the Cochrane Library. Review methods For each study, relative risks and 95% confidence intervals were extracted and pooled with a random effect model, weighting for the inverse of the variance. Heterogeneity, publication bias, subgroup, and meta-regression analyses were performed. Criteria for inclusion were prospective adult population study, assessment of salt intake as baseline exposure, assessment of either stroke or total cardiovascular disease as outcome, follow-up of at least three years, indication of number of participants exposed and number of events across different salt intake categories. RESULTS: There were 19 independent cohort samples from 13 studies, with 177 025 participants (follow-up 3.5-19 years) and over 11 000 vascular events. Higher salt intake was associated with greater risk of stroke (pooled relative risk 1.23, 95% confidence interval 1.06 to 1.43; P=0.007) and cardiovascular disease (1.14, 0.99 to 1.32; P=0.07), with no significant evidence of publication bias. For cardiovascular disease, sensitivity analysis showed that the exclusion of a single study led to a pooled estimate of 1.17 (1.02 to 1.34; P=0.02). The associations observed were greater the larger the difference in sodium intake and the longer the follow-up. CONCLUSIONS: High salt intake is associated with significantly increased risk of stroke and total cardiovascular disease. Because of imprecision in measurement of salt intake, these effect sizes are likely to be underestimated. These results support the role of a substantial population reduction in salt intake for the prevention of cardiovascular disease.

Obesity is a critical risk factor for the development of type 2 diabetes (T2D), and its prevalence is rising worldwide. White adipose tissue (WAT) has a crucial role in regulating systemic energy homeostasis. Adipose tissue expands by a combination of an increase in adipocyte size (hypertrophy) and number (hyperplasia). The recruitment and differentiation of adipose precursor cells in the subcutaneous adipose tissue (SAT), rather than merely inflating the cells, would be protective from the obesity-associated metabolic complications. In metabolically unhealthy obesity, the storage capacity of SAT, the largest WAT depot, is limited, and further caloric overload leads to the fat accumulation in ectopic tissues (e.g., liver, skeletal muscle, and heart) and in the visceral adipose depots, an event commonly defined as "lipotoxicity." Excessive ectopic lipid accumulation leads to local inflammation and insulin resistance (IR). Indeed, overnutrition triggers uncontrolled inflammatory responses in WAT, leading to chronic low-grade inflammation, therefore fostering the progression of IR. This review summarizes the current knowledge on WAT dysfunction in obesity and its associated metabolic abnormalities, such as IR. A better understanding of the mechanisms regulating adipose tissue expansion in obesity is required for the development of future therapeutic approaches in obesity-associated metabolic complications.

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

BACKGROUND: The diagnosis of pediatric-onset inflammatory bowel disease (PIBD) can be challenging in choosing the most informative diagnostic tests and correctly classifying PIBD into its different subtypes. Recent advances in our understanding of the natural history and phenotype of PIBD, increasing availability of serological and fecal biomarkers, and the emergence of novel endoscopic and imaging technologies taken together have made the previous Porto criteria for the diagnosis of PIBD obsolete. METHODS: We aimed to revise the original Porto criteria using an evidence-based approach and consensus process to yield specific practice recommendations for the diagnosis of PIBD. These revised criteria are based on the Paris classification of PIBD and the original Porto criteria while incorporating novel data, such as for serum and fecal biomarkers. A consensus of at least 80% of participants was achieved for all recommendations and the summary algorithm. RESULTS: The revised criteria depart from existing criteria by defining 2 categories of ulcerative colitis (UC, typical and atypical); atypical phenotypes of UC should be treated as UC. A novel approach based on multiple criteria for diagnosing IBD-unclassified (IBD-U) is proposed. Specifically, these revised criteria recommend upper gastrointestinal endoscopy and ileocolonscopy for all suspected patients with PIBD, with small bowel imaging (unless typical UC after endoscopy and histology) by magnetic resonance enterography or wireless capsule endoscopy. CONCLUSIONS: These revised Porto criteria for the diagnosis of PIBD have been developed to meet present challenges and developments in PIBD and provide up-to-date guidelines for the definition and diagnosis of the IBD spectrum.

BACKGROUND: We tested the safety and efficacy of eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, in patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: We conducted a double-blind, randomized, placebo-controlled, multicenter, phase 3 trial. Patients received either placebo or eculizumab intravenously; eculizumab was given at a dose of 600 mg weekly for 4 weeks, followed 1 week later by a 900-mg dose and then 900 mg every other week through week 26. The two primary end points were the stabilization of hemoglobin levels and the number of units of packed red cells transfused. Biochemical indicators of intravascular hemolysis and the patients' quality of life were also assessed. RESULTS: Eighty-seven patients underwent randomization. Stabilization of hemoglobin levels in the absence of transfusions was achieved in 49% (21 of 43) of the patients assigned to eculizumab and none (0 of 44) of those assigned to placebo (P<0.001). During the study, a median of 0 units of packed red cells was administered in the eculizumab group, as compared with 10 units in the placebo group (P<0.001). Eculizumab reduced intravascular hemolysis, as shown by the 85.8% lower median area under the curve for lactate dehydrogenase plotted against time (in days) in the eculizumab group, as compared with the placebo group (58,587 vs. 411,822 U per liter; P<0.001). Clinically significant improvements were also found in the quality of life, as measured by scores on the Functional Assessment of Chronic Illness Therapy-Fatigue instrument (P<0.001) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Of the 87 patients, 4 in the eculizumab group and 9 in the placebo group had serious adverse events, none of which were considered to be treatment-related; all these patients recovered without sequelae. CONCLUSIONS: Eculizumab is an effective therapy for PNH.

1. INTRODUCTION 1.1 Principles The 2013 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines continue to adhere to some fundamental principles that inspired the 2003 and 2007 guidelines, namely to base recommendations on properly conducted studies identified from an extensive review of the literature; to consider, as the highest priority, data from randomized, controlled trials and their meta-analyses, but not to disregard the results of observational and other studies of appropriate scientific calibre; and to grade the level of scientific evidence and the strength of recommendations in order to more effectively alert physicians on recommendations that are based on the opinions of the experts rather than on evidence (Tables 1 and 2). When appropriately recognized, this can avoid guidelines being perceived as prescriptive and favour the performance of studies wherein opinion prevails and evidence is lacking.TABLE 1: Classes of recommendationsTABLE 2: Levels of evidenceThis shortened version of the ESH/ESC guidelines is for the practicing physician who often requires simplified information. However, whenever the physicians would like to know the source of the data upon which the recommendations are based, they are encouraged to consult the extensive version of the ESH/ESC guidelines wherein adequate references are given. These guidelines, however, do not override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient. 1.2 New aspects Because of new evidence on several diagnostic and therapeutic aspects of hypertension, the present guidelines differ from the 2007 ones in several points: Re-emphasis on integration of blood pressure (BP), cardiovascular risk factors, asymptomatic organ damage and clinical complications for total cardiovascular risk assessment. Update of the prognostic significance of out-of-office BP (both ambulatory and home BP), white-coat hypertension and masked hypertension. Initiation of antihypertensive drug treatment only in patients with SBP or DBP values at least 140 or 90 mmHg, independent of level of total cardiovascular risk. Unified target SBP (<140 mmHg) in both higher and lower cardiovascular risk patients. Revised recommendations on treatment of hypertension in young people and in the elderly. Liberal approach to initial monotherapy, without any all-ranking purpose scheme. Revised therapeutic algorithm for achieving target BP. Revised attention to resistant hypertension. 2. DEFINITIONS AND CLASSIFICATIONS The continuous relationship between BP and cardiovascular and renal events make the distinction between normotension and hypertension difficult. In practice, however, cut-off BP values are universally used to facilitate the decision about treatment (Table 3).TABLE 3: Definitions and classification of office blood pressure levels (mmHg)In order to help prognosis, total cardiovascular risk should be stratified in different categories (low, moderate, high and very high risk referred to the 10-year risk of cardiovascular mortality), based on BP category, cardiovascular risk factors, asymptomatic organ damage and presence of diabetes, and symptomatic cardiovascular disease or chronic kidney disease (CKD), as summarized in Fig. 1.FIGURE 1: Stratification of total cardiovascular risk in categories of low, moderate, high and very high risk according to SBP and DBP and presence of risk factors (RFs), asymptomatic organ damage (OD), diabetes, chronic kidney disease (CKD) stage or symptomatic cardiovascular disease (CVD). Individuals with a high normal office but a raised out-of-office BP (masked hypertension) have a cardiovascular risk in the hypertension range. Individuals with a high office BP but normal out-of-office BP (white-coat hypertension), particularly if there is no diabetes, OD, CVD or CKD, have lower risk than sustained hypertension for the same office BP. BP, blood pressure; CV, cardiovascular; DBP, diastolic blood pressure; HT, hypertension; SBP, systolic blood pressure.3. DIAGNOSTIC EVALUATION The initial evaluation of a patient with hypertension should confirm the diagnosis of hypertension; detect causes of secondary hypertension; and assess cardiovascular risk, organ damage and concomitant clinical conditions. This calls for BP measurement, medical history including family history, physical examination, laboratory investigation and further diagnostic tests. Some of the investigations are needed in all patients; others only in specific patient groups. 3.1 Blood pressure measurement 3.1.1 Office and out-of-office blood pressure Although conventional office BP measurement currently remains the ‘gold standard’ for screening, diagnosis and management of hypertension, it is generally accepted that out-of-office BP provides important adjunct information. At present, BP can no longer be estimated using a mercury manometer in many – although not all – European countries. Auscultatory or oscillometric semiautomatic sphygmomanometers are used instead, but these devices should be validated according to standardized protocols and their accuracy checked periodically. Table 4 gives instructions for correct office BP measurements, and Table 5 provides clinical indications for out-of-office BP measurement, namely measurements at home or over the 24 h.TABLE 4: Office blood pressure measurementTABLE 5: Clinical indications for out-of-office blood pressure measurement for diagnostic purposesOffice BP is usually higher than ambulatory and home BP and the difference increases as office BP increases. Cut-off values for the definition of hypertension by home and ambulatory BP are reported in Table 6.TABLE 6: Definitions of hypertension by office and out-of-office blood pressure levels3.1.2 White-coat and masked hypertension The term ‘white-coat’ or ‘isolated office’ hypertension refers to a condition in which BP is elevated in the office at repeated visits and normal out of the office either on ambulatory blood pressure monitoring or on home blood pressure monitoring. Conversely, BP may be normal in the office and abnormally high out of the medical environment, which is termed ‘masked’ or ‘isolated ambulatory’ hypertension. Cut-off values to be used are those in Table 6. 3.1.3 Central blood pressure Owing to the variable superposition of incoming and reflected pressure waves along the arterial tree, aortic BP (central BP) may be different from brachial BP. Central BP can be estimated indirectly by various methods. The current guidelines consider that, despite the growing interest in these methods, more investigation is needed before recommending the routine measurement of central BP for clinical use. 3.2 Medical history The information to be obtained at the time of the first diagnosis of hypertension is indicated in Table 7.TABLE 7: Personal and family medical history3.3 Physical examination Physical examination aims to establish or verify the diagnosis of hypertension, establish current BP, screen for secondary causes of hypertension and refine global cardiovascular risk. Procedures for BP measurement are indicated in Tables 4 and 5. Other information to be obtained by physical examination is in Table 8.TABLE 8: Physical examination for secondary hypertension, organ damage and obesity3.4 Laboratory investigations Laboratory investigations are directed at providing evidence for additional risk factors, searching for secondary hypertension and looking for organ damage. Investigations should proceed from the most simple to the more complicated ones, as summarized in Table 9.TABLE 9: Laboratory investigations3.5 Searching for asymptomatic organ damage Owing to the importance of asymptomatic organ damage as an intermediate stage in the continuum of cardiovascular disease, and as a determinant of overall cardiovascular disease, signs of organ involvement should be sought carefully by appropriate techniques as indicated below.Figure3.6 Searching for secondary forms of hypertension A specific, potentially reversible cause of BP elevation can be identified in a relatively small number of adult patients with hypertension. However if basal work-up leads to the suspicion of a secondary form of hypertension, the patient should be referred to a specialized centre where specific diagnostic procedures may be performed. 4. TREATMENT APPROACH 4.1 Recommendations of previous guidelines revised The 2007 ESH/ESC Guidelines, like many other scientific guidelines, recommended the use of antihypertensive drugs in patients with Grade 1 hypertension even in the absence of other risk factors or organ damage after nonpharmacological treatment had proved unsuccessful. This recommendation also specifically included the elderly hypertensive patient. The 2007 Guidelines also suggested drug treatment of patients with diabetes, previous cardiovascular disease (CVD) or CKD even when their BP was in the high normal range (130–139/85–89 mmHg). Furthermore, a lower BP target was recommended for these high or very high risk patients (<130/80 mmHg) than in patients at low–moderate risk (<140/90 mmHg). These recommendations were reappraised in a 2009 ESH Task Force document on the basis of an extensive critical review of the evidence. The following now summarizes the conclusions for the current guidelines: attention should be directed to the Class of recommendation and the Level of evidence, in order to distinguish what is considered compelling and what simply prudent. Figure 2 also summarizes recommendations and suggestions for treatment initiation and BP targets in the context of total risk stratification of hypertensive individuals.FIGURE 2: Initiation of lifestyle changes and antihypertensive drug treatment. Targets of treatment are also indicated. Colours are as in Fig. 1. See 4.3 and 6.5 for evidence that, in patients with diabetes, the optimal DBP target is between 80 and 85 mmHg. In the high normal blood pressure (BP) range, drug treatment should be considered in the presence of a raised out-of-office BP (masked hypertension). See 4.2 and 6.3 for lack of evidence in favour of drug treatment in young individuals with isolated systolic hypertension. CKD, chronic kidney disease; CVD, cardiovascular disease; DBP, diastolic blood pressure; HT, hypertension; OD, organ damage; RF, risk factor; SBP, systolic blood pressure.4.2 When to initiate antihypertensive drug treatmentFigure4.3 Blood pressure treatment targetsFigure5. TREATMENT STRATEGIES 5.1 Lifestyle changes Appropriate lifestyle changes are the cornerstone for the prevention of hypertension. They are also important for its treatment, although they should never delay the initiation of drug therapy in patients at high level of risk. In addition to the BP-lowering effect, lifestyle changes contribute to the control of other cardiovascular risk factors and clinical conditions. The lifestyle measures that have been shown to be capable of reducing BP and therefore recommended are as follows: salt restriction to 5–6 g/day; moderation of alcohol consumption to no more than 20–30 g of ethanol per day in men and 10–20 g/day in women; high consumption of vegetables and fruits and low-fat dairy products; reduction of weight to a BMI of 25 kg/m2 and waist circumference to less than 102 cm in men and less than 88 cm in women; at least 30 min of moderate dynamic exercise on 5 to 7 days per week. 5.2 Pharmacological therapy 5.2.1 Choice of antihypertensive drugs The current guidelines reconfirm that all major classes of antihypertensive agents are suitable for the initiation and maintenance of antihypertensive treatment either in monotherapy or in some combinations, and that no all-purpose ranking of drugs for general antihypertensive usage is evidence based. All classes have their advantages but also contraindications, and may be preferentially used or avoided in specific conditions. Contraindications and preferred indications are listed in Tables 10 and 11.TABLE 10: Compelling and possible contraindications to the use of antihypertensive drugsTABLE 11: Drugs to be preferred in specific conditions5.2.2 Monotherapy and combination therapy The current guidelines share the 2007 Guidelines’ opinion that monotherapy can reduce BP to target only in a limited number of patients and that most patients require the combination of at least two drugs, and they reconfirm that initiation with a drug combination can be considered in patients at high cardiovascular risk or with markedly high BP. The algorithm of Fig. 3, however, is a modification of the 2007 one, to emphasize that adding drugs to drugs should be done with attention to results and any compound overtly ineffective or minimally effective should be replaced, rather than retained in an automatic step-up multiple-drug approach. Combinations to be preferred or avoided are illustrated in Fig. 4.FIGURE 3: Monotherapy vs. drug combination strategies to achieve target blood pressure (BP). CV, cardiovascular.FIGURE 4: Possible combinations of classes of antihypertensive drugs. Green continuous lines: preferred combinations; green dashed line: useful combination (with some limitations); black dashed lines: possible but less well tested combinations; red continuous line: not recommended combination. Although verapamil and diltiazem are sometimes used with a β-blocker to improve ventricular rate control in permanent atrial fibrillation, only dihydropyridine calcium antagonists should normally be combined with β-blockers. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker. *Thiazide diuretics also include thiazide-like compounds (chlorthalidone) and indapamide.Strengths of recommendations about choice of drugs and combinations of antihypertensive agents are given in the summary table below.Figure6. TREATMENT STRATEGIES IN SPECIAL CONDITIONS Summary recommendations for antihypertensive treatment strategies in various conditions are listed below. 6.1 White-coat and masked hypertensionFigure6.2 ElderlyFigure6.3 Young adultsFigure6.4 WomenFigure6.5 Diabetes mellitusFigure6.6 Metabolic syndromeFigure6.7 Diabetic and nondiabetic nephropathyFigure6.8 Cerebrovascular diseaseFigure6.9 Heart diseaseFigure6.10 Atherosclerosis, arteriosclerosis and peripheral artery diseaseFigure6.11 Resistant hypertensionFigure7. TREATMENT OF ASSOCIATED RISK FACTORSFigure8. FOLLOW-UP 8.1 Follow-up visits After initiation of antihypertensive drug therapy, it is important to see the patient at 2-week to 4-week intervals to evaluate the effects on BP and to assess possible side-effects. Some medications will have an effect within days or weeks but a continued delayed response may occur during the first 2 months. Once the target is reached, a visit interval of a few months is reasonable. 8.2 Elevated blood pressure at control visits Patients and physicians have a tendency to interpret an uncontrolled BP at a given visit as due to occasional factors and thus to downplay its clinical significance. Due attention should be given to poor adherence or irregular consumption of drugs (sometimes because of adverse effects), to the white-coat effect and to substances or drugs opposing the antihypertensive effect of treatment. 8.3 Can antihypertensive medication be stopped? In some patients, in whom treatment is accompanied by an effective BP control for an extended period, it may be possible to reduce the number and dosage of drugs. This may be particularly the case if BP control is accompanied by healthy lifestyle changes. Reduction of medications should be made gradually and the patient should frequently be checked because of the risk of reappearance of hypertension. 9. IMPROVEMENT OF BLOOD PRESSURE CONTROL IN HYPERTENSION Despite overwhelming evidence that hypertension is a major cardiovascular risk factor and that BP-lowering substantially reduce the risk, there is evidence that all over the world a noticeable proportion of hypertensive individuals are unaware of this condition or, if aware, do not undergo treatment; target BP values are seldom achieved; failure to achieve BP control is associated with persistence of an elevated cardiovascular risk; and the rate of awareness of hypertension and BP control is improving slowly or not at all. As a consequence, high BP remains a leading cause of death and cardiovascular morbidity in Europe, as elsewhere in the world. Overall, three main causes of the low rate of BP control in real life have been identified: physician inertia; patient low adherence to treatment; and deficiencies of healthcare systems in their approach to chronic diseases. Methods to improve adherence to physicians’ recommendations are listed in Table 12.TABLE 12: Methods to improve adherence to physicians’ recommendations

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Background: The 2019 novel coronavirus (SARS-CoV-2) is a new human coronavirus which is spreading with epidemic features in China and other Asian countries; cases have also been reported worldwide. This novel coronavirus disease (COVID-19) is associated with a respiratory illness that may lead to severe pneumonia and acute respiratory distress syndrome (ARDS). Although related to the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), COVID-19 shows some peculiar pathogenetic, epidemiological and clinical features which to date are not completely understood. Aims: To provide a review of the differences in pathogenesis, epidemiology and clinical features of COVID-19, SARS and MERS. Sources: The most recent literature in the English language regarding COVID-19 has been reviewed, and extracted data have been compared with the current scientific evidence about SARS and MERS epidemics. Content: COVID-19 seems not to be very different from SARS regarding its clinical features. However, it has a fatality rate of 2.3%, lower than that of SARS (9.5%) and much lower than that of MERS (34.4%). The possibility cannot be excluded that because of the less severe clinical picture of COVID-19 it can spread in the community more easily than MERS and SARS. The actual basic reproductive number (R 0 ) of COVID-19 (2.0e2.5) is still controversial. It is probably slightly higher than the R 0 of SARS (1.7e1.9) and higher than that of MERS (<1). A gastrointestinal route of transmission for SARS-CoV-2, which has been assumed for SARS-CoV and MERS-CoV, cannot be ruled out and needs further investigation. Implications: There is still much more to know about COVID-19, especially as concerns mortality and its capacity to spread on a pandemic level. Nonetheless, all of the lessons we learned in the past from the SARS and MERS epidemics are the best cultural weapons with which to face this new global threat.

BACKGROUND: A fluoropyrimidine plus irinotecan or oxaliplatin, combined with bevacizumab (a monoclonal antibody against vascular endothelial growth factor), is standard first-line treatment for metastatic colorectal cancer. Before the introduction of bevacizumab, chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) showed superior efficacy as compared with fluorouracil, leucovorin, and irinotecan (FOLFIRI). In a phase 2 study, FOLFOXIRI plus bevacizumab showed promising activity and an acceptable rate of adverse effects. METHODS: We randomly assigned 508 patients with untreated metastatic colorectal cancer to receive either FOLFIRI plus bevacizumab (control group) or FOLFOXIRI plus bevacizumab (experimental group). Up to 12 cycles of treatment were administered, followed by fluorouracil plus bevacizumab until disease progression. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 12.1 months in the experimental group, as compared with 9.7 months in the control group (hazard ratio for progression, 0.75; 95% confidence interval [CI], 0.62 to 0.90; P=0.003). The objective response rate was 65% in the experimental group and 53% in the control group (P=0.006). Overall survival was longer, but not significantly so, in the experimental group (31.0 vs. 25.8 months; hazard ratio for death, 0.79; 95% CI, 0.63 to 1.00; P=0.054). The incidences of grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia were significantly higher in the experimental group. CONCLUSIONS: FOLFOXIRI plus bevacizumab, as compared with FOLFIRI plus bevacizumab, improved the outcome in patients with metastatic colorectal cancer and increased the incidence of some adverse events. (Funded by the Gruppo Oncologico Nord Ovest and others; ClinicalTrials.gov number, NCT00719797.).

administration. We recognize that in the setting of a variety of predisposing factors, varying cumulative dosages of recognized cardiotoxic agents, and use of other agents that are known to increase oxidative stress and compromise myocyte stability, the algorithm proposed in this document cannot be based on strong clinical data.