Chinese Academy of Medical Sciences & Peking Union Medical College
UniversityBeijing, Beijing, China
Research output, citation impact, and the most-cited recent papers from Chinese Academy of Medical Sciences & Peking Union Medical College (China). Aggregated across the NobleBlocks index of 300M+ scholarly works.
Top-cited papers from Chinese Academy of Medical Sciences & Peking Union Medical College
ResumenFactores pronsticos de mortalidad intrahospitalaria en pacientes ancianos con infeccin por COVID 19 ingresados a un hospital de tercer nivel en Bogot, ColombiaEl presente estudio tiene como objetivo establecer los factores pronsticos asociados al desarrollo de muerte intrahospitalaria en pacientes adultos mayores de 65 aos con infeccin por SARS-CoV2/COVID -19 confirmado en el Hospital Universitario Nacional de Colombia.Mtodos: Este es un estudio observacional analtico.Se evaluaron pacientes adultos mayores de 65 aos con diagnstico de infeccin por SARS-CoV2/COVID-19 confirmado.Los pacientes fueron estratificados por estado de fragilidad y funcionalidad.La mortalidad se determin a los 28 das y se cre un modelo de regresin logstica incondicional, ajustando por factores de confusin.La significancia estadstica se estableci en p 0,05.Resultados: 170 pacientes fueron estratificados en sobrevivientes y no sobrevivientes .El porcentaje de hombres en los sobrevivientes y no sobrevivientes fue similar, sin diferencias significativas en la edad promedio entre ambos grupos, tampoco en relacin a la presencia de sntomas.En el anlisis multivariado, las siguientes variables predijeron la ocurrencia del desenlace mortalidad a 28 das: fragilidad, antecedente de cncer, SDRA, lesin renal aguda y SOFA.Conclusiones: La tasa mortalidad a 28 das en pacientes adultos mayores de 65 aos con infeccin por COVID 19 en este estudio fue de 38%.Al ajustar por antecedente de cncer, desarrollo de lesin renal aguda, SDRA, puntuacin SOFA y PAFI al ingreso, la fragilidad se asoci con una mayor mortalidad en la poblacin estudiada.
The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies. Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics. The 1000 Genomes Project has sought to comprehensively catalogue human genetic variation across populations, providing a valuable public genomic resource. The data obtained so far have found applications ranging from association studies and fine mapping studies to the filtering of likely neutral variants in rare-disease cohorts. The authors now report on the final phase of the project, phase 3, which covers previously uncharacterized areas of human genetic diversity in terms of the populations sampled and categories of characterized variation. The sample now includes more than 2,500 individuals from 26 global populations, with low coverage whole-genome and deep exome sequencing, as well as dense microarray genotyping. They find that while most common variants are shared across populations, rarer variants are often restricted to closely related populations. The authors also demonstrate the use of the phase 3 dataset as a reference panel for imputation to improve the resolution in genetic association studies.
BACKGROUND: Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. METHODS: In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. RESULTS: The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42). CONCLUSIONS: In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb and Pfizer; ARISTOTLE ClinicalTrials.gov number, NCT00412984.).
BACKGROUND: Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer. METHODS: In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. RESULTS: The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin-paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group. CONCLUSIONS: Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)
By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations. This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual. This report by the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations. Integrative analyses reveal profiles of rare and common variants in different populations. The frequencies of rare variants vary across biological pathways, and hundreds of rare, non-coding variants at conserved sites — such as changes disrupting transcription-factor motifs — can be established for each individual.
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,
Tumor progression and the efficacy of immunotherapy are strongly influenced by the composition and abundance of immune cells in the tumor microenvironment. Due to the limitations of direct measurement methods, computational algorithms are often used to infer immune cell composition from bulk tumor transcriptome profiles. These estimated tumor immune infiltrate populations have been associated with genomic and transcriptomic changes in the tumors, providing insight into tumor-immune interactions. However, such investigations on large-scale public data remain challenging. To lower the barriers for the analysis of complex tumor-immune interactions, we significantly improved our previous web platform TIMER. Instead of just using one algorithm, TIMER2.0 (http://timer.cistrome.org/) provides more robust estimation of immune infiltration levels for The Cancer Genome Atlas (TCGA) or user-provided tumor profiles using six state-of-the-art algorithms. TIMER2.0 provides four modules for investigating the associations between immune infiltrates and genetic or clinical features, and four modules for exploring cancer-related associations in the TCGA cohorts. Each module can generate a functional heatmap table, enabling the user to easily identify significant associations in multiple cancer types simultaneously. Overall, the TIMER2.0 web server provides comprehensive analysis and visualization functions of tumor infiltrating immune cells.
BACKGROUND: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. METHODS: ) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. RESULTS: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. CONCLUSIONS: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).
BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction. METHODS: In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. RESULTS: of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin. CONCLUSIONS: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).
BACKGROUND: Public health is a priority for the Chinese Government. Evidence-based decision making for health at the province level in China, which is home to a fifth of the global population, is of paramount importance. This analysis uses data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to help inform decision making and monitor progress on health at the province level. METHODS: We used the methods in GBD 2017 to analyse health patterns in the 34 province-level administrative units in China from 1990 to 2017. We estimated all-cause and cause-specific mortality, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), summary exposure values (SEVs), and attributable risk. We compared the observed results with expected values estimated based on the Socio-demographic Index (SDI). FINDINGS: Stroke and ischaemic heart disease were the leading causes of death and DALYs at the national level in China in 2017. Age-standardised DALYs per 100 000 population decreased by 33·1% (95% uncertainty interval [UI] 29·8 to 37·4) for stroke and increased by 4·6% (-3·3 to 10·7) for ischaemic heart disease from 1990 to 2017. Age-standardised stroke, ischaemic heart disease, lung cancer, chronic obstructive pulmonary disease, and liver cancer were the five leading causes of YLLs in 2017. Musculoskeletal disorders, mental health disorders, and sense organ diseases were the three leading causes of YLDs in 2017, and high systolic blood pressure, smoking, high-sodium diet, and ambient particulate matter pollution were among the leading four risk factors contributing to deaths and DALYs. All provinces had higher than expected DALYs per 100 000 population for liver cancer, with the observed to expected ratio ranging from 2·04 to 6·88. The all-cause age-standardised DALYs per 100 000 population were lower than expected in all provinces in 2017, and among the top 20 level 3 causes were lower than expected for ischaemic heart disease, Alzheimer's disease, headache disorder, and low back pain. The largest percentage change at the national level in age-standardised SEVs among the top ten leading risk factors was in high body-mass index (185%, 95% UI 113·1 to 247·7]), followed by ambient particulate matter pollution (88·5%, 66·4 to 116·4). INTERPRETATION: China has made substantial progress in reducing the burden of many diseases and disabilities. Strategies targeting chronic diseases, particularly in the elderly, should be prioritised in the expanding Chinese health-care system. FUNDING: China National Key Research and Development Program and Bill & Melinda Gates Foundation.
BACKGROUND: The cancer burden in the United States of America (USA) has decreased gradually. However, China is experiencing a transition in its cancer profiles, with greater incidence of cancers that were previously more common in the USA. This study compared the latest cancer profiles, trends, and determinants between China and USA. METHODS: This was a comparative study using open-source data. Cancer cases and deaths in 2022 were calculated using cancer estimates from GLOBOCAN 2020 and population estimates from the United Nations. Trends in cancer incidence and mortality rates in the USA used data from the Surveillance, Epidemiology, and End Results program and National Center for Health Statistics. Chinese data were obtained from cancer registry reports. Data from the Global Burden of Disease 2019 and a decomposition method were used to express cancer deaths as the product of four determinant factors. RESULTS: In 2022, there will be approximately 4,820,000 and 2,370,000 new cancer cases, and 3,210,000 and 640,000 cancer deaths in China and the USA, respectively. The most common cancers are lung cancer in China and breast cancer in the USA, and lung cancer is the leading cause of cancer death in both. Age-standardized incidence and mortality rates for lung cancer and colorectal cancer in the USA have decreased significantly recently, but rates of liver cancer have increased slightly. Rates of stomach, liver, and esophageal cancer decreased gradually in China, but rates have increased for colorectal cancer in the whole population, prostate cancer in men, and other seven cancer types in women. Increases in adult population size and population aging were major determinants for incremental cancer deaths, and case-fatality rates contributed to reduced cancer deaths in both countries. CONCLUSIONS: The decreasing cancer burden in liver, stomach, and esophagus, and increasing burden in lung, colorectum, breast, and prostate, mean that cancer profiles in China and the USA are converging. Population aging is a growing determinant of incremental cancer burden. Progress in cancer prevention and care in the USA, and measures to actively respond to population aging, may help China to reduce the cancer burden.
Since 2002, beta coronaviruses (CoV) have caused three zoonotic outbreaks, SARS-CoV in 2002-2003, MERS-CoV in 2012, and the newly emerged SARS-CoV-2 in late 2019. However, little is currently known about the biology of SARS-CoV-2. Here, using SARS-CoV-2 S protein pseudovirus system, we confirm that human angiotensin converting enzyme 2 (hACE2) is the receptor for SARS-CoV-2, find that SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, that PIKfyve, TPC2, and cathepsin L are critical for entry, and that SARS-CoV-2 S protein is less stable than SARS-CoV S. Polyclonal anti-SARS S1 antibodies T62 inhibit entry of SARS-CoV S but not SARS-CoV-2 S pseudovirions. Further studies using recovered SARS and COVID-19 patients' sera show limited cross-neutralization, suggesting that recovery from one infection might not protect against the other. Our results present potential targets for development of drugs and vaccines for SARS-CoV-2.
BACKGROUND: Olaparib is an oral poly(adenosine diphosphate-ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation. METHODS: We conducted a randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease. Patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with single-agent chemotherapy of the physician's choice (capecitabine, eribulin, or vinorelbine in 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review and was analyzed on an intention-to-treat basis. RESULTS: Of the 302 patients who underwent randomization, 205 were assigned to receive olaparib and 97 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the olaparib group than in the standard-therapy group (7.0 months vs. 4.2 months; hazard ratio for disease progression or death, 0.58; 95% confidence interval, 0.43 to 0.80; P<0.001). The response rate was 59.9% in the olaparib group and 28.8% in the standard-therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard-therapy group, and the rate of treatment discontinuation due to toxic effects was 4.9% and 7.7%, respectively. CONCLUSIONS: Among patients with HER2-negative metastatic breast cancer and a germline BRCA mutation, olaparib monotherapy provided a significant benefit over standard therapy; median progression-free survival was 2.8 months longer and the risk of disease progression or death was 42% lower with olaparib monotherapy than with standard therapy. (Funded by AstraZeneca; OlympiAD ClinicalTrials.gov number, NCT02000622 .).
BACKGROUND: Because of the rapid change in lifestyle in China, there is concern that diabetes may become epidemic. We conducted a national study from June 2007 through May 2008 to estimate the prevalence of diabetes among Chinese adults. METHODS: A nationally representative sample of 46,239 adults, 20 years of age or older, from 14 provinces and municipalities participated in the study. After an overnight fast, participants underwent an oral glucose-tolerance test, and fasting and 2-hour glucose levels were measured to identify undiagnosed diabetes and prediabetes (i.e., impaired fasting glucose or impaired glucose tolerance). Previously diagnosed diabetes was determined on the basis of self-report. RESULTS: The age-standardized prevalences of total diabetes (which included both previously diagnosed diabetes and previously undiagnosed diabetes) and prediabetes were 9.7% (10.6% among men and 8.8% among women) and 15.5% (16.1% among men and 14.9% among women), respectively, accounting for 92.4 million adults with diabetes (50.2 million men and 42.2 million women) and 148.2 million adults with prediabetes (76.1 million men and 72.1 million women). The prevalence of diabetes increased with increasing age (3.2%, 11.5%, and 20.4% among persons who were 20 to 39, 40 to 59, and > or = 60 years of age, respectively) and with increasing weight (4.5%, 7.6%, 12.8%, and 18.5% among persons with a body-mass index [the weight in kilograms divided by the square of the height in meters] of < 18.5, 18.5 to 24.9, 25.0 to 29.9, and > or = 30.0, respectively). The prevalence of diabetes was higher among urban residents than among rural residents (11.4% vs. 8.2%). The prevalence of isolated impaired glucose tolerance was higher than that of isolated impaired fasting glucose (11.0% vs. 3.2% among men and 10.9% vs. 2.2% among women). CONCLUSIONS: These results indicate that diabetes has become a major public health problem in China and that strategies aimed at the prevention and treatment of diabetes are needed.
BACKGROUND: Cancer is one of the leading causes of death globally, but its burden is not uniform. GLOBOCAN 2020 has newly updated the estimates of cancer burden. This study summarizes the most recent changing profiles of cancer burden worldwide and in China and compares the cancer data of China with those of other regions. METHODS: We conducted a descriptive secondary analysis of the GLOBOCAN 2020 data. To depict the changing global profile of the leading cancer types in 2020 compared with 2018, we extracted the numbers of cases and deaths in 2018 from GLOBOCAN 2018. We also obtained cancer incidence and mortality from the 2015 National Cancer Registry Report in China when sorting the leading cancer types by new cases and deaths. For the leading cancer types according to sex in China, we summarized the estimated numbers of incidence and mortality, and calculated China's percentage of the global new cases and deaths. RESULTS: Breast cancer displaced lung cancer to become the most leading diagnosed cancer worldwide in 2020. Lung, liver, stomach, breast, and colon cancers were the top five leading causes of cancer-related death, among which liver cancer changed from the third-highest cancer mortality in 2018 to the second-highest in 2020. China accounted for 24% of newly diagnosed cases and 30% of the cancer-related deaths worldwide in 2020. Among the 185 countries included in the database, China's age-standardized incidence rate (204.8 per 100,000) ranked 65th and the age-standardized mortality rate (129.4 per 100,000) ranked 13th. The two rates were above the global average. Lung cancer remained the most common cancer type and the leading cause of cancer death in China. However, breast cancer became the most frequent cancer type among women if the incidence was stratified by sex. Incidences of colorectal cancer and breast cancer increased rapidly. The leading causes of cancer death varied minimally in ranking from 2015 to 2020 in China. Gastrointestinal cancers, including stomach, colorectal, liver, and esophageal cancers, contributed to a massive burden of cancer for both sexes. CONCLUSIONS: The burden of breast cancer is increasing globally. China is undergoing cancer transition with an increasing burden of lung cancer, gastrointestinal cancer, and breast cancers. The mortality rate of cancer in China is high. Comprehensive strategies are urgently needed to target China's changing profiles of the cancer burden.
It has been reported that ACE2 is the main host cell receptor of 2019-nCoV and plays a crucial role in the entry of virus into the cell to cause the final infection. To investigate the potential route of 2019-nCov infection on the mucosa of oral cavity, bulk RNA-seq profiles from two public databases including The Cancer Genome Atlas (TCGA) and Functional Annotation of The Mammalian Genome Cap Analysis of Gene Expression (FANTOM5 CAGE) dataset were collected. RNA-seq profiling data of 13 organ types with para-carcinoma normal tissues from TCGA and 14 organ types with normal tissues from FANTOM5 CAGE were analyzed in order to explore and validate the expression of ACE2 on the mucosa of oral cavity. Further, single-cell transcriptomes from an independent data generated in-house were used to identify and confirm the ACE2-expressing cell composition and proportion in oral cavity. The results demonstrated that the ACE2 expressed on the mucosa of oral cavity. Interestingly, this receptor was highly enriched in epithelial cells of tongue. Preliminarily, those findings have explained the basic mechanism that the oral cavity is a potentially high risk for 2019-nCoV infectious susceptibility and provided a piece of evidence for the future prevention strategy in dental clinical practice as well as daily life.
The 2010 and 2017 editions of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults are widely recognized among physicians and investigators. There have been major advances in our understanding of AML, including new knowledge about the molecular pathogenesis of AML, leading to an update of the disease classification, technological progress in genomic diagnostics and assessment of measurable residual disease, and the successful development of new therapeutic agents, such as FLT3, IDH1, IDH2, and BCL2 inhibitors. These advances have prompted this update that includes a revised ELN genetic risk classification, revised response criteria, and treatment recommendations.
BACKGROUND: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study. METHODS: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival. RESULTS: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine-venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; P<0.001). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine-venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 85% of the patients in the azacitidine-venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively. CONCLUSIONS: In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax-azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.).
INTRODUCTION Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection (1). Sepsis and septic shock are major healthcare problems, impacting millions of people around the world each year and killing between one in three and one in six of those it affects (2–4). Early identification and appropriate management in the initial hours after the development of sepsis improve outcomes. The recommendations in this document are intended to provide guidance for the clinician caring for adult patients with sepsis or septic shock in the hospital setting. Recommendations from these guidelines cannot replace the clinician's decision-making capability when presented with a unique patient's clinical variables. These guidelines are intended to reflect best practice (Table 1). TABLE 1. - Table of Current Recommendations and Changes From Previous 2016 Recommendations Recommendations 2021 Recommendation Strength and Quality of Evidence Changes From 2016 Recommendations 1. For hospitals and health systems, we recommend using a performance improvement program for sepsis, including sepsis screening for acutely ill, high-risk patients and standard operating procedures for treatment. Strong , moderate-quality evidence (for screening) Changed from Best practice statement "We recommend that hospitals and hospital systems have a performance improvement program for sepsis including sepsis screening for acutely ill, high-risk patients." Strong , very low-quality evidence (for standard operating procedures) 2. We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a single-screening tool for sepsis or septic shock. Strong , moderate-quality evidence NEW 3. For adults suspected of having sepsis, we suggest measuring blood lactate. Weak , low quality of evidence INITIAL RESUSCITATION 4. Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately. Best practice statement 5. For patients with sepsis induced hypoperfusion or septic shock we suggest that at least 30 mL/kg of IV crystalloid fluid should be given within the first 3 hr of resuscitation. Weak, low quality of evidence DOWNGRADE from Strong , low quality of evidence "We recommend that in the initial resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid be given within the first 3 hr" 6. For adults with sepsis or septic shock, we suggest using dynamic measures to guide fluid resuscitation, over physical examination, or static parameters alone. Weak , very low quality of evidence 7. For adults with sepsis or septic shock, we suggest guiding resuscitation to decrease serum lactate in patients with elevated lactate level, over not using serum lactate. Weak , low quality of evidence 8. For adults with septic shock, we suggest using capillary refill time to guide resuscitation as an adjunct to other measures of perfusion. Weak , low quality of evidence NEW MEAN ARTERIAL PRESSURE 9. For adults with septic shock on vasopressors, we recommend an initial target mean arterial pressure (MAP) of 65 mm Hg over higher MAP targets. Strong , moderate-quality evidence ADMISSION TO INTENSIVE CARE 10. For adults with sepsis or septic shock who require ICU admission, we suggest admitting the patients to the ICU within 6 hr. Weak , low quality of evidence INFECTION 11. For adults with suspected sepsis or septic shock but unconfirmed infection, we recommend continuously re-evaluating and searching for alternative diagnoses and discontinuing empiric antimicrobials if an alternative cause of illness is demonstrated or strongly suspected. Best practice statement 12. For adults with possible septic shock or a high likelihood for sepsis, we recommend administering antimicrobials immediately, ideally within 1 hr of recognition. Strong , low quality of evidence (Septic shock) CHANGED from previous: "We recommend that administration of intravenous antimicrobials should be initiated as soon as possible after recognition and within one hour for both a) septic shock and b) sepsis without shock" Strong , very low quality of evidence (Sepsis without shock) strong recommendation , moderate quality of evidence 13. For adults with possible sepsis without shock, we recommend rapid assessment of the likelihood of infectious versus noninfectious causes of acute illness. Best practice statement 14. For adults with possible sepsis without shock, we suggest a time-limited course of rapid investigation and if concern for infection persists, the administration of antimicrobials within 3 hr from the time when sepsis was first recognized. Weak , very low quality of evidence NEW from previous: "We recommend that administration of IV antimicrobials should be initiated as soon as possible after recognition and within 1 hr for both a) septic shock and b) sepsis without shock" strong recommendation , moderate quality of evidence 15. For adults with a low likelihood of infection and without shock, we suggest deferring antimicrobials while continuing to closely monitor the patient. Weak , very low quality of evidence NEW from previous: "We recommend that administration of IV antimicrobials should be initiated as soon as possible after recognition and within 1 hr for both a) septic shock and b) sepsis without shock" strong recommendation , moderate quality of evidence 16. For adults with suspected sepsis or septic shock, we suggest against using procalcitonin plus clinical evaluation to decide when to start antimicrobials, as compared to clinical evaluation alone. Weak , very low quality of evidence 17. For adults with sepsis or septic shock at high risk of MRSA, we recommend using empiric antimicrobials with MRSA coverage over using antimicrobials without MRSA coverage. Best practice statement NEW from previous: "We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage." Strong recommendation , moderate quality of evidence 18. For adults with sepsis or septic shock at low risk of MRSA, we suggest against using empiric antimicrobials with MRSA coverage, as compared with using antimicrobials without MRSA coverage. Weak , low quality of evidence NEW from previous: "We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage." Strong recommendation , moderate quality of evidence 19. For adults with sepsis or septic shock and high risk for multidrug resistant (MDR) organisms, we suggest using two antimicrobials with gram-negative coverage for empiric treatment over one gram-negative agent. Weak , very low quality of evidence 20. For adults with sepsis or septic shock and low risk for multidrug resistant (MDR) organisms, we suggest against using two gram-negative agents for empiric treatment, as compared to one gram-negative agent. Weak , very low quality of evidence 21. For adults with sepsis or septic shock, we suggest against using double gram-negative coverage once the causative pathogen and the susceptibilities are known. Weak , very low quality of evidence 22. For adults with sepsis or septic shock at high risk of fungal infection, we suggest using empiric antifungal therapy over no antifungal therapy. Weak , low quality of evidence NEW from previous: "We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage." Strong recommendation , moderate quality of evidence 23. For adults with sepsis or septic shock at low risk of fungal infection, we suggest against empiric use of antifungal therapy Weak , low quality of evidence NEW from previous: "We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage. " Strong recommendation , moderate quality of evidence 24. We make no recommendation on the use of antiviral agents. No recommendation 25. For adults with sepsis or septic shock, we suggest using prolonged infusion of beta-lactams for maintenance (after an initial bolus) over conventional bolus infusion. Weak , moderate-quality evidence 26. For adults with sepsis or septic shock, we recommend optimising dosing strategies of antimicrobials based on accepted pharmacokinetic/pharmacodynamic (PK/PD) principles and specific drug properties. Best practice statement 27. For adults with sepsis or septic shock, we recommend rapidly identifying or excluding a specific anatomical diagnosis of infection that requires emergent source control and implementing any required source control intervention as soon as medically and logistically practical. Best practice statement 28. For adults with sepsis or septic shock, we recommend prompt removal of intravascular access devices that are a possible source of sepsis or septic shock after other vascular access has been established. Best practice statement 29. For adults with sepsis or septic shock, we suggest daily assessment for de-escalation of antimicrobials over using fixed durations of therapy without daily reassessment for de-escalation. Weak , very low quality of evidence 30. For adults with an initial diagnosis of sepsis or septic shock and adequate source control, we suggest using shorter over longer duration of antimicrobial therapy. Weak , very low quality of evidence 31. For adults with an initial diagnosis of sepsis or septic shock and adequate source control where optimal duration of therapy is unclear, we suggest using procalcitonin AND clinical evaluation to decide when to discontinue antimicrobials over clinical evaluation alone. Weak , low quality of evidence HEMODYNAMIC MANAGEMENT 32. For adults with sepsis or septic shock, we recommend using crystalloids as first-line fluid for resuscitation. Strong , moderate-quality evidence 33. For adults with sepsis or septic shock, we suggest using balanced crystalloids instead of normal saline for resuscitation. Weak , low quality of evidence CHANGED from weak recommendation , low quality of evidence. "We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock" 34. For adults with sepsis or septic shock, we suggest using albumin in patients who received large volumes of crystalloids. Weak , moderate-quality evidence 35. For adults with sepsis or septic shock, we recommend against using starches for resuscitation. Strong , high-quality evidence 36. For adults with sepsis and septic shock, we suggest against using gelatin for resuscitation. Weak , moderate-quality evidence UPGRADE from weak recommendation , low quality of evidence "We suggest using crystalloids over gelatins when resuscitating patients with sepsis or septic shock." 37. For adults with septic shock, we recommend using norepinephrine as the first-line agent over other vasopressors. Strong Dopamine. High-quality evidence Vasopressin. Moderate-quality evidence Epinephrine. Low quality of evidence Selepressin. Low quality of evidence Angiotensin II. Very low-quality evidence 38. For adults with septic shock on norepinephrine with inadequate mean arterial pressure levels, we suggest adding vasopressin instead of escalating the dose of norepinephrine. Weak , moderate quality evidence 39. For adults with septic shock and inadequate mean arterial pressure levels despite norepinephrine and vasopressin, we suggest adding epinephrine. Weak , low quality of evidence 40. For adults with septic shock, we suggest against using terlipressin. Weak , low quality of evidence 41. For adults with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate volume status and arterial blood pressure, we suggest either adding dobutamine to norepinephrine or using epinephrine alone. Weak , low quality of evidence 42. For adults with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate volume status and arterial blood pressure, we suggest against using levosimendan. Weak , low quality of evidence NEW 43. For adults with septic shock, we suggest invasive monitoring of arterial blood pressure over noninvasive monitoring, as soon as practical and if resources are available. Weak , very low quality of evidence 44. For adults with septic shock, we suggest starting vasopressors peripherally to restore mean arterial pressure rather than delaying initiation until a central venous access is secured. Weak , very low quality of evidence NEW 45. There is insufficient evidence to make a recommendation on the use of restrictive versus liberal fluid strategies in the first 24 hr of resuscitation in patients with sepsis and septic shock who still have signs of hypoperfusion and volume depletion after the initial resuscitation. No recommendation NEW "We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock" Weak recommendation , low quality of evidence "We suggest using crystalloids over gelatins when resuscitating patients with sepsis or septic shock." Weak recommendation , low quality of evidence VENTILATION 46.There is insufficient evidence to make a recommendation on the use of conservative oxygen targets in adults with sepsis-induced hypoxemic respiratory failure. No recommendation 47. For adults with sepsis-induced hypoxemic respiratory failure, we suggest the use of high flow nasal oxygen over noninvasive ventilation. Weak , low quality of evidence NEW 48. There is insufficient evidence to make a recommendation on the use of noninvasive ventilation in comparison to invasive ventilation for adults with sepsis-induced hypoxemic respiratory failure. No recommendation 49. For adults with sepsis-induced ARDS, we recommend using a low tidal volume ventilation strategy (6 mL/kg), over a high tidal volume strategy (> 10 mL/kg). Strong , high-quality evidence 50. For adults with sepsis-induced severe ARDS, we recommend using an upper limit goal for plateau pressures of 30 cm H2O, over higher plateau pressures. Strong , moderate-quality evidence 51. For adults with moderate to severe sepsis-induced ARDS, we suggest using higher PEEP over lower PEEP. Weak , moderate-quality evidence 52. For adults with sepsis-induced respiratory failure (without ARDS), we suggest using low tidal volume as compared with high tidal volume ventilation. Weak , low quality of evidence 53. For adults with sepsis-induced moderate-severe ARDS, we suggest using traditional recruitment maneuvers. Weak , moderate-quality evidence 54. When using recruitment maneuvers, we recommend against using incremental PEEP titration/strategy. Strong , moderate-quality evidence 55. For adults with sepsis-induced moderate-severe ARDS, we recommend using prone ventilation for greater than 12 hr daily. Strong , moderate-quality evidence 56. For adults with sepsis induced moderate-severe ARDS, we suggest using intermittent NMBA boluses, over NMBA continuous infusion. Weak , moderate-quality evidence 57. For adults with sepsis-induced severe ARDS, we suggest using Veno-venous (VV) ECMO when conventional mechanical ventilation fails in experienced centers with the infrastructure in place to support its use. Weak , low quality of evidence NEW ADDITIONAL THERAPIES 58. For adults with septic shock and an ongoing requirement for vasopressor therapy we suggest using IV corticosteroids. Weak , moderate-quality evidence UPGRADE from Weak recommendation , low quality of evidence "We suggest against using IV hydrocortisone to treat septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (see goals for Initial Resuscitation). If this is not achievable, we suggest IV hydrocortisone at a dose of 200 mg/day." 59. For adults with sepsis or septic shock we suggest against using polymyxin B hemoperfusion. Weak , low quality of evidence NEW from previous: "We make no recommendation regarding the use of blood purification techniques" 60. There is insufficient evidence to make a recommendation on the use of other blood purification techniques. No recommendation 61. For adults with sepsis or septic shock we recommend using a restrictive (over liberal) transfusion strategy. Strong , moderate-quality evidence 62. For adults with sepsis or septic shock we suggest against using IV immunoglobulins. Weak , low quality of evidence 63. For adults with sepsis or septic shock, and who have risk factors for gastrointestinal (GI) bleeding, we suggest using stress ulcer prophylaxis. Weak , moderate-quality evidence 64. For adults with sepsis or septic shock, we recommend using pharmacologic venous thromboembolism (VTE) prophylaxis unless a contraindication to such therapy exists. Strong , moderate-quality evidence 65. For adults with sepsis or septic shock, we recommend using low molecular weight heparin over unfractionated heparin for VTE prophylaxis Strong , moderate-quality evidence 66. For adults with sepsis or septic shock, we suggest against using mechanical VTE prophylaxis, in addition to pharmacological prophylaxis, over pharmacologic prophylaxis alone. Weak , low quality of evidence 67. In adults with sepsis or septic shock and AKI, we suggest using either continuous or intermittent renal replacement therapy. Weak , low quality of evidence 68. In adults with sepsis or septic shock and AKI, with no definitive indications for renal replacement therapy, we suggest against using renal replacement therapy. Weak , moderate-quality evidence 69. For adults with sepsis or septic shock, we recommend initiating insulin therapy at a glucose level of ≥ 180mg/dL (10 mmol/L). Strong , moderate-quality evidence 70. For adults with sepsis or septic shock we suggest against using IV vitamin C. Weak , low quality of evidence NEW 71. For adults with septic shock and hypoperfusion-induced lactic acidemia, we suggest against using sodium bicarbonate therapy to improve hemodynamics or to reduce vasopressor requirements. Weak , low quality of evidence 72. For adults with septic shock and severe metabolic acidemia (pH ≤ 7.2) and acute kidney injury (AKIN score 2 or 3), we suggest using sodium bicarbonate therapy Weak , low quality of evidence 73. For adult patients with sepsis or septic shock who can be fed enterally, we suggest early (within 72 hr) initiation of enteral nutrition. Weak , very low quality of evidence LONG-TERM OUTCOMES AND GOALS OF CARE 74. For adults with sepsis or septic shock, we recommend discussing goals of care and prognosis with patients and families over no such discussion. Best practice statement 75. For adults with sepsis or septic shock, we suggest addressing goals of care early (within 72 hr) over late (72 hr or later). Weak , low quality of evidence 76. For adults with sepsis or septic shock, there is insufficient evidence to make a recommendation on any specific standardized criterion to trigger goals of care discussion. No recommendation 77. For adults with sepsis or septic shock, we recommend that the principles of palliative care (which may include palliative care consultation based on clinician judgement) be integrated into the treatment plan, when appropriate, to address patient and family symptoms and suffering. Best practice statement 78. For adults with sepsis or septic shock, we suggest against routine formal palliative care consultation for all patients over palliative care consultation based on clinician judgement. Weak , low quality of evidence 79. For adult survivors of sepsis or septic shock and their families, we suggest referral to peer support groups over no such referral. Weak , very low quality of evidence 80. For adults with sepsis or septic shock, we suggest using a handoff process of critically important information at transitions of care over no such handoff process. Weak , very low quality of evidence 81. For adults with sepsis or septic shock, there is insufficient evidence to make a recommendation on the use of any specific structured handoff tool over usual handoff processes. No recommendation 82. For adults with sepsis or septic shock and their families, we recommend screening for economic and social support (including housing, nutritional, financial, and spiritual support), and make referrals where available to meet these needs. Best practice statement 83. For adults with sepsis or septic shock and their families, we suggest offering written and verbal sepsis education (diagnosis, treatment, and post-ICU/post-sepsis syndrome) prior to hospital discharge and in the follow-up setting. Weak , very low quality of evidence 84. For adults with sepsis or septic shock and their families, we recommend the clinical team provide the opportunity to participate in shared decision making in post-ICU and hospital discharge planning to ensure discharge plans are acceptable and feasible. Best practice statement 85. For adults with sepsis and septic shock and their families, we suggest using a critical care transition program, compared with usual care, upon transfer to the floor. Weak , very low quality of evidence 86. For adults with sepsis and septic shock, we recommend reconciling medications at both ICU and hospital discharge. Best practice statement 87. For adult survivors of sepsis and septic shock and their families, we recommend including information about the ICU stay, sepsis and related diagnoses, treatments, and common impairments after sepsis in the written and verbal hospital discharge summary. Best practice statement 88. For adults with sepsis or septic shock who developed new impairments, we recommend hospital discharge plans include follow-up with clinicians able to support and manage new and long-term sequelae. Best practice statement 89. For adults with sepsis or septic shock and their families, there is insufficient evidence to make a recommendation on early post-hospital discharge follow-up compared with routine post-hospital discharge follow-up. No recommendation 90. For adults with sepsis or septic shock, there is insufficient evidence to make a recommendation for or against early cognitive therapy. No recommendation 91. For adult survivors of sepsis or septic shock, we recommend assessment and follow-up for physical, cognitive, and emotional problems after hospital discharge. Best practice statement 92. For adult survivors of sepsis or septic shock, we suggest referral to a post-critical illness follow-up program if available. Weak , very low quality of evidence 93. For adult survivors of sepsis or septic shock receiving mechanical ventilation for > 48hr or an ICU stay of > 72 hr, we suggest referral to a post-hospital rehabilitation program. Weak , very low quality of evidence (References 5–24 are referred to in the Methodology section which can be accessed at Supplemental Digital Content: Methodology.) SCREENING AND EARLY TREATMENT Screening for Patients With Sepsis and Septic Shock - Recommendation 1. For hospitals and health systems, we recommend using a performance improvement program for sepsis, including sepsis screening for acutely ill, high-risk patients and standard operating procedures for treatment. Strong recommendation, moderate quality of evidence for screening. Strong recommendation, very low-quality evidence for standard operating procedures. Rationale Sepsis performance improvement programs generally consist of sepsis screening, education, measurement of sepsis bundle performance, patient outcomes, and actions for identified opportunities (25,26). Despite some inconsistency, a meta-analysis of 50 observational studies on the effect of performance improvement programs showed that these programs were associated with better adherence to sepsis bundles along with a reduction in mortality (OR, 0.66; 95% CI, 0.61–0.72) in patients with sepsis and septic shock (27). The specific components of performance improvement did not appear to be as important as the presence of a program that included sepsis screening and metrics. Sepsis screening tools are designed to promote early identification of sepsis and consist of manual methods or automated use of the electronic health record (EHR). There is wide variation in diagnostic accuracy of these tools with most having poor predictive values, although the use of some was associated with improvements in care processes (28–31). A variety of clinical variables and tools are used for sepsis screening, such as systemic inflammatory response syndrome (SIRS) criteria, vital signs, signs of infection, quick Sequential Organ Failure Score (qSOFA) or Sequential Organ Failure Assessment (SOFA) criteria, National Early Warning Score (NEWS), or Modified Early Warning Score (MEWS) (26,32). Machine learning may improve performance of screening tools, and in a meta-analysis of 42,623 patients from seven studies for predicting hospital acquired sepsis the pooled area under the receiving operating curve (SAUROC) (0.89; 95% CI, 0.86−0.92); sensitivity (81%; 95% CI, 80−81), and specificity (72%; 95% CI, 72−72) was higher for machine learning than the SAUROC for traditional screening tools such as SIRS (0.70), MEWS (0.50), and SOFA (0.78) (32). Screening tools may target patients in various locations, such as in-patient wards, emergency departments, or ICUs (28–30,32). A pooled analysis of three RCTs did not demonstrate a mortality benefit of active screening (RR, 0.90; 95% CI, 0.51−1.58) (33–35). However, while there is wide variation in sensitivity and specificity of sepsis screening tools, they are an important component of identifying sepsis early for timely intervention. Standard operating procedures are a set of practices that specify a preferred response to specific clinical circumstances Sepsis standard operating as Early have to which a standard with components of the sepsis early and A large the between of sepsis and A of sepsis to hospitals in the in a mortality and after of sepsis with a control from other In this time mortality was lower in hospitals with higher with the sepsis bundles may a A meta-analysis of two RCTs in higher mortality (RR, 95% CI, with standard operating procedures compared with usual care, while it was in one observational 95% CI, - Recommendation 2. We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a screening tool for sepsis or septic shock. Strong recommendation, moderate-quality evidence. Rationale The qSOFA three variables to and prolonged ICU stay in patients with or suspected a Score a respiratory ≥ and a blood pressure ≤ mm When any two of these variables are the patient is qSOFA analysis used to support the recommendations of the on the of Sepsis identified qSOFA as a of poor in patients with or suspected infection, but no analysis was to support its use as a screening tool that time studies have the use of the qSOFA as a screening tool for sepsis The have been as to its have that qSOFA is more specific but than having two of SIRS for early identification of infection induced organ dysfunction SIRS qSOFA are screening tools for sepsis and the clinician to the of In the that of patients a qSOFA score 2 or but these patients for of poor have been when against the National Early Score and the Modified Early Score (MEWS) the presence of a qSOFA should the clinician to the of sepsis in all given the poor sensitivity of the the a strong recommendation against its use as a screening -
autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.