Richard L. Roudebush VA Medical Center

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,

BACKGROUND: Finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, reduced albuminuria in short-term trials involving patients with chronic kidney disease (CKD) and type 2 diabetes. However, its long-term effects on kidney and cardiovascular outcomes are unknown. METHODS: . All the patients were treated with renin-angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer's label that did not cause unacceptable side effects. The primary composite outcome, assessed in a time-to-event analysis, was kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes. The key secondary composite outcome, also assessed in a time-to-event analysis, was death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. RESULTS: During a median follow-up of 2.6 years, a primary outcome event occurred in 504 of 2833 patients (17.8%) in the finerenone group and 600 of 2841 patients (21.1%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.93; P = 0.001). A key secondary outcome event occurred in 367 patients (13.0%) and 420 patients (14.8%) in the respective groups (hazard ratio, 0.86; 95% CI, 0.75 to 0.99; P = 0.03). Overall, the frequency of adverse events was similar in the two groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone than with placebo (2.3% and 0.9%, respectively). CONCLUSIONS: In patients with CKD and type 2 diabetes, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo. (Funded by Bayer; FIDELIO-DKD ClinicalTrials.gov number, NCT02540993.).

BACKGROUND: The delivery of autologous cells to increase angiogenesis is emerging as a treatment option for patients with cardiovascular disease but may be limited by the accessibility of sufficient cell numbers. The beneficial effects of delivered cells appear to be related to their pluripotency and ability to secrete growth factors. We examined nonadipocyte stromal cells from human subcutaneous fat as a novel source of therapeutic cells. METHODS AND RESULTS: Adipose stromal cells (ASCs) were isolated from human subcutaneous adipose tissue and characterized by flow cytometry. ASCs secreted 1203+/-254 pg of vascular endothelial growth factor (VEGF) per 10(6) cells, 12 280+/-2944 pg of hepatocyte growth factor per 10(6) cells, and 1247+/-346 pg of transforming growth factor-beta per 10(6) cells. When ASCs were cultured in hypoxic conditions, VEGF secretion increased 5-fold to 5980+/-1066 pg/10(6) cells (P=0.0016). The secretion of VEGF could also be augmented 200-fold by transfection of ASCs with a plasmid encoding VEGF (P<0.05). Conditioned media obtained from hypoxic ASCs significantly increased endothelial cell growth (P<0.001) and reduced endothelial cell apoptosis (P<0.05). Nude mice with ischemic hindlimbs demonstrated marked perfusion improvement when treated with human ASCs (P<0.05). CONCLUSIONS: Our experiments delineate the angiogenic and antiapoptotic potential of easily accessible subcutaneous adipose stromal cells by demonstrating the secretion of multiple potentially synergistic proangiogenic growth factors. These findings suggest that autologous delivery of either native or transduced subcutaneous ASCs, which are regulated by hypoxia, may be a novel therapeutic option to enhance angiogenesis or achieve cardiovascular protection.

BACKGROUND: An accurate, noninvasive test could improve the effectiveness of colorectal-cancer screening. METHODS: We compared a noninvasive, multitarget stool DNA test with a fecal immunochemical test (FIT) in persons at average risk for colorectal cancer. The DNA test includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay. Results were generated with the use of a logistic-regression algorithm, with values of 183 or more considered to be positive. FIT values of more than 100 ng of hemoglobin per milliliter of buffer were considered to be positive. Tests were processed independently of colonoscopic findings. RESULTS: Of the 9989 participants who could be evaluated, 65 (0.7%) had colorectal cancer and 757 (7.6%) had advanced precancerous lesions (advanced adenomas or sessile serrated polyps measuring ≥1 cm in the greatest dimension) on colonoscopy. The sensitivity for detecting colorectal cancer was 92.3% with DNA testing and 73.8% with FIT (P=0.002). The sensitivity for detecting advanced precancerous lesions was 42.4% with DNA testing and 23.8% with FIT (P<0.001). The rate of detection of polyps with high-grade dysplasia was 69.2% with DNA testing and 46.2% with FIT (P=0.004); the rates of detection of serrated sessile polyps measuring 1 cm or more were 42.4% and 5.1%, respectively (P<0.001). Specificities with DNA testing and FIT were 86.6% and 94.9%, respectively, among participants with nonadvanced or negative findings (P<0.001) and 89.8% and 96.4%, respectively, among those with negative results on colonoscopy (P<0.001). The numbers of persons who would need to be screened to detect one cancer were 154 with colonoscopy, 166 with DNA testing, and 208 with FIT. CONCLUSIONS: In asymptomatic persons at average risk for colorectal cancer, multitarget stool DNA testing detected significantly more cancers than did FIT but had more false positive results. (Funded by Exact Sciences; ClinicalTrials.gov number, NCT01397747.).

To test the hypothesis that obesity/insulin resistance impairs both endothelium-dependent vasodilation and insulin-mediated augmentation of endothelium-dependent vasodilation, we studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of methacholine chloride (MCh) or sodium nitroprusside (SNP) during saline infusion and euglycemic hyperinsulinemia in lean insulin-sensitive controls (C), in obese insulin-resistant subjects (OB), and in subjects with non-insulin-dependent diabetes mellitus (NIDDM). MCh induced increments in LBF were approximately 40% and 55% lower in OB and NIDDM, respectively, as compared with C (P < 0.05). Euglycemic hyperinsulinemia augmented the LBF response to MCh by - 50% in C (P < 0.05 vs saline) but not in OB and NIDDM. SNP caused comparable increments in LBF in all groups. Regression analysis revealed a significant inverse correlation between the maximal LBF change in response to MCh and body fat content. Thus, obesity/insulin resistance is associated with (a) blunted endothelium-dependent, but normal endothelium-independent vasodilation and (b) failure of euglycemic hyperinsulinemia to augment endothelium-dependent vasodilation. Therefore, obese/insulin-resistant subjects are characterized by endothelial dysfunction and endothelial resistance to insulin's effect on enhancement of endothelium-dependent vasodilation. This endothelial dysfunction could contribute to the increased risk of atherosclerosis in obese insulin-resistant subjects.

Effective rehabilitative therapies are needed for patients with long-term deficits after stroke.In this multicenter, randomized, controlled trial involving 127 patients with moderate-to-severe upper-limb impairment 6 months or more after a stroke, we randomly assigned 49 patients to receive intensive robot-assisted therapy, 50 to receive intensive comparison therapy, and 28 to receive usual care. Therapy consisted of 36 1-hour sessions over a period of 12 weeks. The primary outcome was a change in motor function, as measured on the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke, at 12 weeks. Secondary outcomes were scores on the Wolf Motor Function Test and the Stroke Impact Scale. Secondary analyses assessed the treatment effect at 36 weeks.At 12 weeks, the mean Fugl-Meyer score for patients receiving robot-assisted therapy was better than that for patients receiving usual care (difference, 2.17 points; 95% confidence interval [CI], -0.23 to 4.58) and worse than that for patients receiving intensive comparison therapy (difference, -0.14 points; 95% CI, -2.94 to 2.65), but the differences were not significant. The results on the Stroke Impact Scale were significantly better for patients receiving robot-assisted therapy than for those receiving usual care (difference, 7.64 points; 95% CI, 2.03 to 13.24). No other treatment comparisons were significant at 12 weeks. Secondary analyses showed that at 36 weeks, robot-assisted therapy significantly improved the Fugl-Meyer score (difference, 2.88 points; 95% CI, 0.57 to 5.18) and the time on the Wolf Motor Function Test (difference, -8.10 seconds; 95% CI, -13.61 to -2.60) as compared with usual care but not with intensive therapy. No serious adverse events were reported.In patients with long-term upper-limb deficits after stroke, robot-assisted therapy did not significantly improve motor function at 12 weeks, as compared with usual care or intensive therapy. In secondary analyses, robot-assisted therapy improved outcomes over 36 weeks as compared with usual care but not with intensive therapy. (ClinicalTrials.gov number, NCT00372411.)

This paper presents the conclusions of a workshop entitled 'Impact of Molecular Genetics on the Classification of Renal Cell Tumours', which was held in Heidelberg in October 1996. The focus on 'renal cell tumours' excludes any discussion of Wilms' tumour and its variants, or of tumours metastatic to the kidneys. The proposed classification subdivides renal cell tumours into benign and malignant parenchymal neoplasms and, where possible, limits each subcategory to the most commonly documented genetic abnormalities. Benign tumours are subclassified into metanephric adenoma and adenofibroma, papillary renal cell adenoma, and renal oncocytoma. Malignant tumours are subclassified into common or conventional renal cell carcinoma; papillary renal cell carcinoma; chromophobe renal cell carcinoma; collecting duct carcinoma, with medullary carcinoma of the kidney; and renal cell carcinoma, unclassified. This classification is based on current genetic knowledge, correlates with recognizable histological findings, and is applicable to routine diagnostic practice.

The purpose of this study was to examine whether insulin's effect to vasodilate skeletal muscle vasculature is mediated by endothelium-derived nitric oxide (EDNO). N-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO synthase, was administered directly into the femoral artery of normal subjects at a dose of 16 mg/min and leg blood flow (LBF) was measured during an infusion of saline (NS) or during a euglycemic hyperinsulinemic clamp (HIC) designed to approximately double LBF. In response to the intrafemoral artery infusion of L-NMMA, LBF decreased from 0.296 +/- 0.032 to 0.235 +/- 0.022 liters/min during NS and from 0.479 +/- 0.118 to 0.266 +/- 0.052 liters/min during HIC, P < 0.03. The proportion of NO-dependent LBF during NS and HIC was approximately 20% and approximately 40%, respectively, P < 0.003 (NS vs. HIC). To elucidate whether insulin increases EDNO synthesis/release or EDNO action, vasodilative responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (MCh) or the endothelium-independent vasodilator sodium nitroprusside (SNP) were studied in normal subjects during either NS or HIC. LBF increments in response to intrafemoral artery infusions of MCh but not SNP were augmented during HIC versus NS, P < 0.03. In summary, insulin-mediated vasodilation is EDNO dependent. Insulin vasodilation of skeletal muscle vasculature most likely occurs via increasing EDNO synthesis/release. Thus, insulin appears to be a novel modulator of the EDNO system.

AIMS: The complementary studies FIDELIO-DKD and FIGARO-DKD in patients with type 2 diabetes and chronic kidney disease (CKD) examined cardiovascular and kidney outcomes in different, overlapping stages of CKD. The purpose of the FIDELITY analysis was to perform an individual patient-level prespecified pooled efficacy and safety analysis across a broad spectrum of CKD to provide more robust estimates of safety and efficacy of finerenone compared with placebo. METHODS AND RESULTS: For this prespecified analysis, two phase III, multicentre, double-blind trials involving patients with CKD and type 2 diabetes, randomized 1:1 to finerenone or placebo, were combined. Main time-to-event efficacy outcomes were a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure, and a composite of kidney failure, a sustained ≥57% decrease in estimated glomerular filtration rate from baseline over ≥4 weeks, or renal death. Among 13 026 patients with a median follow-up of 3.0 years (interquartile range 2.3-3.8 years), the composite cardiovascular outcome occurred in 825 (12.7%) patients receiving finerenone and 939 (14.4%) receiving placebo [hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.78-0.95; P = 0.0018]. The composite kidney outcome occurred in 360 (5.5%) patients receiving finerenone and 465 (7.1%) receiving placebo (HR, 0.77; 95% CI, 0.67-0.88; P = 0.0002). Overall safety outcomes were generally similar between treatment arms. Hyperkalaemia leading to permanent treatment discontinuation occurred more frequently in patients receiving finerenone (1.7%) than placebo (0.6%). CONCLUSION: Finerenone reduced the risk of clinically important cardiovascular and kidney outcomes vs. placebo across the spectrum of CKD in patients with type 2 diabetes. KEY QUESTION: Does finerenone, a novel selective, nonsteroidal mineralocorticoid receptor antagonist, added to maximum tolerated renin-angiotensin system inhibition reduce cardiovascular disease and kidney disease progression over a broad range of chronic kidney disease in patients with type 2 diabetes? KEY FINDING: In a prespecified, pooled individual-level analysis from two randomized trials, we found reductions both in cardiovascular events and kidney failure outcomes with finerenone. Because 40% of the patients had an estimated glomerular filtration rate of >60 mL/min/1.73m2 they were identified solely on the basis of albuminuria. TAKE HOME MESSAGE: Finerenone reduces the risk of clinical cardiovascular outcomes and kidney disease progression in a broad range of patients with chronic kidney disease and type 2 diabetes. Screening for albuminuria to identify at-risk patients among patients with type 2 diabetes facilitates reduction of both cardiovascular and kidney disease burden.

Alzheimer's disease is a form of localized amyloidosis characterized by cerebral cortical amyloid plaques, neurofibrillary tangles, and amyloid deposits within the walls of leptomeningeal vessels. Although most cases of Alzheimer's disease are sporadic, kindreds with autosomal-dominant inheritance of the syndrome suggest that a single mutation may be important in pathogenesis. Direct sequencing of DNA from a family with autopsy-proven Alzheimer's disease revealed a single amino acid substitution (Phe for Val) in the transmembrane domain of the amyloid precursor protein. This mutation correlates with the presence of Alzheimer's disease in all patients in this study, and may be the inherited factor causing both amyloid fibril formation and dementia.

Serrated lesions of the colorectum are the precursors of perhaps one-third of colorectal cancers (CRCs). Cancers arising in serrated lesions are usually in the proximal colon, and account for a disproportionate fraction of cancer identified after colonoscopy. We sought to provide guidance for the clinical management of serrated colorectal lesions based on current evidence and expert opinion regarding definitions, classification, and significance of serrated lesions. A consensus conference was held over 2 days reviewing the topic of serrated lesions from the perspectives of histology, molecular biology, epidemiology, clinical aspects, and serrated polyposis. Serrated lesions should be classified pathologically according to the World Health Organization criteria as hyperplastic polyp, sessile serrated adenoma/polyp (SSA/P) with or without cytological dysplasia, or traditional serrated adenoma (TSA). SSA/P and TSA are premalignant lesions, but SSA/P is the principal serrated precursor of CRCs. Serrated lesions have a distinct endoscopic appearance, and several lines of evidence suggest that on average they are more difficult to detect than conventional adenomatous polyps. Effective colonoscopy requires an endoscopist trained in the endoscopic appearance of serrated lesions. We recommend that all serrated lesions proximal to the sigmoid colon and all serrated lesions in the rectosigmoid > 5 mm in size, be completely removed. Recommendations are made for post-polypectomy surveillance of serrated lesions and for surveillance of serrated polyposis patients and their relatives.

BACKGROUND AND METHODS: The clinical significance of a distal colorectal polyp is uncertain. We determined the risk of advanced proximal neoplasia, defined as a polyp with villous features, a polyp with high-grade dysplasia, or cancer, among persons with distal hyperplastic or neoplastic polyps as compared with the risk among persons with no distal polyps. We analyzed data from 1994 consecutive asymptomatic adults (age, 50 years or older) who underwent colonoscopic screening for the first time between September 1995 and December 1998 as part of a program sponsored by an employer. The location and histologic features of all polyps were recorded. Colonoscopy to the level of the cecum was completed in 97.0 percent of the patients. RESULTS: Sixty-one patients (3.1 percent) had advanced lesions in the distal colon, including 5 with cancer, and 50 (2.5 percent) had advanced proximal lesions, including 7 with cancer. Twenty-three patients with advanced proximal neoplasms (46 percent) had no distal polyps. The prevalence of advanced proximal neoplasia among patients with no distal polyps was 1.5 percent (23 cases among 1564 persons; 95 percent confidence interval, 0.9 to 2.1 percent). Among patients with distal hyperplastic polyps, those with distal tubular adenomas, and those with advanced distal polyps, the prevalence of advanced proximal neoplasia was 4.0 percent (8 cases among 201 patients), 7.1 percent (12 cases among 168 patients), and 11.5 percent (7 cases among 61 patients), respectively. The relative risk of advanced proximal neoplasia, adjusted for age and sex, was 2.6 for patients with distal hyperplastic polyps, 4.0 for those with distal tubular adenomas, and 6.7 for those with advanced distal polyps, as compared with patients who had no distal polyps. Older age and male sex were associated with an increased risk of advanced proximal neoplasia (relative risk, 1.3 for every five years of age and 3.3 for male sex). CONCLUSIONS: Asymptomatic persons 50 years of age or older who have polyps in the distal colon are more likely to have advanced proximal neoplasia than are persons without distal polyps. However, if colonoscopic screening is performed only in persons with distal polyps, about half the cases of advanced proximal neoplasia will not be detected.

The KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD represents a selective update of the prior CKD-MBD Guideline published in 2009. This update, along with the 2009 publication, is intended to assist the practitioner caring for adults and children with chronic kidney disease (CKD), those on chronic dialysis therapy, or individuals with a kidney transplant. This review highlights key aspects of the 2017 CKD-MBD Guideline Update, with an emphasis on the rationale for the changes made to the original guideline document. Topic areas encompassing updated recommendations include diagnosis of bone abnormalities in CKD–mineral and bone disorder (MBD), treatment of CKD-MBD by targeting phosphate lowering and calcium maintenance, treatment of abnormalities in parathyroid hormone in CKD-MBD, treatment of bone abnormalities by antiresorptives and other osteoporosis therapies, and evaluation and treatment of kidney transplant bone disease. The KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD represents a selective update of the prior CKD-MBD Guideline published in 2009. This update, along with the 2009 publication, is intended to assist the practitioner caring for adults and children with chronic kidney disease (CKD), those on chronic dialysis therapy, or individuals with a kidney transplant. This review highlights key aspects of the 2017 CKD-MBD Guideline Update, with an emphasis on the rationale for the changes made to the original guideline document. Topic areas encompassing updated recommendations include diagnosis of bone abnormalities in CKD–mineral and bone disorder (MBD), treatment of CKD-MBD by targeting phosphate lowering and calcium maintenance, treatment of abnormalities in parathyroid hormone in CKD-MBD, treatment of bone abnormalities by antiresorptives and other osteoporosis therapies, and evaluation and treatment of kidney transplant bone disease. In 2009, Kidney Disease: Improving Global Outcomes (KDIGO) published the KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar At that time, the Work Group acknowledged the lack of high-quality evidence on which to base recommendations. Over the years that followed, multiple randomized controlled trials (RCTs) and prospective cohort studies examined some of the key issues underlying the assessment, development, progression, and treatment of CKD-MBD. KDIGO recognizes the need to reexamine the currency of its guidelines on a periodic basis, and therefore convened a Controversies Conference in 2013, titled “CKD-MBD: Back to the Future.”2Ketteler M. Elder G.J. Evenepoel P. et al.Revisiting KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference.Kidney Int. 2015; 87: 502-528Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar The conference participants concluded that most of the 2009 recommendations1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar were still applicable in current practice; however, a total of 12 recommendations were identified for revision, based on new data. As a result, a Work Group was convened to undertake a “selective update”3Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar of the 2009 KDIGO CKD-MBD Guideline (Table 1).1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar Notably, despite the availability of results from several new key clinical trials, large gaps of knowledge still remained. Accordingly, many of the “opinion-based” recommendation statements from the 2009 Guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar remain unchanged (see summary of KDIGO CKD-MBD recommendations).Table 1Comparison of the 2017 and 2009 KDIGO CKD-MBD Guideline recommendations2017 revised KDIGO CKD-MBD recommendations3Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar2009 KDIGO CKD-MBD recommendations1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google ScholarBrief rationale for updating3.2.1. In patients with CKD G3a–G5D with evidence of CKD-MBD and/or risk factors for osteoporosis, we to risk results treatment In patients with CKD G3a–G5D with evidence of CKD-MBD, we that risk in the and the of new prospective studies that in patients with CKD The of recommendations was a the to a bone In patients with CKD is to a bone knowledge of the of treatment In patients with CKD is to a bone in bone and prior to with in patients with CKD-MBD for was the with osteoporosis in patients with and a risk of The to a bone from patients risk of In patients with CKD of CKD-MBD based on of and new recommendation was in to the and of CKD-MBD In patients with CKD we lowering phosphate the In patients with we phosphate in the In patients with CKD we lowering phosphate the is an of that to phosphate in the of to CKD some Treatment In patients with CKD we In children with CKD we calcium in the In patients with CKD we calcium in the and in the of in to calcium in In patients with CKD we a calcium and and In patients with CKD we a calcium and and studies of however, for of and calcium of and and the is the evidence is from to In patients with CKD treatment based on or phosphate In patients with CKD and we in the treatment of is that the of phosphate CKD of other of CKD-MBD, therapies, and the that treatment is by (see The treatment is of In patients with CKD G3a–G5D we the of phosphate In children with CKD is to base the of treatment on calcium In patients with CKD G3a–G5D and we the of phosphate and/or the of or in the of or In patients with CKD G3a–G5D and we the of phosphate in the of and/or bone disease and/or evidence from a recommendation to phosphate in patients of In patients with CKD we phosphate in the treatment of or in with other is to phosphate in recommendations In patients with CKD we phosphate in the treatment of or in with other on phosphate were to include an to the In patients with CKD on the is we that patients with of or the for the for phosphate and In patients with CKD on the is we that patients with of the of the for and is to abnormalities with or of the phosphate and phosphate calcium and/or Work Group that in an to kidney and revised to include the the treatment based on a In patients with CKD on we that and is to the of and for patients with CKD with and In patients with CKD on in is and the of for the despite of we treatment with or of to in risk of and to calcium in the In patients with CKD therapy, we or or a of with or In patients with CKD and or we or or or a of and or to is that the for the treatment of based on calcium and phosphate and other aspects of CKD-MBD is that calcium or phosphate that to of phosphate and calcium in patients with or or in patients with or or in patients with or on and clinical and the the of for the and/or or recommendation for by the KDIGO Controversies Conference in to a of and of the the Work Group to its the of the Work Group were to of for patients based on The Work however, to treatment or in In patients with CKD G3a–G5D with abnormalities of CKD-MBD and and/or we that treatment the and of the abnormalities and the of with of a bone In patients with CKD with abnormalities of CKD-MBD and and/or we that treatment the and of the abnormalities and the of with of a bone the for a bone prior to and other osteoporosis 2009 and 2017 is from CKD to CKD In patients with CKD abnormalities of CKD-MBD, and and/or we with bone prior to with In patients with with risk factors for osteoporosis, we that to risk results In patients with an we in the kidney transplant or risk factors for osteoporosis in the and were to 2017 In patients with CKD we that risk in the and the of kidney transplant bone disease In patients in the 12 kidney transplant with an and we that treatment with and/or that treatment by the of CKD-MBD, by of and is to a bone to treatment to treatment the 12 In patients in the 12 kidney transplant with an and we that treatment with or that treatment by the of CKD-MBD, by of and is to a bone to the of to the of bone disease to treatment the 12 is with the new bone recommendation 2017 bone chronic kidney bone parathyroid randomized controlled to the recommendations in of several guideline 2009 2017 2009 2017 2009 2017 and 2009 2017 in a new bone chronic kidney bone parathyroid randomized controlled to the recommendations in of several guideline 2009 2017 2009 2017 2009 2017 and 2009 2017 to the original 2009 KDIGO CKD-MBD Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar of the 2017 Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar a of evidence review and based on of results from clinical The was the et evidence and summary of Full Text Full Text PDF PubMed Scopus Google Scholar which to the of the evidence and for the Work Group based on that were of a evidence the of high-quality evidence identified in several areas to CKD-MBD, the Work Group was to a guideline that is of to the The of recommendations in of the 2017 CKD-MBD Guideline Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar which in the evidence base in CKD-MBD. At the of of the 2009 KDIGO CKD-MBD Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar the the to risk in CKD from bone by was to studies that in CKD patients with and a results were studies and to the lack of evidence that in CKD patients in the and the of to the of bone the 2009 Guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar that in patients with CKD to and CKD-MBD. The review for the 2017 KDIGO CKD-MBD Guideline Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar identified prospective cohort studies in adults that the from CKD to studies a the original 2009 Guideline was Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar the that the studies were a of CKD the that was and studies to those in the of on the Work Group concluded that is a or to to or osteoporosis is bone and is of the bone abnormalities of CKD-MBD. Bone is the for the diagnosis and of The 2009 KDIGO CKD-MBD Guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar that of concluded that the of was by and in parathyroid hormone to results the 2017 Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar the Work Group the of to a bone is a the results to changes in The 2009 Guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar a bone prior to in patients with CKD to and evidence of abnormalities of CKD-MBD, and/or the Work Group is that clinical and evaluation of bone is evidence that in patients with CKD to and and evidence that bone disease. the 2017 Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar a bone prior to of The from the 2009 KDIGO CKD-MBD Guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar treatment based on phosphate in of The evidence to a in that is an risk of with of phosphate in a and and results were The Work Group to the of of and is to the of on the Work Group to the 2009 new recommendation based on and recommendation based on the of the 2009 KDIGO CKD-MBD Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar high-quality evidence of phosphate with patients with CKD to or is still a lack of that to phosphate The 2009 Guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar phosphate in the for patients with CKD to and the evidence for the 2017 Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar the Work Group several the phosphate and clinical is evidence is to the of phosphate for lowering phosphate in patients with CKD to the of phosphate in is and is an of that phosphate clinical the Work Group the to phosphate in the that treatment on patients with The Work Group recognizes that of in patients with CKD to that current to the or of an The 2009 KDIGO CKD-MBD Guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar that phosphate in the treatment of and is evidence that the of with calcium and phosphate lowering in CKD patients on with and a the 2017 Update Work Group to on the current the Work Group concluded that an to phosphate in the of CKD patients on the 2017 Update Work Group that in the of or and to a for to and of The Work Group the of and evidence a need to the 2009 recommendation the of phosphate to the of and phosphate the Work Group concluded that to calcium or of of other of risk bone or the Work Group in the 2009 that still in of the Work Group the evidence that to In of the studies calcium on the of in KDIGO guidelines intended for a and or in the of that treatment is to the clinical to and the Work Group an recommendation a of to to the of the of a of calcium on of to calcium or in The Work Group concluded that was evidence to recommendation in to calcium was the 2009 KDIGO CKD-MBD Guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar recommendation on phosphate to phosphate the Work Group acknowledged that the of the original was with to new evidence on phosphate and the 2017 Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar on and cohort of some for evidence the Work Group that some of issues that of in the in or to and in and The of by is with current that phosphate is the to of other for of phosphate and of phosphate is the of in based on the of and the of to of phosphate is with is The Work Group the to patients and to by the Work Group that of results for aspects of phosphate the Work Group to the recommendation on phosphate the Work Group a that phosphate and on As is the for evidence calcium to in adults with CKD the of the 2009 KDIGO CKD-MBD Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar new studies of calcium with and in the of therapy, the Work Group an to the treatment of the of for or still The 2009 Guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar that a calcium of calcium on new the 2017 Work Group that recommendation in 2009. studies of the evidence from to is by a by several and which to abnormalities in bone and The 2009 KDIGO CKD-MBD Guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar risk factors for patients with a the of for the is still an of that an for patients with CKD to The 2017 Update Work Group that in an to kidney to and bone to the Update Work Group revised the 2009 Guideline recommendation to the that treatment based on a the Work Group an risk phosphate studies that phosphate in in and that phosphate phosphate is the Work Group acknowledged that for of phosphate and and treatment of is in with CKD-MBD, and with and in CKD many and other the for in individuals with The 2009 KDIGO CKD-MBD Guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar multiple studies that of or and in of was a lack of trials in of or published the 2009 Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar of and a risk of in patients with with in the of on with the that an the 2017 Update Work Group to that the of was the Update Work Group that the of or for and Accordingly, the Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar of or its in CKD to This the Work Group that the participants in the and trials with and in those with and were identified that the of or on or and the of in CKD to is with to in phosphate and the Work Group concluded for and or with of the and based on the the 2017 Update Work Group to the of in patients with CKD new trials treatment with and new a still new trials of or that in The Update Work Group the were to the were to a for patients with and CKD is that the of the was The is that on on or from trials with or other the lack of the Work with the of the 2009 recommendation for patients with CKD was to treatment in The to by and the calcium and phosphate In the of calcium that a treatment in from the 2009 KDIGO CKD-MBD Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar The current the for a bone prior to and other osteoporosis the original from the 2009 KDIGO CKD-MBD Guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar was and was from CKD to CKD treatment antiresorptives bone and The risk of antiresorptives the of the diagnosis of the underlying bone The 2009 KDIGO CKD-MBD Guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar in the in patients with an or risk factors for was that in those with CKD to As in the 2017 Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar is evidence that the of CKD prospective cohort studies in patients with CKD to that to transplant the current Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar in transplant in those with CKD to the results treatment The current the for a bone prior to and other osteoporosis the 2009 bone in transplant of and in CKD we in CKD In patients with CKD is to base the of and on the and of and the of of CKD CKD for calcium and and for based on and CKD CKD for calcium and and for CKD for calcium and and for CKD for 12 or in the of (see CKD patients for CKD-MBD, or in abnormalities is to the of to for and treatment and In patients with CKD we that and by and that and treatment for the In patients with CKD we that based on on a CKD-MBD In patients with CKD we that of calcium and to clinical practice the of In of for patients with CKD we that clinical of the in and in or and to the of In patients with CKD G3a–G5D with evidence of CKD-MBD and/or risk factors for osteoporosis, we to risk results treatment In patients with CKD is to a bone knowledge of the of treatment In patients with CKD we that of or to bone disease or underlying bone In patients with CKD we of and or that with CKD children with CKD for In patients with CKD G3a–G5D with evidence of CKD-MBD and/or risk factors for osteoporosis, we to risk results treatment In patients with CKD is to a bone knowledge of the of treatment In patients with CKD we that a to the or of and an to the or of to that patients with CKD G3a–G5D with or risk is to to the of CKD-MBD In patients with CKD of CKD-MBD based on of and In patients with CKD we lowering phosphate the In patients with CKD we In children with CKD we calcium in the In patients with CKD we a calcium and and In patients with CKD treatment based on or phosphate In patients with CKD G3a–G5D we the of phosphate In children with CKD is to base the of treatment on calcium In patients with CKD we the of phosphate and in patients with CKD to In patients with CKD we phosphate in the treatment of or in with other is to phosphate in recommendations In patients with CKD we phosphate in the treatment of In patients with CKD of CKD-MBD based on of and In patients with CKD we lowering phosphate the In patients with CKD we In children with CKD we calcium in the In patients with CKD we a calcium and and In patients with CKD treatment based on or phosphate In patients with CKD G3a–G5D we the of phosphate In children with CKD is to base the of treatment on calcium In patients with CKD we phosphate in the treatment of or in with other is to phosphate in recommendations In patients with CKD on the is we that patients with of or the for the for phosphate and In patients with CKD on we and is to the of and for patients with CKD with and and to calcium in the In patients with CKD we in the of to the for the that changes in in an or in to to of In patients with CKD therapy, we or or a of with or In patients with CKD G3a–G5D with to to or therapy, we In patients with CKD on the is we that patients with of or the for the for phosphate and In patients with CKD on we and is to the of and for patients with CKD with and and to calcium in the In patients with CKD therapy, we or or a of with or In patients with CKD with osteoporosis and/or risk of identified by we for the In patients with CKD with in the and osteoporosis and/or risk of identified by we treatment for the In patients with CKD G3a–G5D with abnormalities of CKD-MBD and and/or we that treatment the and of the abnormalities and the of with of a bone In children and with CKD and we treatment with hormone is and abnormalities of CKD-MBD In patients with CKD G3a–G5D with abnormalities of CKD-MBD and and/or we that treatment the and of the abnormalities and the of with of a bone In patients in the transplant we calcium and phosphate In patients the transplant is to base the of and on the and of and the of of CKD CKD for calcium and and for with on and CKD CKD for calcium and and for CKD for calcium and and for CKD of or in the of (see CKD patients for CKD-MBD, or in abnormalities is to the of to for and is to abnormalities for patients with CKD (see and In patients with CKD we that and by and In patients with CKD we that and treatment for the In patients with CKD with risk factors for osteoporosis, we that to risk results In patients in the 12 kidney transplant with an and we that treatment with and/or that treatment by the of CKD-MBD, by of and is to a bone to treatment to treatment the 12 In patients with CKD with we for patients with CKD on in and In patients with CKD with risk factors for osteoporosis, we that to risk results In patients in the 12 kidney transplant with an and we that treatment with and/or that treatment by the of CKD-MBD, by of and is to a bone to treatment to treatment the 12 Kidney Disease: Improving Global Outcomes (KDIGO) to or of that a of an or a or of a of the Work of the Work Group to and a and that or of This is updated and is in the Work Group and of the KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder in Kidney KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder is to the of the PDF Evenepoel et summary of the 2017 KDIGO Chronic Kidney Disease–Mineral and Bone Disorder Guideline and Kidney Int. the PDF

Importance: Limited evidence is available regarding long-term outcomes of opioids compared with nonopioid medications for chronic pain. Objective: To compare opioid vs nonopioid medications over 12 months on pain-related function, pain intensity, and adverse effects. Design, Setting, and Participants: Pragmatic, 12-month, randomized trial with masked outcome assessment. Patients were recruited from Veterans Affairs primary care clinics from June 2013 through December 2015; follow-up was completed December 2016. Eligible patients had moderate to severe chronic back pain or hip or knee osteoarthritis pain despite analgesic use. Of 265 patients enrolled, 25 withdrew prior to randomization and 240 were randomized. Interventions: Both interventions (opioid and nonopioid medication therapy) followed a treat-to-target strategy aiming for improved pain and function. Each intervention had its own prescribing strategy that included multiple medication options in 3 steps. In the opioid group, the first step was immediate-release morphine, oxycodone, or hydrocodone/acetaminophen. For the nonopioid group, the first step was acetaminophen (paracetamol) or a nonsteroidal anti-inflammatory drug. Medications were changed, added, or adjusted within the assigned treatment group according to individual patient response. Main Outcomes and Measures: The primary outcome was pain-related function (Brief Pain Inventory [BPI] interference scale) over 12 months and the main secondary outcome was pain intensity (BPI severity scale). For both BPI scales (range, 0-10; higher scores = worse function or pain intensity), a 1-point improvement was clinically important. The primary adverse outcome was medication-related symptoms (patient-reported checklist; range, 0-19). Results: Among 240 randomized patients (mean age, 58.3 years; women, 32 [13.0%]), 234 (97.5%) completed the trial. Groups did not significantly differ on pain-related function over 12 months (overall P = .58); mean 12-month BPI interference was 3.4 for the opioid group and 3.3 for the nonopioid group (difference, 0.1 [95% CI, -0.5 to 0.7]). Pain intensity was significantly better in the nonopioid group over 12 months (overall P = .03); mean 12-month BPI severity was 4.0 for the opioid group and 3.5 for the nonopioid group (difference, 0.5 [95% CI, 0.0 to 1.0]). Adverse medication-related symptoms were significantly more common in the opioid group over 12 months (overall P = .03); mean medication-related symptoms at 12 months were 1.8 in the opioid group and 0.9 in the nonopioid group (difference, 0.9 [95% CI, 0.3 to 1.5]). Conclusions and Relevance: Treatment with opioids was not superior to treatment with nonopioid medications for improving pain-related function over 12 months. Results do not support initiation of opioid therapy for moderate to severe chronic back pain or hip or knee osteoarthritis pain. Trial Registration: clinicaltrials.gov Identifier: NCT01583985.

BACKGROUND AND PURPOSE: Clinical stroke trials are increasingly measuring patient-centered outcomes such as functional status and health-related quality of life (HRQOL). No stroke-specific HRQOL measure is currently available. This study presents the initial development of a valid, reliable, and responsive stroke-specific quality of life (SS-QOL) measure, for use in stroke trials. METHODS: Domains and items for the SS-QOL were developed from patient interviews. The SS-QOL, Short Form 36, Beck Depression Inventory, National Institutes of Health Stroke Scale, and Barthel Index were administered to patients 1 and 3 months after ischemic stroke. Items were eliminated with the use of standard psychometric criteria. Construct validity was assessed by comparing domain scores with similar domains of established measures. Domain responsiveness was assessed with standardized effect sizes. RESULTS: All 12 domains of the SS-QOL were unidimensional. In the final 49-item scale, all domains demonstrated excellent internal reliability (Cronbach's alpha values for each domain >/=0.73). Most domains were moderately correlated with similar domains of established outcome measures (r2 range, 0.3 to 0.5). Most domains were responsive to change (standardized effect sizes >0.4). One- and 3-month SS-QOL scores were associated with patients' self-report of HRQOL compared with before their stroke (P<0.001). CONCLUSIONS: The SS-QOL measures HRQOL, its primary underlying construct, in stroke patients. Preliminary results regarding the reliability, validity, and responsiveness of the SS-QOL are encouraging. Further studies in diverse stroke populations are needed.

Abstract In this paper we report on an in‐depth study of engineering design processes. Specifically, we extend our previous research on engineering student design processes to compare the design behavior of students and expert engineers. Nineteen experts from a variety of engineering disciplines and industries each designed a playground in a lab setting, and gave verbal reports of their thoughts during the design task. Measures of their design processes and solution quality were compared to pre‐existing data from 26 freshmen and 24 seniors. The experts spent significantly more time on the task overall and in each stage of engineering design, including significantly more time problem scoping. The experts also gathered significantly more information covering more categories. Results support the argument that problem scoping and information gathering are major differences between advanced engineers and students, and important competencies for engineering students to develop. Timeline representations of the expert designers' processes illustrate characteristic distinctions we found and may help students gain insights into their own design processes.

It has been shown that stromal-vascular fraction isolated from adipose tissues contains an abundance of CD34+ cells. Histological analysis of adipose tissue revealed that CD34+ cells are widely distributed among adipocytes and are predominantly associated with vascular structures. The majority of CD34+ cells from freshly isolated stromal-vascular fraction were CD31-/CD144- and could be separated from a distinct population of CD34+/CD31+/CD144+ (endothelial) cells by differential attachment on uncoated plastic. The localization of CD34+ cells within adipose tissue suggested that the nonendothelial population of these cells occupied a pericytic position. Analysis of surface and intracellular markers of the freshly isolated CD34+/CD31-/CD144- adipose-derived stromal cells (ASCs) showed that >90% coexpress mesenchymal (CD10, CD13, and CD90), pericytic (chondroitin sulfate proteoglycan, CD140a, and CD140b), and smooth muscle (alpha-actin, caldesmon, and calponin) markers. ASCs demonstrated polygonal self-assembly on Matrigel, as did human microvascular endothelial cells. Coculture of ASCs with human microvascular endothelial cells on Matrigel led to cooperative network assembly, with enhanced stability of endothelial networks and preferential localization of ASCs on the abluminal side of cords. Bidirectional paracrine interaction between these cells was supported by identification of angiogenic factors (vascular endothelial growth factor, hepatocyte growth factor, basic fibroblast growth factor), inflammatory factors (interleukin-6 and -8 and monocyte chemoattractant protein-1 and -2), and mobilization factors (macrophage colony-stimulating factor and granulocyte/macrophage colony-stimulating factor) in media conditioned by CD34+ ASCs, as well a robust mitogenic response of ASCs to basic fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor-BB, factors produced by endothelial cells. These results demonstrate for the first time that the majority of adipose-derived adherent CD34+ cells are resident pericytes that play a role in vascular stabilization by mutual structural and functional interaction with endothelial cells.

BACKGROUND: For chronically ill patients, readmission to the hospital can be frequent and costly. We studied the effect of an intervention designed to increase access to primary care after discharge from the hospital, with the goals of reducing readmissions and emergency department visits and increasing patients' quality of life and satisfaction with care. METHODS: In a multicenter randomized, controlled trial at nine Veterans Affairs Medical Centers, we randomly assigned 1396 veterans hospitalized with diabetes, chronic obstructive pulmonary disease, or congestive heart failure to receive either usual care or an intensive primary care intervention. The intervention involved close follow-up by a nurse and a primary care physician, beginning before discharge and continuing for the next six months. RESULTS: The patients were severely ill. Half of those with congestive heart failure (504 patients) had disease in New York Heart Association class III or IV; 30 percent of those with diabetes (751 patients) had end-organ damage; and a quarter of those with chronic obstructive pulmonary disease (583 patients) required home oxygen treatment or oral corticosteroids. The patients had extremely poor quality-of-life scores. Although they received more intensive primary care than the controls, the patients in the intervention group had significantly higher rates of readmission (0.19 vs 0.14 per month, P = 0.005) and more days of rehospitalization (10.2 vs 8.8, P = 0.041). The patients in the intervention group were more satisfied with their care (P < 0.001), but there was no difference between the study groups in quality-of-life scores, which remained very low (P = 0.53). CONCLUSIONS: For veterans discharged from Veterans Affairs hospitals, the primary care intervention we studied increased rather than decreased the rate of rehospitalization, although patients in the intervention group were more satisfied with their care.

Colorectal cancer (CRC) is the third most common cancer in men and women in the United States. CRC screening efforts are directed toward removal of adenomas and sessile serrated lesions and detection of early-stage CRC. The purpose of this article is to update the 2009 American College of Gastroenterology CRC screening guidelines. The guideline is framed around several key questions. We conducted a comprehensive literature search to include studies through October 2020. The inclusion criteria were studies of any design with men and women age 40 years and older. Detailed recommendations for CRC screening in average-risk individuals and those with a family history of CRC are discussed. We also provide recommendations on the role of aspirin for chemoprevention, quality indicators for colonoscopy, approaches to organized CRC screening and improving adherence to CRC screening. CRC screening must be optimized to allow effective and sustained reduction of CRC incidence and mortality. This can be accomplished by achieving high rates of adherence, quality monitoring and improvement, following evidence-based guidelines, and removing barriers through the spectrum of care from noninvasive screening tests to screening and diagnostic colonoscopy. The development of cost-effective, highly accurate, noninvasive modalities associated with improved overall adherence to the screening process is also a desirable goal.

BACKGROUND: Inadequate pain assessment is a barrier to appropriate pain management, but single-item "pain screening" provides limited information about chronic pain. Multidimensional pain measures such as the Brief Pain Inventory (BPI) are widely used in pain specialty and research settings, but are impractical for primary care. A brief and straightforward multidimensional pain measure could potentially improve initial assessment and follow-up of chronic pain in primary care. OBJECTIVES: To develop an ultra-brief pain measure derived from the BPI. DESIGN: Development of a shortened three-item pain measure and initial assessment of its reliability, validity, and responsiveness. PARTICIPANTS: We used data from 1) a longitudinal study of 500 primary care patients with chronic pain and 2) a cross-sectional study of 646 veterans recruited from ambulatory care. RESULTS: Selected items assess average pain intensity (P), interference with enjoyment of life (E), and interference with general activity (G). Reliability of the three-item scale (PEG) was alpha = 0.73 and 0.89 in the two study samples. Overall, construct validity of the PEG was good for various pain-specific measures (r = 0.60-0.89 in Study 1 and r = 0.77-0.95 in Study 2), and comparable to that of the BPI. The PEG was sensitive to change and differentiated between patients with and without pain improvement at 6 months. DISCUSSION: We provide strong initial evidence for reliability, construct validity, and responsiveness of the PEG among primary care and other ambulatory clinic patients. The PEG may be a practical and useful tool to improve assessment and monitoring of chronic pain in primary care.