Indiana University – Purdue University Indianapolis

A concept for the optimization of nonlinear functions using particle swarm methodology is introduced. The evolution of several paradigms is outlined, and an implementation of one of the paradigms is discussed. Benchmark testing of the paradigm is described, and applications, including nonlinear function optimization and neural network training, are proposed. The relationships between particle swarm optimization and both artificial life and genetic algorithms are described.

The optimization of nonlinear functions using particle swarm methodology is described. Implementations of two paradigms are discussed and compared, including a recently developed locally oriented paradigm. Benchmark testing of both paradigms is described, and applications, including neural network training and robot task learning, are proposed. Relationships between particle swarm optimization and both artificial life and evolutionary computation are reviewed.

Evolutionary computation techniques, genetic algorithms, evolutionary strategies and genetic programming are motivated by the evolution of nature. A population of individuals, which encode the problem solutions are manipulated according to the rule of survival of the fittest through "genetic" operations, such as mutation, crossover and reproduction. A best solution is evolved through the generations. In contrast to evolutionary computation techniques, Eberhart and Kennedy developed a different algorithm through simulating social behavior (R.C. Eberhart et al., 1996; R.C. Eberhart and J. Kennedy, 1996; J. Kennedy and R.C. Eberhart, 1995; J. Kennedy, 1997). As in other algorithms, a population of individuals exists. This algorithm is called particle swarm optimization (PSO) since it resembles a school of flying birds. In a particle swarm optimizer, instead of using genetic operators, these individuals are "evolved" by cooperation and competition among the individuals themselves through generations. Each particle adjusts its flying according to its own flying experience and its companions' flying experience. We introduce a new parameter, called inertia weight, into the original particle swarm optimizer. Simulations have been done to illustrate the significant and effective impact of this new parameter on the particle swarm optimizer.

Four hundred M-mode echocardiographic surveys were distributed to determine interobserver variability in M-mode echocardiographic measurements. This was done with a view toward examining the need and determining the criteria for standardization of measurement. Each survey consisted of five M-mode echocardiograms with a calibration marker, measured by the survey participants anonymously. The echoes were judged of adequate quality for measurement of structures. Seventy-six of the 400 (19%) were returned, allowing comparison of interobserver variability as well as examination of the measurement criteria which were used. Mean measurements and percent uncertainty were derived for each structure for each criterion of measurement. For example, for the aorta, 33% of examiners measured the aorta as an outer/inner or leading edge dimension, and 20% measured it as an outer/outer dimension. The percent uncertainty for the measurement (1.97 SD divided by the mean) showed a mean of 13.8% for the 25 packets of five echoes measured using the former criteria and 24.2% using the latter criteria. For ventricular chamber and cavity measurements, almost one-half of the examiners used the peak of the QRS and one-half of the examiners used the onset of the QRS for determining end-diastole. Estimates of the percent of measurement uncertainty for the septum, posterior wall and left ventricular cavity dimension in this study were 10--25%. They were much higher (40--70%) for the right ventricular cavity and right ventricular anterior wall. The survey shows significant interobserver and interlaboratory variation in measurement when examining the same echoes and indicates a need for ongoing education, quality control and standardization of measurement criteria. Recommendations for new criteria for measurement of M-mode echocardiograms are offered.

Potential conflict of interest: Dr. Chalasani consults for and received grants from Eli Lilly. He consults for NuSirt, AbbVie, Afimmune, Tobira, Madrigal, Shire, Cempra, Ardelyx, Axovant, and Amarin. He received grants from Intercept, Gilead, Galectin, and Cumberland. Dr. Younossi consults for Bristol‐Myers Squibb, Gilead, Intercept, Allergan, and GlaxoSmithKline. He advises for Vertex and Janssen. Dr. Brunt advises for Gilead. Dr. Charlton consults for and received grants from Gilead, Intercept, NGM Bio, Genfit, and Novartis. He received grants from Conatus. Dr. Cusi consults for and received grants from Novo Nordisk. He consults for Tobira. He received grants from Cirius, Novartis, Janssen, Zydus, Nordic, and Lilly. Dr. Rinella consults for Intercept, Gilead, Genfit, Novartis, NGM Bio, and Nusirt. She advises for Fibrogen, Immuron, Enanta, and AbbVie. Dr. Harrison consults for Madrigal, NGM Bio, Genfit, Echosens, Prometheus, Cirius, Perspectum, and HistoIndex. He advises for Garland, Intercept, Novartis, and Pfizer. He is on the speakers' bureau for AbbVie, Gilead, and Alexion. Dr. Sanyal consults for and received grants from Salix, Conatus, Galectin, Gilead, malinckrodt, Echosens‐Sandhill, Novartis, and Sequana. He consults for and is employed by Sanyal Bio. He consults for and owns stock in GenFit, Hemoshear, Durect, and Indalo. He consults for Immuron, Intercept, Pfizer, Boehringer Ingleheim, Nimbus, Nitto Denko, Lilly, Novo Nordisk, Fractyl, Allergan, Chemomab, Affimmune, Teva, and Ardelyx. He received grants from Bristol‐Myers Squibb and Merck. He received royalties from UptoDate. He owns stock in Exhalenz, Arkana, and NewCo LLC. The funding for the development of this Practice Guidance was provided by the American Association for the Study of Liver Diseases. This practice guidance was approved by the American Association for the Study of Liver Diseases on June 15, 2017. Preamble This guidance provides a data‐supported approach to the diagnostic, therapeutic, and preventive aspects of nonalcoholic fatty liver disease (NAFLD) care. A “Guidance” document is different from a “Guideline.” Guidelines are developed by a multidisciplinary panel of experts and rate the quality (level) of the evidence and the strength of each recommendation using the Grading of Recommendations, Assessment Development, and Evaluation system. A guidance document is developed by a panel of experts in the topic, and guidance statements, not recommendations, are put forward to help clinicians understand and implement the most recent evidence. This Practice Guidance was commissioned by the American Association for the Study of Liver Diseases (AASLD) and is an update to the Practice Guideline published in 2012 in conjunction with the American Gastroenterology Association and the American College of Gastroenterology (ACG).1 Sections where there have been no notable newer publications are not modified, so some paragraphs remain unchanged. This narrative review and guidance statements are based on the following: (1) a formal review and analysis of the recently published world literature on the topic (Medline search up to August 2016); (2) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines2; (3) guideline policies of the AASLD; and (4) the experience of the authors and independent reviewers with regard to NAFLD. This practice guidance is intended for use by physicians and other health professionals. As clinically appropriate, guidance statements should be tailored for individual patients. Specific guidance statements are evidence based whenever possible, and, when such evidence is not available or is inconsistent, guidance statements are made based on the consensus opinion of the authors.3 This is a practice guidance for clinicians rather than a review article, and interested readers can refer to several recent comprehensive reviews.4 Because this guidance document is lengthy, to make it easier for the reader, a list of all guidance statements and recommendations are provided in a tabular form there be (1) evidence of by or and (2) of of such use of a or the of is with such and can be nonalcoholic fatty liver or nonalcoholic is the of evidence of in the form of is the of and with with or this guidance document be to or or of fatty liver of of and the of in from fatty liver to to of evidence of in the form of of the or evidence of The of to and liver is of with and with or This can to liver and liver of with or evidence of or of with no with are with such and of and is a to in liver in with in is A of and and of in the is a of the of in the A have of from are a for of by was a of for of by was the of using and was to be a of for an of of developed by to an rate of The for in the of are A from using of an rate for of the of such this most the of A from an rate of A recent the of from to be the rate from the is to be to the there is a of publications the of in the are in a recent of the of The the of by is The of is from the and the rate is from As the for a liver liver is not in of the there is no of the or of there have been some to the of by The the of in the are in the The of liver for a is to be The of liver a for is from to the of in the and of in of are not in with of the of This and of been this provides a list of the and and and independent of are with and is the most and for NAFLD. the of from to and is with NAFLD. this the of with have is a of in with some have to of have is to the of and this and can in a the of in with or the of in with NAFLD. this and and are in with NAFLD. The of in with been to be a a the based on to and to The rate of was the rate for with the to and to was the rate in the with the was and The of to and the of and of liver disease to with Association of the of or of the (1) than in or than in (2) or (3) than in and than in (4) or or or and or been a for NAFLD. the of in is than in The of and on have the to have a of have a of the of and to be to be is most of the recent the for be by the to the the of the from to and of the have the of with is evidence with with some of are for such and have the following: with have to The most of in with is disease independent of other is the of in the it is the or of with is the of in with with have an a recent and and to be and and and The for and for to be and The most of with is to or are of is the of in the to the of with the the of the of been to a with are have a have and are to from liver than other of from a of from the not have other was with in the of This of in is to most with have is This of with have a of and with the with or in the of in of the for liver disease is of the recent in with a rate of the of in to with a rate of and in with to with a recent of with and a of an of rate not different from with This is with of with with or liver is the of and the of in the are with As of liver disease is the development of The rate was to be of with of the to to liver to and to it is the for in is the of with the and of the of evidence for or recent of of the of in with is A consensus for be in and in a liver to the on and a is of the of in published literature been Guidance or recent on in and on in is a for when with NAFLD. Evaluation of and for other than liver or A recent of with be for based on the the and and for this have not been Guidance with on have or to liver disease or have liver should be have and up with on or and have liver should be for or and for such or for in and can be there should be for with or not with have of the available evidence of and of there are in the and of NAFLD. A analysis using a for in with is not of with available liver can be in with not be to liver or are is experts recently have for for liver disease in with not Guidance for in or is not this of and with of to and of should be a of for and in with such or or can be to or for or of of a of with have a a of with and for and the of liver was and fatty liver was in of of with in the of and the of have been from no in a to in a of an of in using to and and not and, the of and was and Guidance of for is not Evaluation of the The of (1) there is by or (2) there is no (3) there are no for and (4) there are no of of are disease and a with it is to for liver and liver can in with not the of liver of this are and is a of not it can disease the are of was with in a of and are in a with should be in the with in with and the is Liver should be in the of and a to the or of and to in a with NAFLD. of and are in with and are to be an of no liver to a of from the in or in and not with disease or other are should be for the of or and Guidance a with it is to for and with and in the of or a liver should be of in with other of liver disease or to should a for liver of with should the of such or and Assessment of and in The of is is can to liver and liver Liver is the most approach for the of and in with it is is by and and and such and not the of liver in with NAFLD. there been in and for in with is the of this practice of the of and and the and of in with by or by is an for and is in The use of to is a for in an the of in with in is The of is a for the of in with is with of the of an of such and to the of liver with and such and are the for of have been for the of in with This is not available in a The for the of in to Liver and or and The is based on available and and is using the published a of of the an the of for with or A and to a and to the of is an based on and with are with are to have A recent and liver and (1) than other such and and (2) for in with The panel of of of and an of with and for or This panel been recently approved for use in is not available for use in the liver was recently approved by the and for use in and with liver recent the of in with using an on the of in with from the The liver for was with and The for was in of the the on the of using an with in with The rate for in this was The for for and was The recently experience with in with in the using a with an or rate for a liver was is for of in with the by than for or in or for and and have several with and in with for in is not Guidance with the of and can be to for a liver or are clinically for with of or or are clinically for in with NAFLD. to a Liver in Liver the for liver in with NAFLD. is for and some and it should be in the most from and Guidance Liver should be in with are of The of or or liver by or be for are for Liver should be in with in for and the of be a liver of The of are of with the of not by The for of liver in a with or the and on of the is the to from on of and The for have been by the by not with or and or not all for with of or in or and and of have no or of up to is or is and is with and is of in from in in be or in and and be in is readers refer to other recent publications for of of fatty liver disease in and are for of in from the and from the Liver of the and for The was developed a of in from a the the for for use in and from with the of and in with other of liver there is a for and for with based and to the of in and and The by a of was with in and when a a Guidance should a with and with and and A on or be Specific such be The or of should be a to and is of The of should of liver disease the such and with or have from a liver liver disease should be to with and Guidance liver disease should be to with and of and been to with NAFLD. The to is the to in the of a of with to of in was with have been by a recent with liver in this a was the the of the the in such was with in all of and it is to or in of the of to a in this with a the is with of liver and in The of the to to be than the of in are by a of and by or by in in and The in fatty been in to a for and, there was no in in in the with are recommendations to can be The of are in and this been with an of and the of on in are a recent an in with no in The and of than or by than have in independent of This is by a of of a a or for was with the in of development or in independent of the The of on are from a of of or was not with in or recommendations have in of the recommendations was to have a on and are for with to the of and on are on in a analysis of in a than on a review of and in liver liver with of the to of a recommendations to in a of to in and Guidance by or in conjunction with A of a by and is to the of of of to a is to the of the of in with or to other aspects of liver the of on liver in with several have an in and not liver published not liver in with and Guidance is not for in patients. are for the with on and on and The of to and in and have to in with an in not of or is no available in most and in the of of an in no was an review of all evidence by the an an of in with and or and and The with in to of and there was a in to a recent Cusi with or with a from and or for by an with The was a of in the different of with the and of and of no different was with and a of is of in with an with or for in with not to and the for the of with a in with to or for The was an in by with in and in the or and no in the This was in in the to in the and in the Because this of and a of was to be a there with this not the of a was in a of than and and there no in other is the most with from and from to in of to been a with or for up to and no and use of or of in with Guidance liver in with and with it be to patients. and should be with each and should not be to been an in the of in with and a recently published of with for was with of and of As was with Guidance is to to liver disease in with or is a of and disease in with is an and been a for is of for the different of and of the use of other or other and to most and not or of for it can be (1) the use of is with a in in with (2) in in in and and of in a of with and (3) not have an on the the form of was a of for The was in a of to to the of Liver in or in with of was in with than in with recent with in with are the of of with this been several with and A and other such not A analysis of with the of the by in in the in A and from to not a and a published in a of was and with a in the of of of and this be by or with Guidance a of liver in with and be for this and should be with each is not to in liver or all is in for is in all of most is to and to or disease in most and and from and the most of in there are no of in to be in the there are several and and with liver and with liver of and and in with and in and to there was a in the and of and and with or there was a in and and of or and with no in liver and a in was the to this of and there is no clinically in can be to the a on with with the of and of in to in of a of available in the of to or the of and by a by in the of The and of in with is not analysis from the and for with and to was in with and in with A recent review of in with A and is with with Guidance can be in with or is to an to The and of in with to are not with or be on a by an have and to and in with and liver in with have been with of a no in with fatty approved in the to have been to in and in a review of the published literature in evidence to the use of fatty in with to liver the of was by and recently to for fatty in with or than a other have been in and is the of this Guidance is not for the of or fatty should not be a of or be to in with NAFLD. in and is a for and should be by with and or than on or than in or than on or in several have a of than on the or by and of a recent analysis of from the of by are are no the of on disease or of or The of on the and have not been in with NAFLD. Guidance with should not of are to make recommendations with regard to of by with NAFLD. is a and of and for the and a and to and of is there are and of the and and of are not and with have a by and to a of with to be by and the of rather than by the of have evidence of the of with of in with or and A recent analysis of the The and Evaluation and in with to analysis of the The and a of in with in to it is to in with based on to use in with or and several have the of in with liver disease of in liver the of is not in with are not in liver from is in of for are and have with liver or not all and on when this was not a of in liver or liver Guidance with are for and of should be in all with NAFLD. with or are not for liver from can be to in with and be in with should be in with and are are in a a and a in a this was with and This was recently approved by the for with are to in a up to in a recently an for a this was with there was a in Guidance and available in with should not be to and and are and, in is on a to the most for in the with is with an of and to an analysis of the for a of and and with the of when for not to an of or The of on and in the of the of a in of or for not been for and been in a of with been in and and in for The of an to of all to the is is with been an independent of and Because of the of and with and a of is with some of and have all been to be in this As is with a of with is in with with to when is or is with an of disease and in the most for liver in the Because of the of with rate of or of with the is than of are from are for with and and are to other The of is an of and in evidence of is or by for is in of by the of the a rate is than for other than with for than and is in of by the A recent experience of to this from and recommendations for are to for other with and and a and are in the of is by and is in with a of are some to the of patients. and and Guidance with have of should be to clinically or the Guidance to Practice with should be for to the and practice with of should be for to the practice evidence not and for in with evidence not a liver in with or this be on a of Specific to and in be to or to with of in be most for or The of and in are the in with are and with of of in for the in based the of or the for and the and of the A of in and using a of to using the of liver to from The was when for and A recent the of to be in from and in based on This the of in to with with a of with with and with the of was to be with of to in with and or in with so use of the of liver a of with and from of of on the of was in of with liver other than in was the most and was in of the with NAFLD. with the a of and a of of been in of with The of and to was in to a with than to to an and NAFLD. A the of in for of of the and of The the on with received with of the liver developed the was to and the or in of and in not to be and with are on of to the of in is in of of or of by health than of with for with not be and for of by As in with of such and are for and of with of of for in health in for and there are no to with in this the of an for liver disease with and in with and with in the with other the to the of in of fatty or and in are in a of with and, on some liver is to and the of use or is in and for are the no panel of or can and in Guidance with fatty liver are or not should be for of such fatty and in to for of are in with in with or to should a liver to and Because of a of a formal recommendation be made with regard to for in with and A The to a liver in a to the of be the with and the the with an of than or of to of there is an in or of all with to a liver it be to are to have or to with for liver on in of and of have been to for The of the to of with based on of As in development of or to for or disease is of and are can be to in with a of and with is in in with an of of the or of with of a liver a with and the Guidance Liver in with should be in in the is or in there is of or A liver to a of should be on for of with can from in some in of and there is a in This is by or and in the of The and to be different in with Guidance liver should the in with to NAFLD. for are by a of and on to The is to a quality of and and liver and of should be made to from Because most have this is the in with in in and by in most with NAFLD. of the to this using and Because liver not the of the the of on liver not be with to or and not liver in in and the of with and in an or in to on of or the of to aspects of in is are to the of for should with a to quality of and of of American Association and in As in for or have in or liver on and A using in a the of or to in to with the of of was not different the there in and of with to this a no on liver or liver The from the of to this the in of or of was not the a in on to been some to fatty to in a of and to in for in in Guidance and liver in with and should be the of no to with and should not be to or The of a is not to some with of in is be to in and should be with each in

INTRODUCTION: Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. METHODS: Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. RESULTS: The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. CONCLUSION: We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.

For the purposes of classification, it should be specified whether osteoarthritis (OA) of the knee is of unknown origin (idiopathic, primary) or is related to a known medical condition or event (secondary). Clinical criteria for the classification of idiopathic OA of the knee were developed through a multicenter study group. Comparison diagnoses included rheumatoid arthritis and other painful conditions of the knee, exclusive of referred or para-articular pain. Variables from the medical history, physical examination, laboratory tests, and radiographs were used to develop sets of criteria that serve different investigative purposes. In contrast to prior criteria, these proposed criteria utilize classification trees, or algorithms.

BACKGROUND: A number of self-administered questionnaires are available for assessing depression severity, including the 9-item Patient Health Questionnaire depression module (PHQ-9). Because even briefer measures might be desirable for use in busy clinical settings or as part of comprehensive health questionnaires, we evaluated a 2-item version of the PHQ depression module, the PHQ-2. METHODS: The PHQ-2 inquires about the frequency of depressed mood and anhedonia over the past 2 weeks, scoring each as 0 ("not at all") to 3 ("nearly every day"). The PHQ-2 was completed by 6000 patients in 8 primary care clinics and 7 obstetrics-gynecology clinics. Construct validity was assessed using the 20-item Short-Form General Health Survey, self-reported sick days and clinic visits, and symptom-related difficulty. Criterion validity was assessed against an independent structured mental health professional (MHP) interview in a sample of 580 patients. RESULTS: As PHQ-2 depression severity increased from 0 to 6, there was a substantial decrease in functional status on all 6 SF-20 subscales. Also, symptom-related difficulty, sick days, and healthcare utilization increased. Using the MHP reinterview as the criterion standard, a PHQ-2 score > or =3 had a sensitivity of 83% and a specificity of 92% for major depression. Likelihood ratio and receiver operator characteristic analysis identified a PHQ-2 score of 3 as the optimal cutpoint for screening purposes. Results were similar in the primary care and obstetrics-gynecology samples. CONCLUSION: The construct and criterion validity of the PHQ-2 make it an attractive measure for depression screening.

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: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS: ), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS: In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis. An integrated transcriptome, genome, methylome and proteome analysis of over 200 lung adenocarcinomas reveals high rates of somatic mutations, 18 statistically significantly mutated genes including RIT1 and MGA, splicing changes, and alterations in MAPK and PI(3)K pathway activity. This report from The Cancer Genome Atlas Research Network presents molecular profiling of 230 resected untreated lung adenocarcinomas. Integrated analyses of transcriptome, genome, methylome and proteome collectively identify high rates of somatic mutation, significantly mutated genes including RIT1 and MGA, splicing alterations driven by somatic genomic changes, and point to as yet unidentified lesions that alter MAPK and PI(3)K pathway activity. These data establish a foundation for classification and further investigations of the leading cause of cancer death worldwide.

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.

Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.

BACKGROUND: We conducted a randomized study to determine whether any of three chemotherapy regimens was superior to cisplatin and paclitaxel in patients with advanced non-small-cell lung cancer. METHODS: A total of 1207 patients with advanced non-small-cell lung cancer were randomly assigned to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. RESULTS: The response rate for all 1155 eligible patients was 19 percent, with a median survival of 7.9 months (95 percent confidence interval, 7.3 to 8.5), a 1-year survival rate of 33 percent (95 percent confidence interval, 30 to 36 percent), and a 2-year survival rate of 11 percent (95 percent confidence interval, 8 to 12 percent). The response rate and survival did not differ significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the three experimental regimens. Treatment with cisplatin and gemcitabine was associated with a significantly longer time to the progression of disease than was treatment with cisplatin and paclitaxel but was more likely to cause grade 3, 4, or 5 renal toxicity (in 9 percent of patients, vs. 3 percent of those treated with cisplatin plus paclitaxel). Patients with a performance status of 2 had a significantly lower rate of survival than did those with a performance status of 0 or 1. CONCLUSIONS: None of four chemotherapy regimens offered a significant advantage over the others in the treatment of advanced non-small-cell lung cancer.

The particle swarm algorithm adjusts the trajectories of a population of "particles" through a problem space on the basis of information about each particle's previous best performance and the best previous performance of its neighbors. Previous versions of the particle swarm have operated in continuous space, where trajectories are defined as changes in position on some number of dimensions. The paper reports a reworking of the algorithm to operate on discrete binary variables. In the binary version, trajectories are changes in the probability that a coordinate will take on a zero or one value. Examples, applications, and issues are discussed.

Much of the prior research on interorganizational learning has focused on the role of absorptive capacity, a firm's ability to value, assimilate, and utilize new external knowledge. However, this definition of the construct suggests that a firm has an equal capacity to learn from all other organizations. We reconceptualize the firm-level construct absorptive capacity as a learning dyad-level construct, relative absorptive capacity. One firm's ability to learn from another firm is argued to depend on the similarity of both firms' (1) knowledge bases, (2) organizational structures and compensation policies, and (3) dominant logics. We then test the model using a sample of pharmaceutical–biotechnology R&D alliances. As predicted, the similarity of the partners' basic knowledge, lower management formalization, research centralization, compensation practices, and research communities were positively related to interorganizational learning. The relative absorptive capacity measures are also shown to have greater explanatory power than the established measure of absorptive capacity, R&D spending. © 1998 John Wiley & Sons, Ltd.

This paper focuses on the engineering and computer science aspects of developments, applications, and resources related to particle swarm optimization. Developments in the particle swarm algorithm since its origin in 1995 are reviewed. Included are brief discussions of constriction factors, inertia weights, and tracking dynamic systems. Applications, both those already developed, and promising future application areas, are reviewed. Finally, resources related to particle swarm optimization are listed, including books, Web sites, and software. A particle swarm optimization bibliography is at the end of the paper.

BACKGROUND: Depression and anxiety are common in medical patients and are associated with diminished health status and increased health care utilization. This article presents a quantitative review and synthesis of studies correlating medical patients' treatment noncompliance with their anxiety and depression. METHODS: Research on patient adherence catalogued on MEDLINE and PsychLit from January 1, 1968, through March 31, 1998, was examined, and studies were included in this review if they measured patient compliance and depression or anxiety (with n>10); involved a medical regimen recommended by a nonpsychiatrist physician to a patient not being treated for anxiety, depression, or a psychiatric illness; and measured the relationship between patient compliance and patient anxiety and/or depression (or provided data to calculate it). RESULTS: Twelve articles about depression and 13 about anxiety met the inclusion criteria. The associations between anxiety and noncompliance were variable, and their averages were small and nonsignificant. The relationship between depression and noncompliance, however, was substantial and significant, with an odds ratio of 3.03 (95% confidence interval, 1.96-4.89). CONCLUSIONS: Compared with nondepressed patients, the odds are 3 times greater that depressed patients will be noncompliant with medical treatment recommendations. Recommendations for future research include attention to causal inferences and exploration of mechanisms to explain the effects. Evidence of strong covariation of depression and medical noncompliance suggests the importance of recognizing depression as a risk factor for poor outcomes among patients who might not be adhering to medical advice.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

We empirically study the performance of the particle swarm optimizer (PSO). Four different benchmark functions with asymmetric initial range settings are selected as testing functions. The experimental results illustrate the advantages and disadvantages of the PSO. Under all the testing cases, the PSO always converges very quickly towards the optimal positions but may slow its convergence speed when it is near a minimum. Nevertheless, the experimental results show that the PSO is a promising optimization method and a new approach is suggested to improve PSO's performance near the optima, such as using an adaptive inertia weight.