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 as Supporting Table S1. Definitions For defining NAFLD, there must be (1) evidence of hepatic steatosis (HS), either by imaging or histology, and (2) lack of secondary causes of hepatic fat accumulation such as significant alcohol consumption, long‐term use of a steatogenic medication, or monogenic hereditary disorders (Table 1). In the majority of patients, NAFLD is commonly associated with metabolic comorbidities such as obesity, diabetes mellitus, and dyslipidemia. NAFLD can be categorized histologically into nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH; Table 2). NAFL is defined as the presence of ≥5% HS without evidence of hepatocellular injury in the form of hepatocyte ballooning. NASH is defined as the presence of ≥5% HS and inflammation with hepatocyte injury (e.g., ballooning), with or without any fibrosis. For defining “advanced” fibrosis, this guidance document will be referring specifically to stages 3 or 4, that is, bridging fibrosis or cirrhosis. Table 1 - Common Causes of Secondary HS Macrovesicular steatosis ‐ Excessive alcohol consumption ‐ Hepatitis C (genotype 3) ‐ WD ‐ Lipodystrophy ‐ Starvation ‐ Parenteral nutrition ‐ Abetalipoproteinemia ‐ Medications (e.g., mipomersen, lomitapide, amiodarone, methotrexate, tamoxifen, corticosteroids) Microvesicular steatosis ‐ Reye's syndrome ‐ Medications (valproate, antiretroviral medicines) ‐ Acute fatty liver of pregnancy ‐ HELLP syndrome ‐ Inborn errors of metabolism (e.g., lecithin‐cholesterol acyltransferase deficiency, cholesterol ester storage disease, Wolman's disease) Table 2 - NAFLD and Related Definitions NAFLD Encompasses the entire spectrum of FLD in individuals without significant alcohol consumption, ranging from fatty liver to SH to cirrhosis NAFL Presence of ≥5% HS without evidence of hepatocellular injury in the form of ballooning of the hepatocytes or evidence of fibrosis. The risk of progression to cirrhosis and liver failure is considered minimal. NASH Presence of ≥5% HS with inflammation and hepatocyte injury with or without fibrosis. This can to liver and liver NASH cirrhosis Presence of cirrhosis with or evidence of steatosis or SH cirrhosis Presence of cirrhosis with no with cirrhosis are with metabolic risk such as and of and ballooning is a to in liver in with NAFLD in is A of steatosis inflammation ballooning), and and of NAFLD in the NAFLD is a of the of NAFLD in the A have of NAFLD from are In a that for of NAFLD by was In a of for of NAFLD by was In the of NAFLD using imaging and was to be In a of NAFLD for an of of developed NAFLD by to an rate of The for NAFLD in the of are commonly A from using of an rate for NAFLD of the of such as this most the of A from an rate of A recent that the of NAFLD from to be the rate from the is to be NAFLD In to the there is a of publications the of NAFLD in the are in a recent of the of The that the of NAFLD by imaging is The of NAFLD is from the and the rate is from As the for NASH a liver that liver is not in of the there is no of the or of there have been some to the of NASH by The the of NASH in the are in the The of NASH NAFLD liver for a is to be The of NASH NAFLD liver without a for is from to that the of NASH in the and of NAFLD in of metabolic syndrome are not in with NAFLD, of the risk of This NAFLD and of been In this Table 3 provides a list of the 2 and and and syndrome independent of that are associated with and is the most and risk for NAFLD. In the entire spectrum of obesity, ranging from to and is associated with NAFLD. In this the majority of with will have 2 diabetes is a of NAFLD in individuals with In some have that to of have is to the of NAFLD and In this and NAFLD can in a the of NAFLD in with or the of in with NAFLD. this and and are in with NAFLD. 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Evaluation of and imaging for other than liver or A recent that of with HS be risk for hepatic fibrosis based on the NAFLD fibrosis the and and for this have not been Guidance with HS on imaging have or to liver disease or have liver should be as have NAFLD and up with HS on imaging lack any or and have liver should be for metabolic risk (e.g., obesity, diabetes mellitus, or and causes for HS such as significant alcohol consumption or for NAFLD in and can be that there should be for NAFLD, individuals with diabetes or For not with 2 diabetes have of NAFLD, the available evidence of NASH and stages of fibrosis 2 diabetes there are significant in the and of NAFLD. A analysis using a that for NASH in individuals with diabetes is not of associated with available that liver can be in with NAFLD, not be to as liver or are as is experts recently have for for liver disease in with 2 not Guidance for NAFLD in or is not this of and with lack of to long‐term and of should be a of for NAFLD and NASH in with 2 such as or or can be to or risk for fibrosis fibrosis or of of In a that of with NASH have a In a of with and without NAFLD, for and the of liver fat was and fatty liver was in of of with NAFLD in the of and the of NAFLD have been ranging from no in a to in a of In an of in using to steatosis and fibrosis, steatosis and fibrosis not and, the of HS and was and Guidance of for NAFLD is not Evaluation of the NAFLD The of NAFLD that (1) there is HS by imaging or histology, (2) there is no significant alcohol consumption, (3) there are no for and (4) there are no causes of Common causes of HS are significant alcohol consumption, disease and (Table 1). a with NAFLD, it is to for liver disease, deficiency, and liver can in with NAFLD that not the presence of liver of this are and is a of NAFLD that not hepatic it can disease the are of was associated with fibrosis in a of and are in a with NAFLD, should be in the with in with NAFLD, and the is Liver should be considered in the of and a to the presence or of hepatic accumulation and to significant hepatic injury in a with NAFLD. of and are in with NAFLD and are considered to be an of no liver to In a of NAFLD from the NASH significant in or in and not associated with disease or other are should be for the presence of commonly associated obesity, diabetes or and Guidance a with NAFLD, it is to for steatosis and In with NAFLD, and in the of or a liver should be of in with other of liver disease or to should a for liver of with NAFLD should the presence of commonly associated comorbidities such as obesity, or and Assessment of and in NAFLD The of NAFLD is is NASH can to liver and liver Liver is the most approach for the presence of steatohepatitis and fibrosis in with NAFLD, it is that is by and and and imaging such as and not the spectrum of liver in with NAFLD. there been significant in and for SH in with NAFLD, is the of this practice NAFLD that of steatosis the of (e.g., ballooning and and the and of diabetes in with either by or by fat is an for HS and is in NAFLD The use of to is a for hepatic fat in an the of HS in with NAFLD in is NAFLD The presence of is a for the presence of SH in with NAFLD is associated with of the presence of an of metabolic such as 2 and obesity, to the risk of liver with NAFLD and risk such as and are the risk for of have been as for the presence of SH in with This is not available in a NAFLD The commonly for the presence of fibrosis in NAFLD (e.g., NAFLD fibrosis to Liver and or imaging and The is based on available and and is using the published In a of of the an the of for fibrosis bridging fibrosis with or A and to fibrosis, a and to the presence of fibrosis. is an based on and that with are with are to have A recent that risk and as as liver that and (1) than other such as and and (2) as as for fibrosis in with The panel of of 3 of and an of with and for fibrosis fibrosis 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 NAFLD using an on the of in with NAFLD from the The liver for fibrosis was with and The for fibrosis was in of the the on the of using an with in with NAFLD The failure rate for in this was The for for fibrosis fibrosis and was The NASH recently experience with in with NAFLD in the using a with either an or rate for a liver was is for of fibrosis in with In the by than for fibrosis 2 or in fibrosis 3 or bridging for and and have associated several with SH and fibrosis in with for in is not Guidance In with NAFLD, the presence of and presence can be to for a liver or are clinically for NAFLD with of bridging fibrosis 3) or cirrhosis or are clinically for fibrosis in with NAFLD. to a Liver in NAFLD Liver the for liver in with NAFLD. is for and some and it should be in the most from and Guidance Liver should be considered in with NAFLD are risk of SH fibrosis. 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NAFLD all stages is in for is in all of NAFLD, fibrosis, most is to and to or disease in most and long‐term and from and the most causes of in there are no of in NASH to be in the there are several and and with liver and metabolic with liver of and 1 and in with and in and to there was a significant in the and of steatosis and ballooning 1 and In with or NASH there was a significant in and and of or NASH 1 and 1 with no in liver 1 and a in fibrosis was the to this of fibrosis and bridging fibrosis, that there is no clinically significant in fibrosis that can be to the In a on with NASH with NASH the of and 1 of NASH in to fibrosis 1 in of a of available in that the majority of to or the of and ballooning. by a by in the of The and of in with NASH cirrhosis is not analysis from the and for with and without cirrhosis. to without cirrhosis was in with cirrhosis and in with cirrhosis A recent review of in with cirrhosis A and is associated with with cirrhosis Guidance can be considered in individuals with NAFLD or is to as an to specifically The and of in individuals with cirrhosis to NAFLD are not In with NASH or be considered on a by an have and to and steatosis in with NAFLD and liver in with have been with of a that no in with fatty approved in the to have been to NAFLD in and in In a review of the published literature in evidence to the use of fatty in with NAFLD to liver disease, the of was by and recently to for fatty in with NAFLD or than a other have been in and is the of this Guidance is not for the of NAFLD or fatty should not be as a of NAFLD or be considered to in with NAFLD. in NAFLD and NASH alcohol consumption is a risk for and should be by with NAFLD and or as than on any or than in or than on any or in several have a of alcohol consumption than on the presence either or by and of NAFLD, a recent analysis of from the of by are are no the of alcohol consumption on disease or of NAFLD or The of on the and have not been in individuals with NAFLD. Guidance with NAFLD should not of are to make recommendations with regard to consumption of alcohol by individuals with NAFLD. is a NAFLD and risk of and that for risk the NAFLD and NAFLD, a risk and to and of risk is there are NAFLD and stages of the and and of are not and with NAFLD have a by and to as as a of with to be by hepatic and the of rather than by the presence of have evidence of the long‐term of with NAFLD of in with diabetes or and A recent analysis of the The and Evaluation that and in with to analysis of the The and a of in with in to it is to in with NAFLD based on to use in with or NAFLD and several have the of in with liver disease of in liver the risk of is not in with are not in liver injury from is in of as for NASH are and have with liver or not all and

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.

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.).

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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.

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.

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.

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.

BACKGROUND: Anxiety, although as common as depression, has received less attention and is often undetected and undertreated. OBJECTIVE: To determine the current prevalence, impairment, and comorbidity of anxiety disorders in primary care and to evaluate a brief measure for detecting these disorders. DESIGN: Criterion-standard study performed between November 2004 and June 2005. SETTING: 15 U.S. primary care clinics. PARTICIPANTS: 965 randomly sampled patients from consecutive clinic patients who completed a self-report questionnaire and agreed to a follow-up telephone interview. MEASUREMENTS: 7-item anxiety measure (Generalized Anxiety Disorder [GAD]-7 scale) in the clinic, followed by a telephone-administered, structured psychiatric interview by a mental health professional who was blinded to the GAD-7 results. Functional status (Medical Outcomes Study Short Form-20), depressive and somatic symptoms, and self-reported disability days and physician visits were also assessed. RESULTS: Of the 965 patients, 19.5% (95% CI, 17.0% to 22.1%) had at least 1 anxiety disorder, 8.6% (CI, 6.9% to 10.6%) had posttraumatic stress disorder, 7.6% (CI, 5.9% to 9.4%) had a generalized anxiety disorder, 6.8% (CI, 5.3% to 8.6%) had a panic disorder, and 6.2% (CI, 4.7% to 7.9%) had a social anxiety disorder. Each disorder was associated with substantial impairment that increased significantly (P < 0.001) as the number of anxiety disorders increased. Many patients (41%) with an anxiety disorder reported no current treatment. Receiver-operating characteristic curve analysis showed that both the GAD-7 scale and its 2 core items (GAD-2) performed well (area under the curve, 0.80 to 0.91) as screening tools for all 4 anxiety disorders. LIMITATION: The study included a nonrandom sample of selected primary care practices. CONCLUSIONS: Anxiety disorders are prevalent, disabling, and often untreated in primary care. A 2-item screening test may enhance detection.

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.

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.