University of California San Diego Medical Center

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.

Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met 'possible' criteria, and 104 (76%) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with 'possible' and 'probable' criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.

Studies of human amnesia and studies of an animal model of human amnesia in the monkey have identified the anatomical components of the brain system for memory in the medial temporal lobe and have illuminated its function. This neural system consists of the hippocampus and adjacent, anatomically related cortex, including entorhinal, perirhinal, and parahippocampal cortices. These structures, presumably by virtue of their widespread and reciprocal connections with neocortex, are essential for establishing long-term memory for facts and events (declarative memory). The medial temporal lobe memory system is needed to bind together the distributed storage sites in neocortex that represent a whole memory. However, the role of this system is only temporary. As time passes after learning, memory stored in neocortex gradually becomes independent of medial temporal lobe structures.

OBJECTIVE: This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA). METHODS: Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22–28 weeks) and very low birth weight (401–1500 g) who were born at network centers between January 1, 2003, and December 31, 2007. RESULTS: Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at ≤12 hours, with most early deaths occurring at 22 and 23 weeks (85% and 43%, respectively). Rates of prenatal steroid use (13% and 53%, respectively), cesarean section (7% and 24%, respectively), and delivery room intubation (19% and 68%, respectively) increased markedly between 22 and 23 weeks. Infants at the lowest GAs were at greatest risk for morbidities. Overall, 93% had respiratory distress syndrome, 46% patent ductus arteriosus, 16% severe intraventricular hemorrhage, 11% necrotizing enterocolitis, and 36% late-onset sepsis. The new severity-based definition of bronchopulmonary dysplasia classified more infants as having bronchopulmonary dysplasia than did the traditional definition of supplemental oxygen use at 36 weeks (68%, compared with 42%). More than one-half of infants with extremely low GAs had undetermined retinopathy status at the time of discharge. Center differences in management and outcomes were identified. CONCLUSION: Although the majority of infants with GAs of ≥24 weeks survive, high rates of morbidity among survivors continue to be observed.

BACKGROUND: The aim of this study was to revise the 2003 Fenton Preterm Growth Chart, specifically to: a) harmonize the preterm growth chart with the new World Health Organization (WHO) Growth Standard, b) smooth the data between the preterm and WHO estimates, informed by the Preterm Multicentre Growth (PreM Growth) study while maintaining data integrity from 22 to 36 and at 50 weeks, and to c) re-scale the chart x-axis to actual age (rather than completed weeks) to support growth monitoring. METHODS: Systematic review, meta-analysis, and growth chart development. We systematically searched published and unpublished literature to find population-based preterm size at birth measurement (weight, length, and/or head circumference) references, from developed countries with: Corrected gestational ages through infant assessment and/or statistical correction; Data percentiles as low as 24 weeks gestational age or lower; Sample with greater than 500 infants less than 30 weeks. Growth curves for males and females were produced using cubic splines to 50 weeks post menstrual age. LMS parameters (skew, median, and standard deviation) were calculated. RESULTS: Six large population-based surveys of size at preterm birth representing 3,986,456 births (34,639 births < 30 weeks) from countries Germany, United States, Italy, Australia, Scotland, and Canada were combined in meta-analyses. Smooth growth chart curves were developed, while ensuring close agreement with the data between 24 and 36 weeks and at 50 weeks. CONCLUSIONS: The revised sex-specific actual-age growth charts are based on the recommended growth goal for preterm infants, the fetus, followed by the term infant. These preterm growth charts, with the disjunction between these datasets smoothing informed by the international PreM Growth study, may support an improved transition of preterm infant growth monitoring to the WHO growth charts.

As triage and resuscitation protocols evolve, it is critical to determine the major extracranial variables influencing outcome in the setting of severe head injury. We prospectively studied the outcome from severe head injury (GCS score < or = 8) in 717 cases in the Traumatic Coma Data Bank. We investigated the impact on outcome of hypotension (SBP < 90 mm Hg) and hypoxia (Pao2 < or = 60 mm Hg or apnea or cyanosis in the field) as secondary brain insults, occurring from injury through resuscitation. Hypoxia and hypotension were independently associated with significant increases in morbidity and mortality from severe head injury. Hypotension was profoundly detrimental, occurring in 34.6% of these patients and associated with a 150% increase in mortality. The increased morbidity and mortality related to severe trauma to an extracranial organ system appeared primarily attributable to associated hypotension. Improvements in trauma care delivery over the past decade have not markedly altered the adverse influence of hypotension. Hypoxia and hypotension are common and detrimental secondary brain insults. Hypotension, particularly, is a major determinant of outcome from severe head injury. Resuscitation protocols for brain injured patients should assiduously avoid hypovolemic shock on an absolute basis.

The purpose of this study was to develop and validate automatic scoring methods to distinguish sleep from wakefulness based on wrist activity. Forty-one subjects (18 normals and 23 with sleep or psychiatric disorders) wore a wrist actigraph during overnight polysomnography. In a randomly selected subsample of 20 subjects, candidate sleep/wake prediction algorithms were iteratively optimized against standard sleep/wake scores. The optimal algorithms obtained for various data collection epoch lengths were then prospectively tested on the remaining 21 subjects. The final algorithms correctly distinguished sleep from wakefulness approximately 88% of the time. Actigraphic sleep percentage and sleep latency estimates correlated 0.82 and 0.90, respectively, with corresponding parameters scored from the polysomnogram (p < 0.0001). Automatic scoring of wrist activity provides valuable information about sleep and wakefulness that could be useful in both clinical and research applications.

Cytoscape is one of the most successful network biology analysis and visualization tools, but because of its interactive nature, its role in creating reproducible, scalable, and novel workflows has been limited. We describe Cytoscape Automation (CA), which marries Cytoscape to highly productive workflow systems, for example, Python/R in Jupyter/RStudio. We expose over 270 Cytoscape core functions and 34 Cytoscape apps as REST-callable functions with standardized JSON interfaces backed by Swagger documentation. Independent projects to create and publish Python/R native CA interface libraries have reached an advanced stage, and a number of automation workflows are already published.

Amnesic patients and nondemented patients with Parkinson's disease were given a probabilistic classification task in which they learned which of two outcomes would occur on each trial, given the particular combination of cues that appeared. Amnesic patients exhibited normal learning of the task but had severely impaired declarative memory for the training episode. In contrast, patients with Parkinson's disease failed to learn the probabilistic classification task, despite having intact memory for the training episode. This double dissociation shows that the limbic-diencephalic regions damaged in amnesia and the neostriatum damaged in Parkinson's disease support separate and parallel learning systems. In humans, the neostriatum (caudate nucleus and putamen) is essential for the gradual, incremental learning of associations that is characteristic of habit learning. The neostriatum is important not just for motor behavior and motor learning but also for acquiring nonmotor dispositions and tendencies that depend on new associations.

BACKGROUND: Uncontrolled studies suggested that aerosolized iloprost, a stable analogue of prostacyclin, causes selective pulmonary vasodilatation and improves hemodynamics and exercise capacity in patients with pulmonary hypertension. METHODS: We compared repeated daily inhalations of 2.5 or 5.0 microg of iloprost (six or nine times per day; median inhaled dose, 30 microg per day) with inhalation of placebo. A total of 203 patients with selected forms of severe pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (New York Heart Association [NYHA] functional class III or IV) were included. The primary end point was met if, after week 12, the NYHA class and distance walked in six minutes were improved by at least one class and at least 10 percent, respectively, in the absence of clinical deterioration according to predefined criteria and death. RESULTS: The combined clinical end point was met by 16.8 percent of the patients receiving iloprost, as compared with 4.9 percent of the patients receiving placebo (P=0.007). There were increases in the distance walked in six minutes of 36.4 m in the iloprost group as a whole (P=0.004) and of 58.8 m in the subgroup of patients with primary pulmonary hypertension. Overall, 4.0 percent of patients in the iloprost group (including one who died) and 13.7 percent of those in the placebo group (including four who died) did not complete the study (P=0.024); the most common reason for withdrawal was clinical deterioration. As compared with base-line values, hemodynamic values were significantly improved at 12 weeks when measured after iloprost inhalation (P<0.001), were largely unchanged when measured before iloprost inhalation, and were significantly worse in the placebo group. Further significant beneficial effects of iloprost treatment included an improvement in the NYHA class (P=0.03), dyspnea (P=0.015), and quality of life (P=0.026). Syncope occurred with similar frequency in the two groups but was more frequently rated as serious in the iloprost group, although this adverse effect was not associated with clinical deterioration. CONCLUSIONS: Inhaled iloprost is an effective therapy for patients with severe pulmonary hypertension.

Neuroelectric and imaging studies of meditation are reviewed. Electroencephalographic measures indicate an overall slowing subsequent to meditation, with theta and alpha activation related to proficiency of practice. Sensory evoked potential assessment of concentrative meditation yields amplitude and latency changes for some components and practices. Cognitive event-related potential evaluation of meditation implies that practice changes attentional allocation. Neuroimaging studies indicate increased regional cerebral blood flow measures during meditation. Taken together, meditation appears to reflect changes in anterior cingulate cortex and dorsolateral prefrontal areas. Neurophysiological meditative state and trait effects are variable but are beginning to demonstrate consistent outcomes for research and clinical applications. Psychological and clinical effects of meditation are summarized, integrated, and discussed with respect to neuroimaging data.

BACKGROUND: In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection. METHODS: We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of ledipasvir-sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir plus ribavirin. No patient in either 12-week group discontinued ledipasvir-sofosbuvir owing to an adverse event. The most common adverse events were fatigue, headache, insomnia, and nausea. CONCLUSIONS: Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection. (Funded by Gilead Sciences; ION-1 ClinicalTrials.gov number NCT01701401.).

Acute kidney injury (AKI) and chronic kidney disease are increasingly recognized as interconnected entities and the term acute kidney disease (AKD) has been proposed to define ongoing pathophysiologic processes following an episode of AKI. In this Consensus statement, the Acute Disease Quality Initiative 16 Workgroup propose definitions and staging criteria for AKD, and strategies for the management of affected patients. They also make recommendations for areas of future research with the aims of improving understanding of the underlying processes and improving outcomes. Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of >90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD.

The drug sensitivities of human immunodeficiency virus (HIV) isolates from a group of patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) who were receiving zidovudine (3'-azido-3'-deoythymidine, AZT) therapy were tested by means of a newly developed plaque assay in CD4+ HeLa cells. Fifty percent inhibitory dose (ID50) values of 18 isolates from untreated individuals ranged between 0.01 microM and 0.05 microM. In contrast, most isolates from patients who had received zidovudine for 6 months or more exhibited decreased sensitivity characterized by changes in ID50 or ID95 values (or both), with isolates from several patients (5/15) showing 100-fold increases in ID50. The latter isolates were also insensitive to 3'-azido-2',3'-dideoxyuridine; however, the isolates were still sensitive to 2',3'-dideoxycytidine, 2',3'-dideoxy-2',3'-didehydrothymidine, or phosphonoformate. It cannot be determined from this small sample of patients whether development of a less sensitive virus phenotype results in clinical resistance. Appearance of such variants was not associated with a consistent increase in viral p24 concentrations in patient plasma and did not herald any sudden deterioration in clinical status. More extensive studies are required to determine the clinical significance. Thus, it would be premature to alter any treatment protocols for HIV-infected individuals at present.

Here, we review the research we have conducted on social contagion. We describe the methods we have employed (and the assumptions they have entailed) to examine several datasets with complementary strengths and weaknesses, including the Framingham Heart Study, the National Longitudinal Study of Adolescent Health, and other observational and experimental datasets that we and others have collected. We describe the regularities that led us to propose that human social networks may exhibit a 'three degrees of influence' property, and we review statistical approaches we have used to characterize interpersonal influence with respect to phenomena as diverse as obesity, smoking, cooperation, and happiness. We do not claim that this work is the final word, but we do believe that it provides some novel, informative, and stimulating evidence regarding social contagion in longitudinally followed networks. Along with other scholars, we are working to develop new methods for identifying causal effects using social network data, and we believe that this area is ripe for statistical development as current methods have known and often unavoidable limitations.

The neurosciences have grown rapidly over the last half century. This growth has been stimulated by two important developments. First, molecular biology has transformed cellular neurobiology and has led to a new conceptual framework for signaling, a molecular framework that encompasses not only signaling in nerve cells but in all the cells of the body. Second, work on brain and cognition, which was traditionally associated with a number of different disciplines, has merged into a single discipline: cognitive neuroscience. This has provided a new framework for the study of memory, perception, action, language, and perhaps even conscious awareness. In this review, we will consider the second development by focusing on one aspect of cognitive neuroscience: recent progress in memory research. In so doing, we also want to consider the broader question: to what degree can these two independent and disparate strands—molecular neurobiology and cognitive neuroscience—be united? Can molecular biology enlighten the study of cognitive processes, such as learning and memory, as it has other areas of biology, such as development? In turn, can cognitive neuroscience define novel phenomena that will lead to a completely new set of molecular mechanisms and insights? Cognitive neuroscience originated in two disciplines: in psychology, in the development of rigorous methods for analyzing behavior and cognition, and in systems neurobiology, in the effort to understand the structure and function of neuronal circuits of the sensory and motor systems of the brain. The fusion of these two disciplines was facilitated as well by the emergence of a coherent neuroscience—an interdisciplinary approach to the nervous system that encouraged the idea that the techniques and concepts of neurobiology and systems neuroscience might be usefully applied to the analysis of cognition. Until the beginning of the nineteenth century, the study of normal mental activity was a part of philosophy, and the chief method for understanding the mind was introspection. By the middle of the nineteenth century, introspection began to give way to experimental approaches that eventually led to the independent discipline of experimental psychology. In its early years, experimental psychology was concerned primarily with the study of sensation, but by the turn of the century the interests of psychologists turned to behavior itself—learning, memory, attention, perception, and voluntary action. The development of simple experimental methods for studying learning and memory—first in humans by Hermann Ebbinghaus in 1885 and a few years later in experimental animals by Ivan Pavlov and Edgar Thorndike—led to a rigorous empirical school of psychology called behaviorism. Behaviorists, notably James B. Watson and Burrhus F. Skinner, argued that behavior could be studied with the precision achieved in the physical sciences, but only if students of behavior abandoned speculation about what goes on in the mind (the brain) and focused instead on observable aspects of behavior. For behaviorists, unobservable mental processes, especially abstractions like perception, selective attention, and memory, were deemed inaccessible to scientific study. Instead, behaviorists concentrated on examining—objectively and precisely—the relationship between specific physical stimuli and observable responses in intact animals. Their early successes in rigorously studying simple forms of behavior, including learning, encouraged them to treat all processes that intervene between the stimulus (input) and behavior (output) as irrelevant to a scientific study of behavior. Thus, behaviorism largely ignored mental processes. As a result, the science of behavior was defined in terms of the limited techniques used to study it. This emphasis reduced the domain of experimental psychology to a restricted set of problems, and it excluded from study some of the most fascinating features of mental life. By the 1960s, it was not difficult for the founders of cognitive psychology—George Miller, Ulric Neisser, Herbert Simon, and others—to convince the scientific community of the narrowness of behaviorism. These early cognitive psychologists, building on the earlier evidence from Gestalt psychology, European neurology, and work by the British psychologist Frederic Bartlett, sought to demonstrate that our knowledge of the world is based on our biological apparatus for perceiving the world, and that perception is a constructive process dependent not only on the information inherent in a stimulus but also on the mental processing of the perceiver. Thus, cognitive psychology was concerned not simply with specifying the input and output for a particular behavior but also with analyzing the process by which sensory information is transformed into perception and action—that is, with evaluating how a stimulus leads to a particular behavioral response. In redirecting scientific attention to mental operations, cognitive psychologists focused on information processing, on the flow of sensory information from sensory receptors to its eventual use in memory and action. It was implicit in the cognitive approach to behavior that each perceptual or motor act has an internal representation in the brain: a representation of information in patterns of neural activity. Once cognitive psychologists acknowledged that internal representations are an essential component of behavior, they had to come to grips with the fact that most mental processes were still largely inaccessible to experimental analysis. Without direct access to the neural substrates of internal representations it was difficult, if not impossible, to understand the path from perception to action. At about this time, the work of Vernon Mountcastle on somatic sensation, David Hubel and Torsten Wiesel on vision, and Edward Evarts on the control of movement inaugurated the neuronal analysis of perception and voluntary action. Moreover, during the 1970s, Evarts and Mountcastle developed techniques for studying the activity of single cells in the brains of awake, behaving monkeys. In their hands, and in work that followed by Robert Wurtz, Apostolos Georgopoulos, William Newsome, and others, single-unit studies in monkeys led to the first correlations between cognitive processes (such as perception, attention, and decision making) and patterns of firing of individual cells in specific brain regions. This work changed the way behavior was studied both in experimental animals and in humans; the focus now was on the information processing in the brain that leads to behavior. The need for greater anatomical knowledge led to a renaissance of neuroanatomy, evident in the development of new techniques for tracing connections between neurons by Sanford Palay at the NIH, Walle Nauta at MIT, Matthew and Jennifer LaVail at Harvard, and Max Cowan at Washington University. The search for new neuroanatomical methods and the need to bridge anatomy and function led to the application of neuroimaging techniques (positron emission tomography [PET] scanning and functional magnetic resonance imaging [MRI]) to cognitive problems. This major advance, pioneered by Marcus Raichle and Michael Posner and by Seiji Ogawa, Ken Kwong, and others, made it possible to relate changes in activity in large populations of neurons to specific cognitive acts in living humans. By comparing the results of cellular recordings in nonhuman primates and the results of neuroimaging in humans, it has become possible to study directly the neural correlates of sensory processing, motor actions, and cognitive processes. In the 1960s and 1970s, there was also renewed interest in the traditional discipline of neuropsychology. Early students of brain and behavior like Karl Lashley and Donald Hebb used the term neuropsychology broadly to encompass studies of experimental animals as well as studies of humans. In this sense, cognitive neuroscience is the modern forum for the same topics and issues that engaged Lashley and Hebb earlier in this century. Studies of patients with brain injury or disease that affects mental function have always been a vital part of neuropsychology, and such studies formed one of the foundations of cognitive neuroscience. As first clearly shown for language by Pierre Paul Broca in 1863, patients with lesions of specific regions of the brain exhibit quite specific cognitive deficits. Following Broca and Wernicke, the neuropsychological attempt at regional localization remained strong in Europe and in Canada but was in good part neglected in the United States, with the exception of the work of Arthur Benton, Hans-Lukas Teuber, and Norman Geschwind. As we shall see, continuing study of the behavioral consequences of brain lesions proved to be a rich source of information about the organization and anatomy of higher functions, including memory. Lesion studies have shown that cognition is not unitary but that there are several cognitive systems, each with independent information-processing modules. For example, the visual system of primates, a prototypical cognitive system, has specialized anatomical pathways for processing information about color, form, and movement. Finally, computational science has made a distinctive contribution to cognitive neuroscience. Computers made it possible to model the activity of large populations of neurons and to begin to test ideas about how specific components of the brain contribute to particular cognitive processes. To understand the neural organization of a complex behavior like speech, we must understand not only the properties of individual cells and pathways but also the network properties of functional circuits in the brain. While network properties arise from the properties of individual neurons in the network, they need not be explainable in terms of the behavior of individual cells. Computational approaches are helpful for characterizing the system as whole, for obtaining formal descriptions of what the system is capable of doing, and for determining how the interacting constituent elements account for system properties. This review focuses on the topic of memory, but one aspect of cognitive neuroscience. We have not attempted to document fully the remarkable progress that has been achieved in our understanding of how the nervous system learns and remembers. Rather, we focus on two key components in the study of memory, as viewed through the work that the three of us have carried out with our colleagues during the past several decades. The first component is concerned with analyzing what memory is, where it is stored, and what brain systems are involved. This is the systems problem of memory. The second component of memory is concerned with analyzing how memory is stored. This is the molecular problem of memory. The question of where memory is stored emerged at the beginning of the 19th century as part of the larger question—to what degree can any mental process be localized within the brain? The first person to address this question was Franz Joseph Gall, who made two major conceptual contributions. First, Gall attempted to abolish mind–brain dualism. He argued, based on his anatomical studies, that the brain is the organ of the mind. Second, he appreciated that the cerebral cortex is not homogenous but contains distinctive centers that control specific mental functions. Gall therefore proposed the idea of cortical localization. Gall asserted that the brain does not act as a unitary organ but is divided into at least 27 faculties (others were added later), each corresponding to a specific mental faculty. He thought that even the most abstract and complex of human traits, such as generosity and secretiveness, are localized to discrete areas of the brain. Gall was not an experimentalist. He rejected the study of neurological lesions and the surgical manipulation of experimental animals and instead attempted to locate mental faculties by examining the surface of the skulls of individuals well endowed with particular functions. Perhaps not surprisingly, with this approach he misidentified the function of most parts of the cortex. This anatomically oriented approach to personality Gall called organology. Later, Gall's associate, Gaspard Spurzheim, adopted the better-known term phrenology to describe this approach. Gall's ideas were subjected to experimental analysis by Pierre Flourens in France in the late 1820s. Flourens attempted to isolate the contributions of different parts of the nervous system to behavior by removing from the brains of experimental animals the functional centers identified by Gall. From these experiments, Flourens concluded that individual sites in the brain are not sufficient for specific behaviors such as sexual behavior and romantic love and that all regions of the brain—especially the cerebral hemispheres of the forebrain—participate in every mental function. He proposed that any part of the cerebral hemisphere is able to perform all the functions of the hemisphere. Injury to a specific area of the cerebral hemisphere should therefore affect all higher functions equally. Despite the findings of Broca and Wernicke on the localization of language, the ensuing debate between cortical localization and equipotentiality in cognitive function dominated thinking about mental processes, including memory, well into the first half of the twentieth century. For example, in the period from 1920 to 1950, this dispute could be followed in the work of Karl Lashley, perhaps the dominant figure in American neuropsychology in the first half of this century. Lashley explored the surface of the cerebral cortex in the rat, systematically removing different cortical areas. In so doing, he failed repeatedly to identify any particular brain region that was special to or necessary for the storage of memory. Based on these experiments, Lashley formulated the law of mass action, according to which the extent of the memory defect was correlated with the size of the cortical area removed, not with its specific location (96Lashley K.S. Brain Mechanisms and Intelligence. Chicago University Press, Chicago1929Google Scholar). Many years later, with additional experimental work, it was possible to arrive at a different understanding of Lashley's famous conclusion. Perhaps the first effective answer to Lashley came from Donald Hebb (Figure 1, right). In his book The Organization of Behavior, 79Hebb D.O. The Organization of Behavior. Wiley, New York1949Google Scholar convinced many that it was possible to think seriously about the brain processes underlying memory. He developed concrete proposals based on biological facts, taking into consideration the neuronal circuitry that might contribute to memory storage. To explain Lashley's result that learning could not be localized to a single brain region, Hebb suggested that assemblies of cells work together to represent information and that these assemblies are distributed over large areas of cortex. Sufficient numbers of interconnected cells will survive most lesions to ensure that information can still be represented. The idea of a distributed memory store was far sighted. With the accumulation of additional evidence, it has become apparent that no single memory center exists, and many parts of the nervous system participate in the representation of any single event. Hebb influenced many students and colleagues—in particular, Brenda Milner, who in 1957 described the remarkable patient H. M. (145Scoville W.B. Milner B. Loss of recent memory after bilateral hippocampal lesions.J. Neurol. Neurosurg. Psychiatry. 1957; 20: 11-21Crossref PubMed Google Scholar). H. M. had sustained a bilateral resection of the medial structures of the temporal lobe in 1953 to relieve severe epilepsy. It was immediately evident following the surgery that H. M. had a very profound impairment of recent memory in the apparent absence of other intellectual loss (144Scoville W.B. The limbic lobe in man.J. Neurosurg. 1954; 11: 64-66Crossref PubMed Google Scholar). He could not remember what he had for breakfast, and he could not find his way around the hospital or recognize members of the hospital staff (except Scoville, whom he had known for many years). It seemed as though his life from the surgery onwards was not contributing to his store of knowledge. He was able to hold immediate impressions in his mind, but as soon as his attention was diverted they were lost. In contrast, old memories from his childhood seemed to be intact. In fact, the encounter with H. M. was not the first encounter with this kind of memory impairment. During the early 1950s, Wilder Penfield (Figure 1, left) began to carry out unilateral removals of parts of the frontal or temporal lobe as a treatment for patients with localized injury causing seizures. The temporal-lobe removals typically included the anterior temporal neocortex together with the uncus, amygdala, and anterior parahippocampal gyrus and hippocampus on the medial aspect of the hemisphere. Milner and Penfield found that these removals produced at most mild material-specific memory deficits that varied in kind with the side of the lesion. But, unexpectedly, Milner and Penfield encountered two patients with a severe, persistent, and generalized impairment of recent memory, following a removal limited to the left temporal lobe. Because both patients had undergone extensive preoperative testing, it was easy to establish that this was a selective impairment of memory, with no accompanying intellectual loss (132Penfield W. Milner B. Memory deficits induced by bilateral lesions in the hippocampal zone.Am. Med. Assoc. Arch. Neurol. Psychiatry. 1958; 79: 475-497Crossref PubMed Google Scholar). The impairment was manifested clinically as a profound anterograde amnesia, such that the experiences of daily life were forgotten as soon as the focus of attention shifted to a new topic. In addition, one patient showed a retrograde amnesia covering salient events of the preceding few months and the other showed a retrograde amnesia covering the 4 preceding years. To account for this unexpected memory loss, 120Milner B. Penfield W. The effect of hippocampal lesions on recent memory.Trans. Am. Neurol. Assoc. 1955; 80: 42-48Google Scholar hypothesized that in each case there must have been a pre-existing, but undetected, atrophic lesion in the hippocampal region of the opposite hemisphere, so that when the surgeon removed the anterior hippocampus and parahippocampal gyrus in the left hemisphere, he effectively deprived the patients of medial temporal-lobe function bilaterally. The reason that Milner and Penfield focused on the hippocampal region was that one patient, P. B., had had his temporal lobectomy in two stages, and it was only after removal of the medial structures of the temporal lobe that the memory loss was seen. Their hypothesis was confirmed 9 years later, when P. B. died of a pulmonary embolism and the autopsy findings revealed the presence of long-standing extensive right hippocampal atrophy, whereas the rest of the right temporal lobe, including the amygdala and the parahippocampal gyrus, showed no significant abnormality. In contrast, on the operated (left) side, the of the hippocampus that remained to be normal W. Memory autopsy findings and on the of the hippocampus in Neurol. PubMed Google Scholar). Milner and Penfield these two at the of the American in and their He called Penfield and that he thought he had a memory in a patient of his in whom he had carried out a bilateral medial temporal-lobe also in an attempt to control seizures. Penfield Milner if like to to to study the patient, and that is how the memory in H. M. H. memory to that of two that it was there had been no intellectual in fact, H. had from to he was far seizures. for sustained attention was also Thus, Milner showed that he could the number for at least by and the according to an but the his attention was diverted by a new the was H. in a number for in the absence of was at first with that can hold a simple provided that no activity their attention Memory and the hippocampal Neurol. PubMed Google Scholar). it was that for H. M. a key in this In contrast, simple stimuli were forgotten by within a The evidence for this from and In described a method for memory of single which was later for work with human by The effect of lesions of the brain and visual recent memory in man.J. Neurol. Neurosurg. Psychiatry. PubMed Google This called by Milner of two stimuli in by a The must the second stimulus is the same as or different from the This that must an of the first stimulus in to the second one with it. be by the or by an B. of learning and memory after temporal-lobe lesions in Neurosurg. Google Scholar used the method to demonstrate H. of simple perceptual different of stimuli visual and two each set a The stimuli used were of and At least were to each to as far as possible the use of to bridge the stimuli were at These proved to be easy for normal who made even with a and an In contrast, H. M. all well at but with his so that at the were the and were not by M. additional of immediate memory in a patient with bilateral hippocampal Google Scholar confirmed a that the of to how far the of a stimulus from the stimulus as the In the of their H. M. was to which one of the With he most of the time, a normal of but with his at the no any control over his In contrast, H. M. had no with a of the which the of as with other memory he only by his could be the These and other studies B. hemisphere in after cerebral evidence for PubMed Google in that H. M. can perceptual information but that the information to be to within about B. of learning and memory after temporal-lobe lesions in Neurosurg. Google Scholar suggested that such results the between a memory process with a and an process in H. by which the storage of information is H. on and which memory after a single not out the that he might be capable of some learning with or that of learning might at a normal Milner and students on a of learning studies with H. including both visual B. learning in of bilateral bilateral and unilateral cerebral Google and learning in of unilateral cortical and bilateral hippocampal Google Scholar). With one these studies to demonstrate H. with new learning, as evident also in his daily life. The exception was in the domain of motor in Milner showed that H. M. could a with from to (Figure M. in a this he was to a between the two of a from the (Figure his and the in a He showed over the of testing, he had no idea that he had the in the number of in each that he the as he the from Milner In this he was to a between the two of a from the (Figure his and the in a He showed over the of testing, he had no idea that he had the in the number of in each that he the as he the from Milner one is shown a of a (Figure and to a between the two one can that very if one has to it and the in a it quite one the of the one to the in the with we can all to the of a in a It is a new a and it is many Milner was able to that H. M. could that kind of quite H. M. through of over and he a learning (Figure at the he had no idea he had the this was learning any of we are well that such are possible following a discrete brain but for Milner, at it for the first time, it was quite some of the early evidence that there is one memory system in the brain. even the study of patient H. M. inaugurated empirical work on the different memory systems of the ideas had been proposed by and psychologists on the of and introspection. For example, in a of mind at proposed the of two of as in knowledge of motor and as in the knowledge of and years later one of the founders of cognitive psychology, called a memory Memory argued, in the case of experiences that the of the his or the by which he but are inaccessible in memory as specific the neural that a behavior is He called a memory with a of information about the and events of life. The of intact motor learning in patient H. M. the beginning of a period of experimental work that eventually the biological of memory This later work made it that the memory

Recent studies of animals with complex nervous systems, including humans and other primates, have improved our understanding of how the brain accomplishes learning and memory. Major themes of recent work include the locus of memory storage, the taxonomy of memory, the distinction between declarative and procedural knowledge, and the question of how memory changes with time, that is, the concepts of forgetting and consolidation. An important recent advance is the development of an animal model of human amnesia in the monkey. The animal model, together with newly available neuropathological information from a well-studied human patient, has permitted the identification of brain structures and connections involved in memory functions.

The Liver Imaging Reporting and Data System (LI-RADS) is composed of four individual algorithms intended to standardize the lexicon, as well as reporting and care, in patients with or at risk for hepatocellular carcinoma in the context of surveillance with US; diagnosis with CT, MRI, or contrast material-enhanced US; and assessment of treatment response with CT or MRI. This report provides a broad overview of LI-RADS, including its historic development, relationship to other imaging guidelines, composition, aims, and future directions. In addition, readers will understand the motivation for and key components of the 2018 update.

OBJECTIVE: The aim was to formulate practice guidelines on the management of hyperglycemia in hospitalized patients in the non-critical care setting. PARTICIPANTS: The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee of The Endocrine Society, six additional experts, and a methodologist. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society members, American Diabetes Association, American Heart Association, American Association of Diabetes Educators, European Society of Endocrinology, and the Society of Hospital Medicine reviewed and commented on preliminary drafts of this guideline. CONCLUSIONS: Hyperglycemia is a common, serious, and costly health care problem in hospitalized patients. Observational and randomized controlled studies indicate that improvement in glycemic control results in lower rates of hospital complications in general medicine and surgery patients. Implementing a standardized sc insulin order set promoting the use of scheduled basal and nutritional insulin therapy is a key intervention in the inpatient management of diabetes. We provide recommendations for practical, achievable, and safe glycemic targets and describe protocols, procedures, and system improvements required to facilitate the achievement of glycemic goals in patients with hyperglycemia and diabetes admitted in non-critical care settings.

BACKGROUND: High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen. METHODS: In this phase 3, open-label study, we randomly assigned 647 previously untreated patients with HCV genotype 1 infection without cirrhosis to receive ledipasvir and sofosbuvir (ledipasvir-sofosbuvir) for 8 weeks, ledipasvir-sofosbuvir plus ribavirin for 8 weeks, or ledipasvir-sofosbuvir for 12 weeks. The primary end point was sustained virologic response at 12 weeks after the end of therapy. RESULTS: The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir-sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir-sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir-sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir-sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, -4 to 6) and the rate in the group that received 8 weeks of ledipasvir-sofosbuvir with ribavirin was 1 percentage point lower (95% CI, -6 to 4); these results indicated noninferiority of the 8-week ledipasvir-sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir-sofosbuvir discontinued treatment owing to adverse events. CONCLUSIONS: Ledipasvir-sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. (Funded by Gilead Sciences; ION-3 ClinicalTrials.gov number, NCT01851330.).