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Introduction: Designing, delivering, and evaluating high-performing primary health care services for complex and vulnerable subpopulations are challenging endeavors. However, there is a relative paucity of research evidence available to support such work., Objective: To provide a case study using HealthConnection Clinic, a public primary care center located in Metropolitan Vancouver's North Shore., Methods: Developmental evaluation approach operationalizing the 10 Building Blocks of High-Performing Primary Care framework using qualitative and quantitative methods., Results: The clinic provided valuable insights to policymakers and researchers related to development of the Building Blocks' foundational elements, particularly engaged leadership, empanelment, and data-driven improvement. The study highlighted the key enablers, achievements, challenges, and barriers related to operationalizing each Building Block. The Building Blocks were a useful heuristic that enabled the development and evaluation of primary care for complex subpopulations. Particularly salient from a Canadian policy perspective was the demonstration that system integration was possible when highly engaged leaders from a Regional Health Authority and a Division of Family Practice shared a common vision and purpose. HealthConnection Clinic's entrepreneurial spirit has enabled the development of innovative, evidence-based tools such as the AMPS complexity assessment tool (attachment, medical conditions, psychological/mental health/addictions challenges, and socioeconomic status), designed to identify and assess biopsychosocial complexity and needs. The study also highlighted the importance of incorporating community orientation and equity into developmental work., Conclusion: The study demonstrates how the Building Blocks approach can be adapted to operationalize high-performing primary care standards in settings serving complex and vulnerable populations.

When humans and other animals make cultural innovations, they also change their environment, thereby imposing new selective pressures that can modify their biological traits. For example, there is evidence that dairy farming by humans favored alleles for adult lactose tolerance. Similarly, the invention of cooking possibly affected the evolution of jaw and tooth morphology. However, when it comes to cognitive traits and learning mechanisms, it is much more difficult to determine whether and how their evolution was affected by culture or by their use in cultural transmission. Here we argue that, excluding very recent cultural innovations, the assumption that culture shaped the evolution of cognition is both more parsimonious and more productive than assuming the opposite. In considering how culture shapes cognition, we suggest that a process-level model of cognitive evolution is necessary and offer such a model. The model employs relatively simple coevolving mechanisms of learning and data acquisition that jointly construct a complex network of a type previously shown to be capable of supporting a range of cognitive abilities. The evolution of cognition, and thus the effect of culture on cognitive evolution, is captured through small modifications of these coevolving learning and data-acquisition mechanisms, whose coordinated action is critical for building an effective network. We use the model to show how these mechanisms are likely to evolve in response to cultural phenomena, such as language and tool-making, which are associated with major changes in data patterns and with new computational and statistical challenges., Competing Interests: The authors declare no conflict of interest.

Aims: To investigate patient experiences during the diagnosis of type 2 diabetes mellitus (T2DM), focusing on how physician-patient communication at diagnosis influences patients' psychosocial stress and subsequent self-management and outcomes., Methods: We surveyed adults with T2DM in 26 countries in a large cross-national study of physician-patient communication during early T2DM treatment (IntroDia®). The self-report questionnaire assessed retrospectively patient experiences during diagnosis conversations (focusing on 43 possible conversational elements, and communication quality) and potential effects on patient-reported outcomes., Results: Data from 3628 people with T2DM who had been prescribed oral treatment at diagnosis were analysed. Exploratory factor analyses of the conversational elements yielded four coherent, meaningful factors: Encouraging (Cronbach's α=0.86); Collaborative (α=0.88); Recommending Other Resources (α=0.75); and Discouraging (α=0.72). Patient-perceived communication quality (PPCQ) at diagnosis was positively associated with Encouraging (β=+1.764, p<0.001) and Collaborative (β=+0.347, p<0.001), negatively associated with Discouraging (β=-1.181, p<0.001) and not associated with Recommending Other Resources (β=+0.087, p=0.096), using a stable path model. PPCQ was associated with less current diabetes distress, greater current well-being and better current self-care. Conversation elements comprising factors associated with better PPCQ (Encouraging and Collaborative) were recalled more frequently by patients than elements associated with poor PPCQ (Discouraging)., Conclusions: Better physician-patient communication at T2DM diagnosis may contribute to subsequent greater patient well-being and self-care, and may be enhanced by greater physician use of Collaborative and Encouraging conversation elements., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A cognitive system faced with contingent events that cause rapid changes in sensory data may (i) incrementally incorporate new data into the ongoing perceptual and motor processing; or (ii) restart processing on each new event; or (iii) sample the data and hold onto the sample until its processing is complete, while disregarding any contingent changes. We offer a set of computational first-principles arguments for a hypothesis, according to which any system that contends with certain classes of perception and behavioral control tasks must include the sample-and-hold option (possibly alongside the other two, which may be useful in other tasks). This hypothesis has implications for understanding the dynamics of perception and action. In particular, a sample-and-hold channel necessarily processes sensory data on some kind of cycle (which does not imply precise periodicity). Further, being prepared to face the world at all times requires that the sampling that initiates each cycle be triggered by every significant action on part of the agent itself, such as saccades. We survey a range of evidence for the sample-and-hold functionality, touching upon diverse phenomena such as attentional blink and backward masking, the yoking of olfaction to respiration, thalamocortical interactions, and metastable brain dynamics in perception and consciousness., (© 2017 Elsevier B.V. All rights reserved.)

MicroRNAs (miRNA) are central regulators of diverse biological processes and are important in the regulation of stem cell self-renewal. One of the widely studied miRNA-protein regulators is the Lin28-Let-7 pair. In this study, we demonstrate that contrary to the well-established models of mouse ES cells (mESC) and transformed human cancer cells, the pluripotent state of human ES cells (hESC) involves expression of mature Let-7 family miRNAs with concurrent expression of all LIN28 proteins. We show that mature Let-7 miRNAs are regulated during hESC differentiation and have opposite expression profile with LIN28B. Moreover, mature Let-7 miRNAs fine tune the expression levels of LIN28B protein in pluripotent hESCs, whereas silencing of LIN28 proteins have no effect on mature Let-7 levels. These results bring novel information to the highly complex network of human pluripotency and suggest that maintenance of hESC pluripotency differs greatly from the mESCs in regard to LIN28-Let-7 regulation., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Insulin production by the pancreas follows a basic pattern where basal levels of insulin are secreted during fasting periods, with prandial increases in insulin associated with food ingestion. The aim of insulin therapy in patients with diabetes is to match the endogenous pattern of insulin secretion as closely as possible without causing hypoglycaemia. There are several optimal pharmacokinetic and pharmacodynamic properties of long-acting basal insulins that can help to achieve this aim, namely, as follows: activity that is flat and as free of peaks as possible, a duration of action of ≥24-h, and as little day-to-day variation as possible. The long-acting basal insulins are a fundamental therapy for patients with type 1 and type 2 diabetes, and those that are currently available have many benefits; however, the development of even longer-acting insulins and improved insulin delivery techniques may lead to better glycemic control for patients in the future. Established long-acting basal insulins available in the United States and Europe include insulin glargine 100 units/mL and insulin detemir, both of which exhibit similar glycemic control to that of the intermediate-acting neutral protamine Hagedorn insulin, but with a reduction in hypoglycaemia. Newer insulin products available include new insulin glargine 300 units/mL (United States and Europe) and the ultra-long-acting insulin degludec (Europe) with basal insulin peglispro currently in development. These new insulins demonstrate different pharmacokinetic/pharmacodynamic profiles and longer durations of action (>24 h) compared with insulin glargine 100 units/mL, which may lead to potential benefits. The introduction of biosimilar insulins may also broaden access to insulins by reducing treatment costs. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

A computational theory of consciousness should include a quantitative measure of consciousness, or MoC, that (i) would reveal to what extent a given system is conscious, (ii) would make it possible to compare not only different systems, but also the same system at different times, and (iii) would be graded, because so is consciousness. However, unless its design is properly constrained, such an MoC gives rise to what we call the boundary problem: an MoC that labels a system as conscious will do so for some-perhaps most-of its subsystems, as well as for irrelevantly extended systems (e.g., the original system augmented with physical appendages that contribute nothing to the properties supposedly supporting consciousness), and for aggregates of individually conscious systems (e.g., groups of people). This problem suggests that the properties that are being measured are epiphenomenal to consciousness, or else it implies a bizarre proliferation of minds. We propose that a solution to the boundary problem can be found by identifying properties that are intrinsic or systemic: properties that clearly differentiate between systems whose existence is a matter of fact, as opposed to those whose existence is a matter of interpretation (in the eye of the beholder). We argue that if a putative MoC can be shown to be systemic, this ipso facto resolves any associated boundary issues. As test cases, we analyze two recent theories of consciousness in light of our definitions: the Integrated Information Theory and the Geometric Theory of consciousness.

We offer and test a simple operationalization of hedonic and eudaimonic well-being ("happiness") as mediating variables that link outcomes to motivation. In six evolutionary agent-based simulation experiments, we compared the relative performance of agents endowed with different combinations of happiness-related traits (parameter values), under four types of environmental conditions. We found (i) that the effects of attaching more weight to longer-term than to momentary happiness and of extending the memory for past happiness are both stronger in an environment where food is scarce; (ii) that in such an environment "relative consumption," in which the agent's well-being is negatively affected by that of its neighbors, is more detrimental to survival when food is scarce; and (iii) that having a positive outlook, under which agents' longer-term happiness is increased by positive events more than it is decreased by negative ones, is generally advantageous.

The original continuous glucose monitors (CGMs) were limited to 3-day, blinded observation periods where glucose data was hidden from patients and later retrospectively analyzed by a provider to help guide the management of diabetes. Unblinded CGM, released several years later, allows patients to view their glucose data in real-time amidst their daily routines, enabling them to better understand how variables such as activity, nutrition, and medications affect glucose levels. Research studies consistently demonstrate improved glycemic control and reduced hypoglycemia in children and adults with type 1 and type 2 diabetes while using unblinded CGM.(1-4) As such, we believe that all CGM usage in clinical practice should be in real-time, unblinded mode for short-term and long-term wear periods., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JP has served as a consultant for Dexcom Inc. SE has served as a consultant and advisory board member for and has received research funding from Dexcom Inc., (© 2016 Diabetes Technology Society.)

Animal acoustic communication often takes the form of complex sequences, made up of multiple distinct acoustic units. Apart from the well-known example of birdsong, other animals such as insects, amphibians, and mammals (including bats, rodents, primates, and cetaceans) also generate complex acoustic sequences. Occasionally, such as with birdsong, the adaptive role of these sequences seems clear (e.g. mate attraction and territorial defence). More often however, researchers have only begun to characterise - let alone understand - the significance and meaning of acoustic sequences. Hypotheses abound, but there is little agreement as to how sequences should be defined and analysed. Our review aims to outline suitable methods for testing these hypotheses, and to describe the major limitations to our current and near-future knowledge on questions of acoustic sequences. This review and prospectus is the result of a collaborative effort between 43 scientists from the fields of animal behaviour, ecology and evolution, signal processing, machine learning, quantitative linguistics, and information theory, who gathered for a 2013 workshop entitled, 'Analysing vocal sequences in animals'. Our goal is to present not just a review of the state of the art, but to propose a methodological framework that summarises what we suggest are the best practices for research in this field, across taxa and across disciplines. We also provide a tutorial-style introduction to some of the most promising algorithmic approaches for analysing sequences. We divide our review into three sections: identifying the distinct units of an acoustic sequence, describing the different ways that information can be contained within a sequence, and analysing the structure of that sequence. Each of these sections is further subdivided to address the key questions and approaches in that area. We propose a uniform, systematic, and comprehensive approach to studying sequences, with the goal of clarifying research terms used in different fields, and facilitating collaboration and comparative studies. Allowing greater interdisciplinary collaboration will facilitate the investigation of many important questions in the evolution of communication and sociality., (© 2014 Cambridge Philosophical Society.)

As a highly consequential biological trait, a memory "bottleneck" cannot escape selection pressures. It must therefore co-evolve with other cognitive mechanisms rather than act as an independent constraint. Recent theory and an implemented model of language acquisition suggest that a limit on working memory may evolve to help learning. Furthermore, it need not hamper the use of language for communication.

Hoffman, Singh, and Prakash (2014) observe that perception evolves to serve as an interface between the perceiver and the world and proceed to reason that percepts need not, or even cannot, resemble their objects. I accept their premise, but argue that there are interesting ways in which perception can be truthful, with regard not to "objects" but to relations, and that evolutionary pressure is expected to favor rather than rule out such veridicality.

Aims: To identify the hypoglycemic concerns of adults with type 2 diabetes (T2D) and examine how these concerns are associated with key patient characteristics., Methods: Qualitative interviews with 16 T2D adults and 11 diabetes care providers were conducted. Survey items were then developed and submitted to exploratory factor analyses (EFAs). Construct validity was assessed by correlations with diabetes distress, anxiety and depressive symptoms, well-being, hypoglycemic fear, hypoglycemia history and glycemic control (A1C)., Results: An EFA with 226 insulin users and 198 non-insulin users yielded 3 factors (14 items): Hypoglycemia Anxiety, Avoidance and Confidence. For both T2D groups, higher Anxiety and Avoidance were significantly associated with more hypoglycemia, lower well-being, and greater diabetes distress, depressive symptoms and hypoglycemic fear. Similar associations, in the converse direction, were found for Confidence. Among insulin users only, Anxiety was independently associated with greater emotional distress and more hypoglycemia, while Confidence was independently linked to less emotional distress and lower A1C. Avoidance was independently associated with greater emotional distress in both groups., Conclusions: Using the new 14-item Hypoglycemic Attitudes and Behavior Scale (HABS), we found that hypoglycemic concerns are significant in T2D adults, are linked to emotional distress and A1C, and merit attention in clinical practice., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The "problem of serial order in behavior," as formulated and discussed by Lashley (1951), is arguably more pervasive and more profound both than originally stated and than currently appreciated. We spell out two complementary aspects of what we term the generalized problem of behavior: (i) multimodality, stemming from the disparate nature of the sensorimotor variables and processes that underlie behavior, and (ii) concurrency, which reflects the parallel unfolding in time of these processes and of their asynchronous interactions. We illustrate these on a number of examples, with a special focus on language, briefly survey the computational approaches to multimodal concurrency, offer some hypotheses regarding the manner in which brains address it, and discuss some of the broader implications of these as yet unresolved issues for cognitive science., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The skills required for the learning and use of language are the focus of extensive research, and their evolutionary origins are widely debated. Using agent-based simulations in a range of virtual environments, we demonstrate that challenges of foraging for food can select for cognitive mechanisms supporting complex, hierarchical, sequential learning, the need for which arises in language acquisition. Building on previous work, where we explored the conditions under which reinforcement learning is out-competed by seldom-reinforced continuous learning that constructs a network model of the environment, we now show that realistic features of the foraging environment can select for two critical advances: (i) chunking of meaningful sequences found in the data, leading to representations composed of units that better fit the prevalent statistical patterns in the environment; and (ii) generalization across units based on their contextual similarity. Importantly, these learning processes, which in our framework evolved for making better foraging decisions, had been earlier shown to reproduce a range of findings in language learning in humans. Thus, our results suggest a possible evolutionary trajectory that may have led from basic learning mechanisms to complex hierarchical sequential learning that can support advanced cognitive abilities of the kind needed for language acquisition., (© 2015 The Author(s) Published by the Royal Society. All rights reserved.)

Natural behaviors, such as foraging, tool use, social interaction, birdsong, and language, exhibit branching sequential structure. Such structure should be learnable if it can be inferred from the statistics of early experience. We report that juvenile zebra finches learn such sequential structure in song. Song learning in finches has been extensively studied, and it is generally believed that young males acquire song by imitating tutors (Zann, 1996). Variability in the order of elements in an individual's mature song occurs, but the degree to which variation in a zebra finch's song follows statistical regularities has not been quantified, as it has typically been dismissed as production error (Sturdy et al., 1999). Allowing for the possibility that such variation in song is non-random and learnable, we applied a novel analytical approach, based on graph-structured finite-state grammars, to each individual's full corpus of renditions of songs. This method does not assume syllable-level correspondence between individuals. We find that song variation can be described by probabilistic finite-state graph grammars that are individually distinct, and that the graphs of juveniles are more similar to those of their fathers than to those of other adult males. This grammatical learning is a new parallel between birdsong and language. Our method can be applied across species and contexts to analyze complex variable learned behaviors, as distinct as foraging, tool use, and language.

Objective: Insulin adjustments to maintain glycemic control in individuals with type 1 diabetes often lead to wide glucose fluctuations, hypoglycemia, and increased body weight. Dapagliflozin, an insulin-independent sodium-glucose cotransporter 2 (SGLT2) inhibitor, increases glucosuria and reduces hyperglycemia in individuals with type 2 diabetes. The primary objective of this study was to assess short-term safety of dapagliflozin in combination with insulin; secondary objectives included pharmacokinetic, pharmacodynamic, and efficacy parameters., Research Design and Methods: A 2-week, dose-ranging, randomized, double-blind, placebo-controlled proof-of-concept study randomly assigned 70 adults with type 1 diabetes (HbA1c 7-10%), who were receiving treatment with stable doses of insulin, to one of four dapagliflozin doses (1, 2.5, 5, or 10 mg) or placebo. The insulin dose was not proactively reduced at randomization but could be adjusted for safety reasons., Results: Sixty-two patients (88.6%) completed the study. Any hypoglycemia was common across all treatments (60.0-92.3%); one major event of hypoglycemia occurred with dapagliflozin 10 mg. No diabetic ketoacidosis occurred. Pharmacokinetic parameters were similar to those observed in patients with type 2 diabetes. Glucosuria increased by 88 g/24 h (95% CI 55 to 121) with dapagliflozin 10 mg and decreased by -21.5 g/24 h (95% CI -53.9 to 11.0) with placebo. Changes from baseline with dapagliflozin 10 mg by day 7 were as follows: -2.29 mmol/L (95% CI -3.71 to -0.87 [-41.3 mg/dL; 95% CI -66.9 to -15.7]) for 24-h daily average blood glucose; -3.77 mmol/L (95% CI -6.09 to -1.45 [-63.1 mg/dL; 95% CI -111.5 to -14.8]) for mean amplitude of glycemic excursion; and -16.2% (95% CI -29.4 to -0.5) for mean percent change in total daily insulin dose. Corresponding changes with placebo were as follows: -1.13 mmol/L (95% CI -3.63 to 1.37), -0.45 mmol/L (95% CI -4.98 to 4.08), and 1.7% (95% CI -22.8 to 33.9), respectively. However, for every efficacy parameter, the 95% CIs for all dapagliflozin doses overlapped those for placebo., Conclusions: This exploratory study of dapagliflozin in adults with type 1 diabetes demonstrated acceptable short-term tolerability and expected pharmacokinetic profiles and increases in urinary glucose excretion. Within the dapagliflozin groups, dose-related reductions in 24-h glucose, glycemic variability, and insulin dose were suggested, which provide hope that SGLT2 inhibition may prove in larger randomized controlled trials to be efficacious in reducing hyperglycemia in type 1 diabetes., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

We introduce a set of biologically and computationally motivated design choices for modeling the learning of language, or of other types of sequential, hierarchically structured experience and behavior, and describe an implemented system that conforms to these choices and is capable of unsupervised learning from raw natural-language corpora. Given a stream of linguistic input, our model incrementally learns a grammar that captures its statistical patterns, which can then be used to parse or generate new data. The grammar constructed in this manner takes the form of a directed weighted graph, whose nodes are recursively (hierarchically) defined patterns over the elements of the input stream. We evaluated the model in seventeen experiments, grouped into five studies, which examined, respectively, (a) the generative ability of grammar learned from a corpus of natural language, (b) the characteristics of the learned representation, (c) sequence segmentation and chunking, (d) artificial grammar learning, and (e) certain types of structure dependence. The model's performance largely vindicates our design choices, suggesting that progress in modeling language acquisition can be made on a broad front-ranging from issues of generativity to the replication of human experimental findings-by bringing biological and computational considerations, as well as lessons from prior efforts, to bear on the modeling approach., (Copyright © 2014 Cognitive Science Society, Inc.)

The efficacy of compounds having agonistic activity at the glycine site associated with the N-methyl-D-aspartate receptor (NMDAR) is presently assessed in psychiatric disorders. In contrast to NMDAR antagonists, the neuropsychiatric effects of NMDAR agonists in the healthy human organism are not known. We studied neuropsychiatric and neurochemical effects of the NMDAR-glycine site obligatory co-agonist d-serine (DSR) in healthy subjects using a randomized, controlled crossover challenge design including a baseline assessment day and two DSR/placebo administration days. Thirty-five subjects aged 23-29 years participated in the study and received a 2.1 g orally administered DSR dose. The main outcome measures were the changes in scores of mood-related Visual Analogue Scale (VAS), Continuous Performance Test-Identical Pairs (CPT-IP), and Rey Auditory Verbal Learning Test (RAVLT). DSR acute administration: (1) was well tolerated and resulted at 2 h in ≥ 200 times increase in DSR serum levels; (2) elicited reduced VAS-measured depression and anxiety feelings; (3) improved attention and vigilance as measured by CPT-IP D-prime score; (4) preferentially improved performance in RAVLT list 7 reflecting ability to retain information over interference; (5) had significant but nonspecific effects on Category Fluency and Benton Visual Retention tests; and (6) did not affect glycine and glutamate serum levels. These data indicate that in healthy subjects, DSR reduces subjective feelings of sadness and anxiety and has procognitive effects that are overall opposed to the known effects of NMDAR antagonists. The findings are relevant to translational research of NMDAR function and the development of NMDAR-glycine site treatments for specific psychiatric entities. ClinicalTrials.gov: Behavioral and Cognitive Effects of the N-methyl-D-aspartate Receptor (NMDAR) Co-agonist D-serine in Healthy Humans; http://www.clinicaltrials.gov/ct2/show/NCT02051426?term=NCT02051426&rank=1; NCT02051426., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Empathy is the ability to recognize and share in the emotions of others. It can be considered a multifaceted concept with cognitive and emotional aspects. Little is known regarding the underlying neurochemistry of empathy and in the current study we used a neurogenetic approach to explore possible brain neurotransmitter pathways contributing to cognitive and emotional empathy. Both the oxytocin receptor (OXTR) and the arginine vasopressin receptor 1a (AVPR1a) genes contribute to social cognition in both animals and humans and hence are prominent candidates for contributing to empathy. The following research examined the associations between polymorphisms in these two genes and individual differences in emotional and cognitive empathy in a sample of 367 young adults. Intriguingly, we found that emotional empathy was associated solely with OXTR, whereas cognitive empathy was associated solely with AVPR1a. Moreover, no interaction was observed between the two genes and measures of empathy. The current findings contribute to our understanding of the distinct neurogenetic pathways involved in cognitive and emotional empathy and underscore the pervasive role of both oxytocin and vasopressin in modulating human emotions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Lactobacillus crispatus is a ubiquitous micro-organism encountered in a wide range of host-associated habitats. It can be recovered from the gastrointestinal tract of animals and it is a common constituent of the vaginal microbiota of humans. Moreover, L. crispatus can contribute to the urogenital health of the host through competitive exclusion and the production of antimicrobial agents. In order to investigate the genetic diversity of this important urogenital species, we performed a comparative genomic analysis of L. crispatus., Results: Utilizing the completed genome sequence of a strain ST1 and the draft genome sequences of nine other L. crispatus isolates, we defined the scale and scope of the pan- and core genomic potential of L. crispatus. Our comparative analysis identified 1,224 and 2,705 ortholog groups present in all or only some of the ten strains, respectively. Based on mathematical modeling, sequencing of additional L. crispatus isolates would result in the identification of new genes and functions, whereas the conserved core of the ten strains was a good representation of the final L. crispatus core genome, estimated to level at about 1,116 ortholog groups. Importantly, the current core was observed to encode bacterial components potentially promoting urogenital health. Using antibody fragments specific for one of the conserved L. crispatus adhesins, we demonstrated that the L. crispatus core proteins have a potential to reduce the ability of Gardnerella vaginalis to adhere to epithelial cells. These findings thereby suggest that L. crispatus core proteins could protect the vagina from G. vaginalis and bacterial vaginosis., Conclusions: Our pan-genome analysis provides insights into the intraspecific genome variability and the collective molecular mechanisms of the species L. crispatus. Using this approach, we described the differences and similarities between the genomes and identified features likely to be important for urogenital health. Notably, the conserved genetic backbone of L. crispatus accounted for close to 60% of the ortholog groups of an average L. crispatus strain and included factors for the competitive exclusion of G. vaginalis, providing an explanation on how this urogenital species could improve vaginal health.

Conflicting clinical evidence regarding the possible association between androgen deprivation therapy (ADT) with heart failure in men with prostate cancer is reviewed, including 2 population-based registries showing such an association, and 1 showing no association. Studies of the effects of androgens on cardiomyocyte contractility at the molecular level, the effects of testosterone on the cardiovascular system, particularly cardiac function, and the beneficial effects of testosterone therapy for patients with heart failure might help illuminate this controversy. Future studies are needed to evaluate the effect of ADT on end points of heart failure. The authors weigh the possible adverse effects of ADT on cardiac function and heart failure against its known benefits to cancer outcomes, defined according to published, randomized trials, in a discussion of the implications of the preclinical and clinical literature on the management of prostate cancer in men at risk for heart failure. In the absence of conclusive evidence that ADT causes heart failure, the authors discuss clinical situations in which ADT may be delayed, given on a short-term or intermittent basis, or withheld from treatment with the goal of reducing the risks of heart failure without compromising prostate cancer outcomes., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Many branded analog insulins will lose patent protection during the next few years. In response, a number of companies are developing biosimilar insulins, which have the potential to lower healthcare costs and increase patient access. Although these products are not yet available in the US, it is important that patients, payers and clinicians be aware of the potential benefits as well as concerns associated with biosimilar insulins., Scope: This report provides information about these new products and discusses key questions clinicians should consider regarding biosimilar insulin., Conclusion: The biosimilar insulins being developed have the potential to provide clinical benefits that are similar to current insulin analogs at a more affordable price, thereby allowing more patients greater access to these effective therapies. However, industry and regulatory agencies must proceed with caution in bringing these new insulins to market. Clinicians must be aware of how availability of these new medications may impact patients' adherence to their treatment regimens and begin taking steps now to address these potential issues.

Objectives: To identify variations in expenditures and utilization of insulin and other antidiabetes medications by comparing patients with type 2 diabetes mellitus using continuous subcutaneous insulin infusion (CSII) pump therapy versus multiple daily injection (MDI) therapy., Study Design: Truven Health Analytics MarketScan Commercial Claims and Encounters Database and Medicare Supplemental Database for 2006 to 2010 were used in a difference-in-differences approach that took advantage of variation in the timing of the switch from MDI therapy to CSII pump therapy., Methods: Continuous users of MDI therapy throughout the study period were compared with those who switched to the CSII pump therapy during this period. Specifications included: coefficient estimates from cross-sectional ordinary least squares (OLS) regressions with: 1) no additional controls, 2) controls for patient demographics and comorbidities, and 3) patient fixed effects. Propensity score matching at baseline mitigated concerns regarding patient selection bias., Results: While insulin expenditures rose during the study period, switching to CSII pump therapy led to sizable reductions in insulin expenditures. This reduction in insulin expenditures due to switching varied between $657 (standard error [SE] $126; P<.01) and $1011 (SE $250.60; P<.01) per year., Conclusions: This study demonstrated a significant reduction in insulin expenditures among MDI patients who switched to CSII pump therapy at various times throughout the study period.

Despite advances in treatment for type 2 diabetes in recent decades, many patients are failing to achieve adequate glycemic control. Poor glycemic control has been shown to have a detrimental effect on patients' health and well-being, and to have significant negative financial implications for both patients and healthcare systems. Insulin therapy has been proven to significantly reduce glycated hemoglobin levels; however, both patients and physicians can be reluctant to initiate insulin therapy. Research shows that both patient and provider factors contribute to a delay in initiation of insulin therapy. This review discusses the most common barriers contributing to this delay with potential solutions to overcome them., (Published by Elsevier Inc.)

Aims: The 5-year, open-label, prospective, observational helping evaluate reduction in obesity (HERO) study (N = 1106) examines efficacy and safety of the LAP-BAND AP(®) laparoscopic adjustable gastric band (LAGB) in obese patients. This interim analysis assessed the control of type 2 diabetes (T2D), 1 year after the implantation of the LAGB., Methods: Baseline T2D was defined by chart review or use of antidiabetic medications or haemoglobin A1c (HbA1c) ≥ 7.0%. Control of T2D at 1 year was defined as A1c <7.0% (with or without antidiabetic medications)., Results: After 1 year, 187 of 273 patients with T2D at baseline had adequate data available to assess T2D status, of which 135 patients (72.2%) achieved target control of T2D compared with 42.8% control rate at baseline. Independent predictors of achieving target control at 1 year included the following: (i) shorter diabetes duration odds ratio (OR) 0.914 [95% confidence interval (CI), 0.839, 0.995, p = 0.038], (ii) not using insulin therapy OR 0.16 (95% CI, 0.06, 0.47, p < 0.001) and (iii) greater mean % weight loss OR 1.176 (95% CI, 1.093, 1.266, p < 0.001). Patients using insulin at baseline were 84% less likely to achieve control of T2D after 1 year; each additional year of diabetes at baseline reduced the likelihood of good control by 9%; and each 1% of weight loss increases the likelihood of good control by 18%. Rates of device-related adverse events and reoperations were low and were not significantly different between patients with and without baseline T2D at 1 year., Conclusions: Greater % weight loss, not using insulin therapy, and shorter disease duration predicted increased likelihood of target control of T2D, 1 year after implantation of the LAGB., (© 2014 John Wiley & Sons Ltd.)

Increasing evidence points to a role of dopaminergic pathways in modulating social behavior. Specifically, a polymorphic region in the third exon of the Dopamine D4 receptor (DRD4) has been associated with a host of social behaviors, often in an environment-sensitive manner. Empathy is thought to be an important motivator of prosocial behaviors and can be seen as multifaceted, combining cognitive empathy (CE) and emotional empathy (EE). In the current study, we analyzed the association between DRD4 and the 2 aspects of empathy, as well as the effect of gender on this association. In Study 1, a large sample of adult participants (N = 477) was inventoried for general empathy, CE, and EE and genotyped for the DRD4 exon 3 polymorphism. Women scored higher than men on all empathy measures and no main effect of genotype was observed. It is important that a significant interaction between genotype and gender emerged specifically for CE, with women carriers of the 7R-allele scoring higher than noncarriers, whereas in men 7R-carriers scored lower than -7R. Notably, these findings were replicated in an independently recruited sample (N = 121) in Study 2. The current report shows that the DRD4 exon3 polymorphism is associated with CE and the direction of the association is gender-sensitive.

Purpose: Despite many advances in diabetes care over the last century, some elements of insulin therapy remain inadequate for optimal care of the patient with diabetes. There is a need for improved pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues to mimic physiologic insulin secretion. In addition, a major barrier to successful insulin therapy has been patient resistance. Alternative routes of insulin administration, including inhaled insulin, have been under investigation for several years. This review discusses the rationale for pulmonary delivery of insulin, compares previous inhaled insulin products, reviews the literature on the safety and efficacy of a current inhaled insulin formulation under investigation, and compares this product with other prandial insulin products., Methods: English-language studies and reviews of inhaled insulin were searched in MEDLINE, the ClinicalTrials.gov registry (through May 2014), and the US Food and Drug Administration Website., Findings: Inhaled insulin has several favorable characteristics due to pulmonary anatomy/physiology and the lack of injections. Pharmacokinetic and pharmacodynamic studies have shown a time-action profile suitable for prandial insulin use. Inhaled insulin seems to be safe and effective compared with other prandial insulin products and may be preferable to subcutaneous rapid-acting insulin analogues in terms of time-action profiles and rates of hypoglycemia. Small decreases in forced expiratory volume in 1 second (FEV1) have been shown with inhaled insulin, although this finding is not progressive over time and reverses with cessation of the medication., Implications: Although several inhaled insulin products have been under investigation, only one (Exubera(®) [Nektar Therapeutics, San Carlos, California/Pfizer Inc, New York, New York]) was approved by the US Food and Drug Administration, and it was pulled from the market after only a short period of time. Technosphere(®) insulin (MannKind Corporation, Valencia, California) is currently the only inhaled insulin that remains under investigation. A review of the past and present literature on inhaled insulin is pertinent in understanding the current status of inhaled insulin and its risks and benefits. The current literature suggests that inhaled insulin could be a valuable option for prandial insulin administration, with a favorable risk to benefit ratio in some patients., (Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.)

Previous cross-sectional analyses demonstrated that CD8(+) and CD4(+) T-cell reactivity to islet-specific antigens was more prevalent in T1D subjects than in healthy donors (HD). Here, we examined T1D-associated epitope-specific CD4(+) T-cell cytokine production and autoreactive CD8(+) T-cell frequency on a monthly basis for one year in 10 HD, 33 subjects with T1D, and 15 subjects with T2D. Autoreactive CD4(+) T-cells from both T1D and T2D subjects produced more IFN-γ when stimulated than cells from HD. In contrast, higher frequencies of islet antigen-specific CD8(+) T-cells were detected only in T1D. These observations support the hypothesis that general beta-cell stress drives autoreactive CD4(+) T-cell activity while islet over-expression of MHC class I commonly seen in T1D mediates amplification of CD8(+) T-cells and more rapid beta-cell loss. In conclusion, CD4(+) T-cell autoreactivity appears to be present in both T1D and T2D while autoreactive CD8(+) T-cells are unique to T1D. Thus, autoreactive CD8(+) cells may serve as a more T1D-specific biomarker., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Biologic drugs, such as currently prescribed insulins, are large, complex, 3-dimensional molecules manufactured in biological systems. The complexity of the structure of the biologic drug and its manufacturing process means that it is challenging to create a biologic drug that is identical to the original branded drug. With the potential availability on the horizon of follow-on insulin products (also known as biosimilar insulins) in the United States and other countries where they are not currently in use, physicians (and other prescribers) need to be aware of the potential benefits and concerns regarding biosimilar insulins in order to facilitate informed decision making and to provide the best possible advice and guidance to their patients with diabetes. This article offers a brief, practical overview regarding biosimilar insulins by answering 10 key questions about the topic.

Unlabelled: Despite sharing common risk factors and biological pathways, the relationship between frailty and osteoporosis (OP) is not clear. This prospective study has shown that frailty defined by the Vulnerable Elders Survey can predict a decrease in bone mineral density after 1 year. Thus, frail older women should be assessed for osteoporosis., Introduction: Frailty and OP share common risk factors such as age, sarcopenia, lack of physical activity, low body weight, and smoking. Despite shared risk factors and biological pathways, the relationship between frailty and OP is not clear. The purpose of our prospective study was to examine this relationship in a community sample of older women., Methods: A sample of 235 community-dwelling women was assessed for demographic, medical, frailty and OP status at baseline, and after at least 1 year. Frailty was assessed using the Cardiovascular Health study (CHS) frailty phenotype and using the Vulnerable Elders Survey (VES-13). OP was measured using dual photon absorptiometry bone mineral density (BMD). Descriptive statistics and regression models were used., Results: At baseline, 235 women with a mean age of 77.6 (SD = 5.4), body mass index (BMI) of 28.3 (SD = 5.2) kg/m(2), and BMD of 0.7 (SD = 0.2) g/cm(2)were assessed. No correlation was found between BMD and the CHS (BMD spine, r = 0.009, p = 0.889; BMD hips, r = 0.050, p = 0.473) or the VES-13 (BMD spine, r = 0.034, p = 0.605; BMD hips, r = -0.042, p = 0.537) frailty scales. One hundred fifty-two (63.9 %) women were assessed after 1 year. In a regression model, women who were frail at baseline (VES-13) were found to have a statistically significantly lower hip and spine BMD at follow-up (controlling for BMI) than women who were non-frail at baseline (p = 0.0393, hip; p = 0.0069, spine)., Conclusions: Frailty status as defined by the VES-13 predicts a decrease in BMD after 1 year.

Continuous, 'always on', learning of structure from a stream of data is studied mainly in the fields of machine learning or language acquisition, but its evolutionary roots may go back to the first organisms that were internally motivated to learn and represent their environment. Here, we study under what conditions such continuous learning (CL) may be more adaptive than simple reinforcement learning and examine how it could have evolved from the same basic associative elements. We use agent-based computer simulations to compare three learning strategies: simple reinforcement learning; reinforcement learning with chaining (RL-chain) and CL that applies the same associative mechanisms used by the other strategies, but also seeks statistical regularities in the relations among all items in the environment, regardless of the initial association with food. We show that a sufficiently structured environment favours the evolution of both RL-chain and CL and that CL outperforms the other strategies when food is relatively rare and the time for learning is limited. This advantage of internally motivated CL stems from its ability to capture statistical patterns in the environment even before they are associated with food, at which point they immediately become useful for planning.

Aims: To identify patient-reported obstacles to self-monitoring of blood glucose among those with Type 2, both insulin users and non-insulin users, and to investigate how obstacles are associated with frequency of self-monitoring and use of self-monitoring data., Methods: Patients with Type 2 diabetes (n = 886, 65% insulin users) who attended a 1-day diabetes education conference in cities across the USA completed a survey on current and recommended self-monitoring of blood glucose frequency, how they used self-monitoring results and perceived obstacles to self-monitoring use. Exploratory factor analysis examined 12 obstacle items to identify underlying factors. Regression analyses examined associations between self-monitoring of blood glucose use and the key obstacle factors identified in the exploratory factor analysis., Results: Three obstacle factors emerged: Avoidance, Pointlessness and Burden. Avoidance was the only significant independent predictor of self-monitoring frequency (β = -0.23, P < 0.001). Avoidance (β = -0.12, P < 0.01) and Pointlessness (β = -0.15, P < 0.001) independently predicted how often self-monitoring data were shared with healthcare professionals and whether or not data were used to make management adjustments (Avoidance: odds ratio = 0.74, P < 0.001; Pointlessness: odds ratio = 0.75, P < 0.01). Burden was not associated with any of the self-monitoring behavioural measures. Few differences between insulin users and non-insulin users were noted., Conclusions: Obstacles to self-monitoring of blood glucose use, both practical and emotional, were common. Higher levels of Avoidance and Pointlessness, but not Burden, were associated with less frequent self-monitoring use. Addressing patients' self-monitoring-related emotional concerns (Avoidance and Pointlessness) may be more beneficial in enhancing interest and engagement with self-monitoring of blood glucose than focusing on day-to-day, behavioural issues (Burden)., (© 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.)

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are a relatively recent addition to the treatment options for type 2 diabetes mellitus (T2DM) and are administered using prefilled pen devices., Method: In this open-label task and interview-based pilot study, 3 GLP-1 receptor agonist pen devices-exenatide (Byetta ® , Bristol-Myers Squibb/AstraZeneca), liraglutide (Victoza ® , Novo Nordisk), and lixisenatide (Lyxumia ® , Sanofi-Aventis)-were comparatively assessed in a randomized order in 30 participants with T2DM for ease of use, using a series of key performance measures (time taken to complete a series of tasks, number of user errors [successful performance], and user satisfaction rating). Linear and logistic regression analysis was conducted for the lixisenatide and liraglutide pens versus the exenatide pen. Participants' mean age was 60 years; 27% and 20% of the participants had visual impairments and reduced manual dexterity, respectively., Results: Tasks were completed faster (P < .001) and with higher successful performance (P = .001) with the lixisenatide pen than with the exenatide pen, whereas the liraglutide pen was not statistically significant versus the exenatide pen on these parameters. Overall, user satisfaction was statistically higher for the lixisenatide and liraglutide pens versus the exenatide pen (P < .001 for both)., Conclusions: Lixisenatide and liraglutide pens are associated with higher user satisfaction compared with the exenatide pen. In addition, the lixisenatide pen is faster and results in fewer errors than its comparator (exenatide). The lixisenatide pen may therefore be a suitable choice for patients with T2DM, including older and pen device-naïve patients, and those with visual impairments and reduced manual dexterity., (© 2014 Diabetes Technology Society.)

The availability of biosimilar insulins can potentially lead to lower insulin costs and increased access for patients with diabetes, worldwide. However, clinicians and regulatory agencies have raised several concerns regarding the safety and efficacy of these new medications. The European regulatory agencies have established guidelines for market approval of biosimilar insulins; however, many issues remain unresolved. Moreover, although the FDA has developed preliminary pathways for biosimilar protein development and is prepared to review each application on a case-by-case basis, insulins do not fall under this pathway at this time. The development of effective postmarketing surveillance protocols, determination of product interchangeability, and product identification/labeling remain key concerns. Numerous issues surround the development and commercialization of biosimilar insulins; thus, it is important that all stakeholders fully understand the complexity of these issues and how they can potentially affect patient care. Bridging the educational gap among clinicians and regulatory agencies will be challenging but necessary for ensuring patient safety., (© 2014 Diabetes Technology Society.)

Despite years of research in the field of type 1 diabetes, patients with the disease remain without a therapeutic agent that can alter the underlying immune response in a clinically beneficial way. Glucagon-like peptide 1 agonist therapies have shown some promising effects in terms of positively affecting overall beta cell health and increasing beta cell mass, primarily in mouse models. The three agents of this class currently available for patients with type 2 diabetes have shown beneficial clinical effects on glucose control in this patient population. The purpose of this article is to review the preclinical and clinical data of these agents to date with a focus on the potential immunological and clinical benefits these drugs may have on patients with type 1 diabetes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Multiple immune parameters such as frequencies of autoreactive CD4(+), CD8(+) T-cells and CD4(+)CD25(+)Foxp3(+) T-cells have been explored as biomarkers in human T1D. However, intra-individual temporal variation of these parameters has not been assessed systematically over time. We determined the variation in each of these parameters in a cohort of T1D and healthy donors (HDs), at monthly intervals for one year. Despite low intra- and inter-assay co-efficient of variation (CV), mean CVs for each of the immune parameters were 119.1% for CD4(+) T-cell-derived IFN-γ, 50.44% for autoreactive CD8(+) T-cells, and 31.24% for CD4(+)CD25(+)Foxp3(+) T-cells. Further, both HDs and T1D donors had similar CVs. The variation neither correlated with BMI, age, disease duration or insulin usage, nor were there detectable cyclical patterns of variation. However, averaging results from multiple visits for an individual provided a better estimate of the CV between visits. Based on our data we predict that by averaging values from three visits a treatment effect on these parameters with a 50% effect size could be detected with the same power using 1.8-4-fold fewer patients within a trial compared to using values from a single visit. Thus, our present data contribute to a more robust, accurate endpoint design for future clinical trials in T1D and aid in the identification of truly efficacious therapies.

Complex network analysis (CNA), a subset of graph theory, is an emerging approach to the analysis of functional connectivity in the brain, allowing quantitative assessment of network properties such as functional segregation, integration, resilience, and centrality. Here, we show how a classification framework complements complex network analysis by providing an efficient and objective means of selecting the best network model characterizing given functional connectivity data. We describe a novel kernel-sum learning approach, block diagonal optimization (BDopt), which can be applied to CNA features to single out graph-theoretic characteristics and/or anatomical regions of interest underlying discrimination, while mitigating problems of multiple comparisons. As a proof of concept for the method's applicability to future neurodiagnostics, we apply BDopt classification to two resting state fMRI data sets: a trait (between-subjects) classification of patients with schizophrenia vs. controls, and a state (within-subjects) classification of wake vs. sleep, demonstrating powerful discriminant accuracy for the proposed framework.

Antagonism of N-methyl-D-aspartate glutamatergic receptors (NMDAR) may represent an effective antidepressant mechanism. D-cycloserine (DCS) is a partial agonist at the NMDAR-associated glycine modulatory site that at high doses acts as a functional NMDAR antagonist. Twenty-six treatment-resistant major depressive disorder patients participated in a double blind, placebo-controlled, 6-wk parallel group trial with a gradually titrated high dose (1000 mg/d) of DCS added to their antidepressant medication. DCS treatment was well tolerated, had no psychotomimetic effects and led to improvement in depression symptoms as measured by Hamilton Depression Rating Scale (HAMD; p = 0.005) and Beck Depression Inventory (p = 0.046). Of the 13 subjects treated with DCS, 54% had a ≥ 50% HAMD score reduction vs. 15% of the 13 patients randomized to placebo (p = 0.039). A significant (p = 0.043) treatment× pre-treatment glycine serum levels interaction was registered. These findings indicate that NMDAR glycine site antagonism may be a cost-effective target for development of mechanistically novel antidepressants. Larger-sized DCS trials are warranted.

Purpose: The study sought to evaluate the longer-term effects of a brief cognitive behavior therapy (CBT) intervention for patients with chronic subjective dizziness (CSD). In addition, it sought to identify predictors of longer-term disability in this group., Materials and Methods: Forty-four patients with CSD referred by a neuro-otological clinic were followed-up six months after completing a brief treatment program based on the CBT model of panic disorder. Patients completed the following measures: Dizziness Handicap Inventory, Depression, Anxiety and Stress Scales, Dizziness Symptoms Inventory, and the Safety Behaviours Inventory. Measures were completed at pre and post-treatment, as well as at one and six months post-treatment., Results: Treatment gains observed immediately after treatment were maintained at one and six months post-treatment. High levels of pre-treatment anxiety predicted higher levels of disability at six months post-treatment. Duration and severity of dizziness, and medical or psychiatric comorbidity did not predict disability at six month follow-up., Conclusions: A brief CBT intervention for patients with CSD produced improvements in physical symptoms, disability, and functional impairment which were sustained at one month and six months post intervention. Patients with high levels of anxiety prior to treatment had higher levels of disability at six months post-treatment. It is possible that more focused interventions that specifically target anxiety might produce further benefits for this cohort., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Self-control, involving processes such as delaying gratification, concentrating, planning, following instructions, and adapting emotions and behavior to situational requirements and social norms, may have a profound impact on children's adjustment. The importance of self-control suggests that parents are likely to modify their parenting based on children's ability for self-control. We study the effect of children's self-control, a trait partially molded by genetics, on their mothers' parenting, a process of evocative gene-environment correlation. Israeli 3.5-year-old twins (N = 320) participated in a lab session in which their mothers' parenting was observed. DNA was available from most children (N = 228). Mothers described children's self-control in a questionnaire. Boys were lower in self-control and received less positive parenting from their mothers, in comparison with girls. For boys, and not for girls, the serotonin transporter linked polymorphic region gene predicted mothers' levels of positive parenting, an effect mediated by boys' self-control. The implications of this evocative gene-environment correlation and the observed sex differences are discussed.

Self-presentation refers to the behavioral strategies a person adopts to convey desired social images of oneself to other people. The Concern for Appropriateness Scale (CAS) measures a defensive and fearful social approach aimed at avoiding social threats whereas the Revised Self-Monitoring Scale (RSMS) measures an active and flexible social approach aimed at gaining power and status. In this study, a significant correlation was found between hypnotizability, as measured by the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C) scores and CAS (r = .43, p = .002) but not between hypnotizability and RSMS (r = .070, p = .631). These results suggest that a protective self-presentation style may incline certain individuals to cooperate with hypnotic suggestions.

Objective: Laparoscopic adjustable gastric banding (LAGB) is an established bariatric surgical procedure that produces meaningful weight loss and improvements in patients with type 2 diabetes mellitus (T2DM) and a body mass index (BMI) ≥ 30 kg/m2. This study examined the effect of LAGB on T2DM status in severely obese patients with T2DM., Methods: This was a 2-year interim analysis of patients with T2DM who required daily hypoglycemic medication at baseline (N = 89) in the 5-year, open-label, prospective, observational LAP-BAND AP® EXperience (APEX) trial. Type 2 diabetes mellitus status was classified as "remission," "improved," "stable," or "worse" based on physician- and patient-reported changes in T2DM control and changes in hypoglycemic medication use., Results: At baseline, 89 (22.5%) of 395 patients required daily hypoglycemic medication; 66 patients had data available after 2 years. Remission of T2DM occurred in 32 (48.5%) patients, improvement occurred in 31 (47.0%) patients, and no change occurred in 3 (4.5%) patients. Overall, 95.5% of patients experienced remission or improvement in T2DM status. Duration of T2DM in patients with remission or improvement after 2 years was 4.0 and 6.7 years, respectively (P = 0.082 between groups), and was associated with change in T2DM status (logistic regression, P = 0.069). Baseline BMI, change in BMI, and percent weight loss were not significantly different between the T2DM response groups. Percent excess weight loss was numerically, but not statistically significantly, greater in remitted (-56.1%) compared with the improved response (-42.9%) group (P = 0.134), and was correlated with change in T2DM status (logistic regression, P = 0.052). After 2 years, patients experienced remission or improvement of other obesity comorbidities. The rate of revisional surgery or explantation was 3.4%, and it was not significantly different between patients with and without T2DM (P = 0.687)., Conclusion: Shorter duration of T2DM and greater percent excess weight loss were associated with an increased likelihood of remission or improvement in T2DM status through LAGB after 2 years. Laparoscopic adjustable gastric banding is a potential adjunctive treatment for obese patients with T2DM.

Purpose: To evaluate the impact of short-course androgen deprivation therapy (ADT) on cancer control outcomes and toxicity in intermediate-risk prostate cancer treated with dose-escalated external beam radiotherapy (high-dose radiotherapy [HDRT])., Methods and Materials: Demographic, disease, and treatment characteristics of prostate cancer patients at 2 institution consortiums were charted. Of 296 men with intermediate-risk prostate cancer (defined as ≥T2b, prostate-specific antigen level >10 ng/mL, or Gleason score [GS] of 7, with none of the following: ≥T3, prostate-specific antigen level >20 ng/mL, GS ≥8, or positive nodes) treated with HDRT to a dose of 72 Gy or greater, 123 received short-course ADT and 173 did not. Univariate and multivariate analyses on biochemical failure-free survival (BFFS) (including subset analysis by disease factors) and on overall survival (OS) were performed, as were comparisons of gastrointestinal (GI) and genitourinary (GU) toxicity rates., Results: For the whole group, the median dose was 75.6 Gy; the minimum follow-up was 2 years, and the median follow-up was 47.4 months. For ADT vs. no ADT, the 5-year BFFS rate was 86% vs. 79% (p = 0.138) and the 5-year OS rate was 87% vs. 80% (p = 0.159). On multivariate analysis, percent positive cores (PPC) (p = 0.002) and GS (p = 0.008) were significantly associated with BFFS, with ADT showing a trend (p = 0.055). The impact of ADT was highest in the subsets with PPC greater than 50% (p = 0.019), GS 4+3 (p = 0.078), and number of risk factors greater than 1 (p = 0.022). Only intensity-modulated radiotherapy use (p = 0.012) and GS (p = 0.023) reached significance for OS, and there were no significant differences in GU or GI toxicity., Conclusions: Although the use of ADT with HDRT did not influence BFFS, our study suggests a benefit in patients with PPC greater than 50%, GS 4+3, or multiple risk factors. No OS benefit was shown, and ADT was not associated with additional radiotherapy-related GI or GU toxicity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In psychology, the concept of similarity has traditionally evoked a mixture of respect, stemming from its ubiquity and intuitive appeal, and concern, due to its dependence on the framing of the problem at hand and on its context. We argue for a renewed focus on similarity as an explanatory concept, by surveying established results and new developments in the theory and methods of similarity-preserving associative lookup and dimensionality reduction-critical components of many cognitive functions, as well as of intelligent data management in computer vision. We focus in particular on the growing family of algorithms that support associative memory by performing hashing that respects local similarity, and on the uses of similarity in representing structured objects and scenes. Insofar as these similarity-based ideas and methods are useful in cognitive modeling and in AI applications, they should be included in the core conceptual toolkit of computational neuroscience. In support of this stance, the present paper (1) offers a discussion of conceptual, mathematical, computational, and empirical aspects of similarity, as applied to the problems of visual object and scene representation, recognition, and interpretation, (2) mentions some key computational problems arising in attempts to put similarity to use, along with their possible solutions, (3) briefly states a previously developed similarity-based framework for visual object representation, the Chorus of Prototypes, along with the empirical support it enjoys, (4) presents new mathematical insights into the effectiveness of this framework, derived from its relationship to locality-sensitive hashing (LSH) and to concomitant statistics, (5) introduces a new model, the Chorus of Relational Descriptors (ChoRD), that extends this framework to scene representation and interpretation, (6) describes its implementation and testing, and finally (7) suggests possible directions in which the present research program can be extended in the future.

Purpose: The aim of this study was to evaluate the effects of a brief cognitive behavior therapy (CBT) intervention on the physical symptoms, illness-related disability, and psychologic distress of patients with chronic subjective dizziness., Materials and Methods: Forty-one patients with chronic subjective dizziness referred by a neurootologic clinic were randomly assigned to immediate treatment or a wait-list control. Three weekly treatment sessions based on the CBT model of panic disorder, adapted for patients with dizziness, were administered by a clinical psychologist. Treatment included psychoeducation, behavioral experiments, exposure to feared stimuli, and attentional refocusing. Outcomes were measured on the Dizziness Handicap Inventory and the Depression, Anxiety and Stress Scales. Two further measures developed for this study; the Dizziness Symptoms Inventory and the Safety Behaviours Inventory were used to measure physical symptoms and safety behaviors., Results: The intervention was associated with significant reductions in disability on the Dizziness Handicap Inventory, reduced dizziness and related physical symptoms on the Dizziness Symptoms Inventory, and reduced avoidance and safety behaviors as measured by the Safety Behaviours Inventory. Pre- to posteffect sizes ranged from 0.98 to 1.15. There was no change in psychologic outcomes measured on the Depression, Anxiety and Stress Scales., Conclusions: A 3-session psychologic intervention based on the CBT model can produce significant improvements in dizziness-related symptoms, disability, and functional impairment among patients with chronic subjective dizziness. This suggests that treatment of this condition may be reasonably simple and cost-effective for most of the patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To compare the biochemical outcome and toxicity scores of men with human immunodeficiency virus (HIV) and prostate cancer with a matched control population with negative or unknown HIV status when treated with external-beam radiotherapy (EBRT)., Methods and Materials: A single-institution database of men with prostate cancer treated with EBRT from 1999 to 2009 was reviewed. Thirteen men with HIV were identified and matched to 2 control patients according to age, race, T stage, prostate-specific antigen level, Gleason score, RT dose, intensity-modulated RT vs. three-dimensional conformal RT, and whole-pelvis vs. prostate-only RT, for a total of 39 cases. The median follow-up time was 39 months (range, 3-110 months)., Results: The 4-year biochemical failure (BF)-free survival rate was 87% in the HIV-positive group vs. 89% in the controls (p = 0.94). Pre- and post-RT viral loads were found to be predictive of BF (p = 0.04 and p = 0.04, respectively). No men with HIV died, whereas 2 in the control group died of causes unrelated to prostate cancer. Acute and chronic genitourinary and gastrointestinal toxicity were less in the HIV-positive patients than in controls (p < 0.001, p < 0.001, p = 0.003, and p < 0.001, respectively). The HIV-positive men experienced an average decline in CD4 count of 193 cells/mm(3)., Conclusions: Our findings suggest that men with HIV treated with EBRT have a similar risk of BF; however, high viral loads may contribute to an increased risk. This analysis supports that HIV-positive men with prostate cancer can be treated with definitive EBRT with similar disease control and toxicity outcomes as in the general population., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Glutamine synthetase (GS) and glucose-6-phosphate isomerase (GPI) were identified as novel adhesive moonlighting proteins of Lactobacillus crispatus ST1. Both proteins were bound onto the bacterial surface at acidic pHs, whereas a suspension of the cells to pH 8 caused their release into the buffer, a pattern previously observed with surface-bound enolase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of L. crispatus. The pH shift was associated with a rapid and transient increase in cell wall permeability, as measured by cell staining with propidium iodide. A gradual increase in the release of the four moonlighting proteins was also observed after the treatment of L. crispatus ST1 cells with increasing concentrations of the antimicrobial cationic peptide LL-37, which kills bacteria by disturbing membrane integrity and was here observed to increase the cell wall permeability of L. crispatus ST1. At pH 4, the fusion proteins His(6)-GS, His(6)-GPI, His(6)-enolase, and His(6)-GAPDH showed localized binding to cell division septa and poles of L. crispatus ST1 cells, whereas no binding to Lactobacillus rhamnosus GG was detected. Strain ST1 showed a pH-dependent adherence to the basement membrane preparation Matrigel. Purified His(6)-GS and His(6)-GPI proteins bound to type I collagen, and His(6)-GS also bound to laminin, and their level of binding was higher at pH 5.5 than at pH 6.5. His(6)-GS also expressed a plasminogen receptor function. The results show the strain-dependent surface association of moonlighting proteins in lactobacilli and that these proteins are released from the L. crispatus surface after cell trauma, under conditions of alkaline stress, or in the presence of the antimicrobial peptide LL-37 produced by human cells.