Theoretical models of infection spread on networks predict that targeting vaccination at individuals with a very large number of contacts (superspreaders) can reduce infection incidence by a significant margin. These models generally assume that superspreaders will always agree to be vaccinated. Hence, they cannot capture unintended consequences such as policy resistance, where the behavioral response induced by a new vaccine policy tends to reduce the expected benefits of the policy. Here, we couple a model of influenza transmission on an empirically-based contact network with a psychologically structured model of influenza vaccinating behavior, where individual vaccinating decisions depend on social learning and past experiences of perceived infections, vaccine complications and vaccine failures. We find that policy resistance almost completely undermines the effectiveness of superspreader strategies: the most commonly explored approaches that target a randomly chosen neighbor of an individual, or that preferentially choose neighbors with many contacts, provide at best a  Superspreaders are the small number of individuals responsible for the majority of infections. Theoretical models have shown how vaccinating superspreaders can be a highly efficient way to control disease. However, these models neglect behavior by assuming that superspreaders will always agree to be vaccinated. This is a problematic assumption for influenza vaccination, which is voluntary in most populations, and for which vaccine coverage is often suboptimal. We developed a model of seasonal influenza transmission on a network of individuals who make decisions about whether or not to get vaccinated based on known determinants of vaccine uptake, such as personal infection history, perceived vaccine risks, and social influences. We found that, because of feedbacks between disease spread and individual vaccinating behavior, attempts to boost vaccine coverage in superspreaders through the use of incentives or recruiting by social contacts are almost completely undermined by such feedbacks. For example, higher vaccine uptake in superspreaders reduces influenza incidence, which in the next season reduces the perceived need for vaccination among non-superspreaders, who then do not become vaccinated as much. Our results suggest that the design of potential strategies to reach influenza superspreaders should account for behavioral feedbacks, since they may blunt policy effectiveness. Seasonal influenza imposes a significant health burden: in the United States alone there are an estimated 25–50 million cases per year, with 30,000 deaths and numerous hospitalizations, especially among the elderly and individuals with severe medical conditions Many infectious diseases exhibit a highly heterogeneous form of transmission known as “superspreading”, wherein a minority of individuals are responsible for the majority of secondary infections Transmission models generally treat vaccine coverage as a fixed control parameter Incorporating behavior into transmission models is increasingly important in an age of vaccine exemption, especially for influenza vaccine, for which coverage is typically suboptimal Previous research has integrated behavioral modelling with transmission modelling to explore aspects of vaccinating behavior for various vaccine-preventable infections  whether superspreader vaccination strategies remain effective when behavior is accounted for; 2) whether economic incentives improve the effectiveness of such strategies; and 3) how perceived vaccine efficacy and the resulting vaccinating decisions are determined by interactions between network structure, transmission heterogeneity, and vaccine-disease dynamics.For our baseline analysis we generated ten contact networks of 10,000 nodes each, by sampling subnetworks from a large contact network derived from empirical contact patterns in Portland, Oregon The contact network contains individuals representing the full spectrum of neighborhood sizes and does not impose a dichotomy between superspreaders and others. However, to assist with interpreting the output of our simulations, we defined a superspreader as an individual who infected more than the SIRVS) natural history. An infectious individual transmits influenza to a susceptible contact We assumed a Susceptible - Infected - Recovered - Vaccinated - Susceptible  on decision making, since niILI can be mistaken for true influenza and thus alter Passive Vaccination (PV) is the baseline strategy corresponding to how most influenza vaccination programs are designed: vaccines are made available , opening times are widely disseminated, and individuals seek out vaccination on their own, without being individually recruited by public health.To capture this, we assume an individual decides to get vaccinated for the current season with probability and  see . We assuIn addition to making PV available, public health may also implement one of four pro-active strategies: 1) random vaccination (RV) which targets a randomly chosen individual; 2) nearest neighbor vaccination (NN), which targets a randomly chosen individual and one of their neighbors (i.e. contacts) 3) chain vaccination (CV), which either targets a randomly chosen individual or a neighbor of an individual targeted the previous day; and 4) improved nearest neighbor vaccination (INN) which targets a randomly chosen individual and one of their most popular neighbors. Under INN, “popular” means having the highest degree, and we assume imperfect knowledge of a neighbor's neighborhood size. We refer to NN, CV and INN as superspreader strategies, as their objective is to target individuals with a large number of contacts The number of individuals targeted by public health each day is held constant at We allowed for the use of economic vaccination incentives under the pro-active strategies. Each time an individual is targeted they receive an incentive of value LYs) see .For each of the ten networks, the transmission probability and amplitude of seasonality were calibrated so that the average seasonal incidence of influenza in the absence of vaccination was y about  , in lineIn the absence of incentives, the improved nearest neighbor strategy (INN) is the most effective in reducing influenza incidence, followed by chain vaccination (CV), nearest neighbor (NN), random vaccination (RV), and the baseline strategy of passive vaccination alone (PV) .This relative ordering is to be expected, since previous research shows the advantages of targeting individuals with many contacts Policy resistance almost completely undermines the benefits of using pro-active strategies: passive vaccination (PV) reduces seasonal influenza incidence from  to  or  . Moreove to  or  . As expe to  or  , Table 2The impact of policy resistance is made clear by considering the case where vaccinating behavior is neglected . Neglecting behavior (NB) significantly overestimates both effectiveness and vaccine coverage for the pro-active strategies, both in superspreaders and non-superspreaders . Hence, We note that the slightly higher effectiveness of the improved nearest neighbor strategy also arises because by preferentially immunizing those individuals with a large number of contacts, susceptible individuals tend to be clustered together on the network, reducing the opportunities for the susceptible-infected contacts necessary for transmission .Individuals with more neighbors were more likely to be infected . This reThe effect of adding vaccinating incentives is likewise blunted by policy resistance . Any incrom  to  .We estimated the net per capita costs  for each strategy. The least expensive strategy was the improved nearest neighbor strategy (INN) without incentives, at a cost of Using vaccinating incentives increased the total cost of all strategies, but not always significantly. Further details appear in On average, most individuals received few incentives and only a few individuals received many incentives . SuperspOur baseline assumption was that superspreading is driven only by heterogeneity in neighborhood size (node degree). Incorporating heterogeneity into the infectious period, transmission rate, or both did not significantly impact the results (the superspreader strategies become slightly less effective in the absence of incentives). We suspect these forms of heterogeneity did not make a difference because an individual's infectious period and infectiousness were not correlated to their node degree, meaning that superspreader strategies on average do not target individuals with higher infectiousness or longer infectious period. This causes differences in effectiveness between the various strategies to be averaged out. Were correlations to exist between node degree on the one hand, and infectious period or transmission rate on the other hand, then we speculate the results could change qualitatively, either in the direction of greater effectiveness of superspreader strategies, or lesser effectiveness, depending on whether the correlation was positive or negative, respectively.For simulations on the hypothetical Poisson or exponential networks instead of the empirically-based network, we found that the pro-active strategies continued to provide very small reductions in incidence compared to passive vaccination alone . ResultsPrevious models of superspreader vaccination strategies have shown how targeting individuals with a very large number of contacts can be a very effective way to control infection Here, we developed a psychologically structured model of influenza vaccinating behavior and coupled it to a model of seasonal influenza transmission through an empirically-based contact network. Our assumptions about vaccinating behavior were based on empirical studies exploring determinants of vaccine uptake This surprisingly strong policy resistance is driven by multiple mechanisms: individuals are less likely to get vaccinated if their most recent influenza infection was a long time ago, if they perceive low susceptibility to infection (which can emerge from herd immunity generated by vaccination), or if they perceive recent vaccine complications or low vaccine efficacy. The presence of non-influenzal influenza-like illness (niILI) reinforces this because it can create the perception of vaccine failure. Moreover, superspreader strategies tend to reach individuals who are already more prone to get vaccinated without the need for active recruitment on account of their history of more frequent infections. Contact-based recruiting was also stymied by the fact that neighbors tended to share similar experiences and information, which led to neighbors more often than not sharing the same opinion regarding vaccination Providing vaccination incentives boosted effectiveness somewhat, including for superspreader strategies, although these gains were again partly mitigated by policy resistance. The most effective overall strategy was the improved nearest neighbor strategy (INN) with Individuals with more contacts were more likely to be infected, which agrees with results from past models As with any model, our model made simplifying assumptions. For example, we assumed a targeted individual who is asked to recommend a contact for vaccination would always comply. We could address this limitation by introducing a parameter for compliance failure. This would result in a similar strategy to the chain vaccination strategy, where occasionally the recruitment process jumps to another individual rather than continuing along the chain of contacts. We also neglected age structure in the model, which did not allow us to address issues such as age-related heterogeneity in infection severity, and correlations between infection severity and neighborhood size.Incorporating greater heterogeneity into the model by stratifying individuals with respect to age would increase model realism. It would also allow us to address other objectives such as how incentives can be designed to boost vaccine coverage in children. However, this would also increase model complexity, and given that current model already required dealing with the extra complexity of incorporating behavior, we opted for the incremental approach of first developing a model without age structure. Another aspect of model development that requires greater attention is the functional forms used to capture psychological effects such as the role of past experiences and social influences, since typically more than one functional form is qualitatively consistent with existing data on determinants of vaccine uptake.These areas suggest potential for further work at the interface of theoretical modeling and empirical surveys. In particular, surveys of determinants of vaccination behavior can be designed to better meet the needs of models that couple disease dynamic models to vaccinating behavior models, for instance by helping to determine which functional forms best capture psychological effects. This will require collecting new psychological data from study populations. In other cases, these models suggest predictions which can be tested. For example, our model predicted that superspreaders would perceive a slightly lower vaccine efficacy than non-superspreaders, and it would be interesting to see whether this effect holds true for any populations.Thoroughly validated “behavior-incidence” models of influenza vaccinating behavior will help public health authorities to optimize influenza vaccine programs. However, as we have found here, vaccination strategies that target superspreaders and/or provide vaccination incentives must be carefully designed to mitigate the potentially strong effects of behavioral feedbacks and policy resistance.Figure S1The top row, a)–c), shows the degree distribution for each network (black) compared to the original empirical network (gray) of Portland, Oregon (TIFF)Click here for additional data file.Figure S2A semi-log plot of the probability of number of incentives received and used by superspreaders (solid line) and non-superspreaders (dashed line) for the four different vaccine strategies a) random vaccination b) nearest neighbor vaccination c) chain vaccination and d) improved nearest neighbor vaccination.(TIFF)Click here for additional data file.Table S1The values and descriptions of the parameters used in the simulations for the Poisson and exponential networks. The values were calibrated for each network using the passive vaccination approach. (PDF)Click here for additional data file.Table S2Percentage of recruitments where recruitment did not matter, whether due to infection, already vaccinated or will be vaccinating in the future (Useless) and the percentage of incentives actually used ((PDF)Click here for additional data file.Table S3The global clustering coefficient among susceptible individuals ((PDF)Click here for additional data file.Table S4The statistics regarding the number of superspreaders that were willing to vaccinate prior to being recruited ((PDF)Click here for additional data file.Table S5The estimated costs of the various vaccination strategies for the Realistic networks. The vaccination programs are the passive, along with the pro-active programs: random vaccination (RV), nearest neighbor (NN), chain (CV) and improved nearest neighbor (INN). (PDF)Click here for additional data file.Table S6Influenza incidence and vaccine coverage for the various vaccination strategies (with and without incentives) where there is heterogeneity in the infectious period and transmission rate . (PDF)Click here for additional data file.Table S7Influenza incidence and vaccine coverage for the various vaccination strategies (with and without incentives) where there is heterogeneity in the infectious period and transmission rate (Poisson network). (PDF)Click here for additional data file.Text S1The supplementary text provides further detailed information pertaining to the modelling of disease dynamics and vaccination behavior, the classification of a superspreader and the various vaccination strategies.(PDF)Click here for additional data file.


Malaria afflicts 350–500 million people annually, and this debilitating and deadly infectious disease exacts a heavy toll on susceptible populations around the globe. Efforts to find effective, safe, and low-cost drugs for malaria have sharply increased in recent years. Almost all of these efforts have focused on the cyclic blood stage of the disease, partly because the parasites can be easily maintained in culture through addition of human red blood cells to the growth medium, and partly because blood stage infection causes malaria's characteristic symptoms. However, the asymptomatic liver stage, which the parasite goes through only once in its life history, presents the best opportunity for developing drugs that both hit new targets and also could be used in highly desirable eradication campaigns. Recent research, especially on the frequency of differentially expressed genes in blood and liver stage parasites, supports the feasibility of discovering stage-specific drugs. Discovering these drugs will require a high-throughput liver stage phenotypic screen comparable to the existing blood stage screens, and the basic tools for such a screen have recently been created.Humans have suffered from the burden of malarial infections for thousands of years, and the disease has greatly influenced human evolution and history Anopheles mosquito. During their obligatory blood meals, infected female mosquitoes transmit protozoan parasites belonging to the genus Plasmodium, and their proliferation in the human host causes malaria's symptoms  used in traditional Chinese medicine to treat fevers, and the compound and its derivatives are presently used worldwide in anti-malarial combination therapies  Phenotypic screens involving whole cells or even whole organisms have the obvious advantage of being able to find new targets. But they have the drawback of being more, often much more, complicated to run. The only widely used phenotypic malaria screens involve blood stage parasites and a growth/no growth phenotype. There are several published screens that use varying reporters, but they all exploit the ability of the parasite to be grown in red blood cell culture. The first published high-throughput assay utilized a fluorescent DNA dye to quantify the parasite's growth, or lack thereof P. vivax, like primaquine, and thereby prevent relapsing malaria. Despite their apparent advantages, progress in developing liver stage drugs has been very limited, and this lack of success undoubtedly reflects the way drugs are currently discovered: large numbers of molecules are screened for blood stage activity and only selected active candidates are screened in the liver stage Liver stage drugs have the potential to hit new targets that are not present or essential during the blood stages of malaria, and these drugs would enjoy a tactical advantage over blood stage drugs because many fewer parasites are involved, which should delay the development of resistance Primaquine, a distant chemical relative of chloroquine whose target has yet to be determined, can inhibit both liver stage infections and blood stage parasites in vitro only during the liver stage and thus represent likely stage-specific drug targets  Our understanding of liver stage malaria research has advanced considerably in recent years, and the pieces for a high-throughput screen for liver stage infection appear to be in place. Arguably the most important advance was developing an in vitro culture system for liver stage infection. Now both human hepatoma cell lines and primary hepatocytes can be infected with sporozoites from different P. yoelii and P. berghei, will be the first to be evaluated as the essential tools are already at hand. Of course, running an assay with today's tools requires the continual infection of liver cells with sporozoites and dissection of infected mosquitoes to isolate these sporozoites. Sporozoite harvesting would currently limit any high-throughput assay. In addition to being tedious, parasite harvesting has an inherent variability as it is difficult to standardize mosquito infections over long periods of time Plasmodium sporozoites may in the future overcome this limitation With both in vitro culturing and reporting methods coming together for a quantitative high-throughput liver stage screen, we anticipate a shift from blood stage to liver stage for high-throughput phenotypic drug screens. It is likely that the rodent malaria strains, including P. cynomolgi sporozoites , 812272 (histone deacetylase), 9221804 (dihydrofolate reductase), 811999 (heat shock protein 90), and 3885966 (dihydroorotate dehydrogenase).


OXTR) promoter methylation and summarize studies that have investigated the role of OXTR methylation in behavioral phenotypes. There is first evidence that OXTR methylation is associated with autism, high callous-unemotional traits, and differential activation of brain regions involved in social perception. Furthermore, psychosocial stress exposure might dynamically regulate OXTR. Given evidence that epigenetic states of genes can be modified by experiences, especially those occurring in sensitive periods early in development, we conclude with a discussion on the effects of traumatic experience on the developing oxytocin system. Epigenetic modification of genes involved in oxytocin signaling might be involved in the mechanisms mediating the long-term influence of early adverse experiences on socio-behavioral outcomes.Genetic approaches have improved our understanding of the neurobiological basis of social behavior and cognition. For instance, common polymorphisms of genes involved in oxytocin signaling have been associated with sociobehavioral phenotypes in healthy samples as well as in subjects with mental disorders. More recently, attention has been drawn to epigenetic mechanisms, which regulate genetic function and expression without changes to the underlying DNA sequence. We provide an overview of the functional importance of oxytocin receptor gene ( Research across species has shown that the neuropeptide oxytocin plays a key role in the regulation of social cognition and behavior. It plays a crucial role in attachment, social exploration, and social recognition, as well as anxiety and stress-related behaviors , have shown associations with social cognition and autism  traits, and differential activation of brain regions involved in social perception. Furthermore, there is tentative evidence that OXTR methylation may be dynamically regulated by psychosocial stress exposure.This review describes the functional importance of Given evidence that epigenetic states of genes can be modified by experiences, especially those occurring in sensitive periods early in development, we conclude with a discussion on the effects of traumatic experience on the developing oxytocin system. We provide an outline for future research efforts to investigate the role that epigenetics plays in mediating the long-term influence of early adverse experiences on sociobehavioral outcomes.In mammalian cells, the majority of DNA methylation occurs on cytosines (C) that precede a guanine (G) nucleotide, referred to as CpG sites. Certain areas of the genome contain regions of high CpG density. These regions, called “CpG islands,” are defined as a >200 bp region with GC content of more than 50% and an observed/predicted CpG ratio of more than 0.6  was about 2-fold higher compared to the construct including the core promoter but lacking the majority of the CpG island (−2860 to +144 bp). Following methylation, transcriptional activity of the reporter gene construct lacking the CpG island was reduced by 19%, whereas activity of the construct including the CpG island was suppressed by 70% when methylated. This indicates that OXTR CpG island methylation functionally suppresses transcription, at least in the investigated hepatoblastoma cell line.Kusui and colleagues  investigOXTR CpG island  was investigated in 20 individuals with autism and 20 matched normotypical controls. Significantly increased methylation in autistic probands was observed for CpGs −860, −934, and −959 (numbering according to translation start site +1). Importantly, a similar pattern of methylation differences was observed in temporal cortex tissue. In an independent sample of 10 autistic and matched controls, increased methylation of CpGs −860, −901, −924, and −934, with correspondingly reduced expression of OXTR mRNA by 20%, was observed. Although investigated in a small sample, these findings suggest functional importance of OXTR promoter methylation with regard to gene regulation, and possibly the etiology of autism.Several lines of evidence have implicated the oxytocin system in the etiology of autism spectrum disorder  passively viewed a scene in which geometrical shapes interact in ways suggestive of animacy.Building on evidence of k et al.  investigOXTR methylation derived from PBMCs demonstrated significantly greater activation in two clusters. The first extended from the superior temporal gyrus into supramarginal gyrus at the temporal parietal junction, and the second was in the dorsal anterior cingulate cortex (dACC). The temporal parietal junction in particular has been linked to the attributions of intentions, perception of biological motion cues, and mentalizing behaviors  who met formal criteria for DSM-IV diagnosis of conduct problems  were investigated. DNA was extracted from blood cells, and methylation levels across five CpG sites  located in the MT2 area were assessed and combined into a mean methylation score. Overall, there was no significant association between methylation and CU traits. However, when taking into account age, a different pattern emerged. Whereas there was no relation between methylation and CU traits in the younger sample (3–8 years), higher methylation of OXTR was associated with elevated CU traits in the older sample (9–16 years).Mostly on theoretical grounds, researchers have argued for a role of oxytocin in psychopathy , a standardized laboratory protocol consisting of extemporaneous public speaking and mental arithmetic tasks. Methylation levels of 35 CpG sites, located mainly in the protein coding part of exon 3  were found in women reporting exposure to childhood abuse as compared to women without such experience (Heim et al., To our knowledge, there is no published research in humans on the effects of early environmental influences on differential Prolonged institutional deprivation in early childhood also seems to interfere with the developing oxytocin system. Changes in oxytocin levels after social interaction were investigated in post-institutionalized children reared in severely depriving conditions (Wismer Fries et al., It has been hypothesized that the observed long-term effects of adverse childhood experiences on deficits in social behavior and cognition (Repetti et al., OXTR methylation obtained from peripheral tissues reflect variation in central nervous nuclei expressing OXTR. A detailed account of the necessary precautions and considerations surrounding the application of epigenetics to behavioral sciences is outside the scope of this mini-review, and the reader is referred to the paper by Heijmans and Mill (Given the excitement surrounding epigenetics research, words of caution have been raised. For instance, all studies included here measured DNA methylation from whole blood. Since blood is a heterogeneous tissue, it is unclear to what extent DNA methylation difference between groups could be confounded by differences in the cellular composition of the samples. Another important question concerns the extent to which peripheral tissues can be used to address questions about variation in inaccessible tissues of interest, such as the brain. It is currently unknown whether differences in and Mill .The study of epigenetics has raised much excitement in the field of behavioral neuroscience, as it provides a compelling mechanism underlying the interplay between psychosocial experience and molecular processes influencing gene expression.OXTR promoter seems to be functionally important for OXTR expression, and differences in the degree of methylation have been observed in childhood disorders characterized by impairments in social cognition. Furthermore, differential methylation of OXTR might be important in explaining individual differences in social behavior and cognition more broadly, and might provide a mechanism for biological embedding of early experience. Potentially, improved epigenetic understanding of “social disorders” might aid translational efforts to develop individualized clinical treatment approaches.Differential methylation of a CpG island in the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Ethical judgments about risk, benefit, and patient eligibility inclinical trials hinge on predictions about harm, therapeutic response,and clinical promise.Predictions for novel interventions in preclinical stages of developmentsuffer from two problems: insufficient attention to threats to validityin preclinical research and a reliance on an overly narrow base ofevidence that includes only animal and clinical studies of theintervention in question .To improve ethical and scientific decision-making in early phase studies,decision-makers should explicitly attend to reporting quality andmethodological features in preclinical experiments that address threatsto internal, construct, and external validity.Decision-makers should also use evidence that sheds light on thereliability of causal claims embedded within a proposed trial. Thisevidence can be gathered from outcomes of previous trials involvingagents targeting related biological pathways (“referenceclasses”).First-in-human clinical trials represent a critical juncture in the translation oflaboratory discoveries. However, because they involve the greatest degree ofuncertainty at any point in the drug development process, their initiation is besetby a series of nettlesome ethical questions The resolution of such ethical questions inevitably turns on claims about futureevents like harms, therapeutic response, and clinical translation. Recurrentfailures in clinical translation, like Eli Lilly's Alzheimer candidatesemagacestat, highlight the severe limitations of current methods of prediction. Inthis case, patients in the active arm of the placebo-controlled trial had earlieronset of dementia and elevated rates of skin cancer Various authoritative accounts of human research ethics state that decision-makingabout risk and benefit should be careful, systematic, and non-arbitrary According to the core tenets of human research ethics, investigators, sponsors, andinstitutional review boards (IRBs) are obligated to ensure that risks to volunteersare minimized and balanced favorably with anticipated benefits to society and, ifapplicable, to the volunteers themselves Naturally, there are limits to the reliability with which forecasts based onexperimental evidence predict clinical outcomes. However, in late stages of clinicaldevelopment, forecasts underwriting ethical and scientific decision-making haveproven fairly reliable. Several analyses of cancer randomized controlled trialsindicate that new interventions are just as likely to prove more effective thancomparator ones as they were to prove inferior Whether decision-makers utilize evidence as effectively when predicting outcomes inearly phase research has not been systematically investigated. Nevertheless, thereare grounds for concern such that a systematic investigation is overdue. Highlypromising preclinical findings in cancer, stroke, HIV vaccines, andneurodegenerative diseases frequently fail clinical translation. In cancer, only5% of products entering trials are eventually licensed In Vivo Experiments Guidelines First, decision-makers may not be adequately responsive to problems in preclinicalresearch practice In the case of semegacestat, it has been over 5 years since the drug was first testedin human beings, and preclinical studies have yet to be published. However,narrative reviews by Eli Lilly scientists indicate trials were launched on the basisof molecular, rather than behavioral, endpoints A second concern about forecasting outcomes in translational trials relates to atendency to base clinical inferences on a relatively narrow class of evidence: thosepreclinical studies that involve the particular agent. We call this“evidential conservatism.” Such evidential conservatism is reflected invarious policies. For example, the American Society of Clinical Oncology states that“the decision to move an agent into phase I evaluation is based…central[ly on]… the observation of sufficient preclinical antitumoractivity, such that a therapeutic effect in human cancer is anticipated” Evidential conservatism, however, fails to address the higher-order question of thereliability of forecasts made from such a narrow evidence base. This higher-orderquestion is of special relevance for early phase research because agents that do notenjoy the support of promising preclinical results will not be plausible candidatesfor translation. Yet when agents are supported by equally promising preclinicalresults they may be differentiated by the maturity of the knowledge surrounding anexus of variables concerning the relationship between test and targetpopulations.For instance, although neuroprotective stroke treatments have moved to translation onthe basis of very encouraging preclinical studies, they have consistently failedrandomized trials. Estimates of the risks and benefits of any particularneuroprotective compound that are based solely on preclinical evaluation of thatcompound will be less reliable than those that incorporate information about therelative success of neuroprotective compounds as a class. In part, this is becausethe success or failure of other interventions in this reference class providesevidence about the degree to which clinical development is guided by a reliableworking knowledge of relevant disease processes.Our claim that decision-makers need to use a broader base of evidence for evaluatingearly phase research is consistent with a recent call for incorporating wholeresearch program outcomes into systematic reviews of particular agents How might researchers depart from evidential conservatisim in a way that is open toscrutiny and amenable to assessment, revision, and improvement? Decision-makers whomake forecasts about agent activity in early phase research must identify referenceclasses that are relevant to the decision at hand. Delimiting the reference class ofrelevant evidence poses a challenge in that interventions possess limitlesscharacteristics. A drug might be classed within neuroprotective compounds, strokedrugs, and drugs beginning with the letter “n.” Decision-makers thusconfront the timeless problem of selecting those characteristics most salient forprediction.There are no simple formulas here. In some cases, choice of reference classes will bestraightforward ; in othercases, consensus may be elusive. Nevertheless, we suggest that the very act ofattending to reference class identity would be a departure from evidentialconservatism. As a starting place, decision-makers should identify reference classesthat index the maturity of knowledge regarding central causal premises embeddedwithin a protocol. In an era in which basic science heavily informs productdevelopment, drug developers themselves often class their agents according toexplicit ambitions about causal pathways. Asserting that a drug targets a particularpathophysiologic process should prompt us to look at how other drugs that target thesame process performed in clinical translation. We can then base our estimates ofthe maturity of knowledge about these causal premises on the success or failure ofpast attempts at redeeming these ambitions. Decision-makers should therefore adjusttheir confidence in clinical generalizations on the basis of outcomes with previousinterventions that addressed the same pathological processes.Semagacestat was screened and designed to target amyloid-β production, which isbelieved to be a key step in dementia onset. Eight other anti-amyloid drugs haveeither failed randomized trials or been abandoned due to toxicity  [29],[30To illustrate how our suggestions interface with ethical decision-making, considerrecent proposals to reinitiate trials of fetal-derived tissues for Parkinson'sdisease According to evidential conservatism, investigators and ethics bodies should evaluatethe risk-benefit balance by consulting preclinical studies and the biologicalrationale for patient-subject selection. One commentator notes that, on the basis ofpreclinical studies showing the intervention is designed to address early diseaseprocesses, performing studies in patients with advanced disease would be unethicalOur proposal directs decision-makers to make risk-benefit decisions in light of twoadditional factors. First, to what degree do the preclinical studies incorporatedesign elements that support reliable inferences about clinical activity? Thisdirects stakeholders to attend to those methodological features of the preclinicalstudies that support credible claims of internal, construct, and external validitiesin preclinical studies. As these preclinical studies are presently underway,researchers have an opportunity to overcome past limitations in addressing validitythreats in Parkinson's disease models Second, our proposal directs stakeholders to consider evidence that sheds light onthe maturity of the knowledge relating to key causal claims presupposed bytherapeutic predictions. As investigators propose to intervene in degenerativeprocesses, a claim of therapeutic action would need to be evaluated in light ofoutcomes in previous Parkinson's trials involving surgically deliveredneuroprotective agents and/or transplanted tissues. No such strategies have producedpositive randomized trials . AccordiThoughtful commentators have argued that, before initiating cell-based dopaminereplacement, strategies should be “clinically competitive” with standardof care Systematic study of preclinical research has centered on stroke and practices focusedon internal validity. Our proposal makes clear the need to broaden the scope of thisresearch agenda to cover a wider range of preclinical research, and to expand itsfocus to include issues of construct and external validity. A key component of thisprocess will involve creating databases for aggregating translational outcomesaccording to relevant reference classes.Some may worry that such an analysis might produce less optimistic predictions, andhence stymie product development. However, we do not see how medicine is advanced byforging ahead on the basis of predictions of dubious reliability. Moreover, thereare many productive ways in which stakeholders may respond to less optimisticprojections. For instance, review of relevant information may prompt researchers totest certain hypotheses before moving ahead with human trials. Investigators mightadjust the design of translational studies to align the risk profile with ethicaljudgments. Or, investigators might decide that moving forward with a protocolrepresents the best way to advance a particular scientific initiative, but thatrisks can only be justified by appealing to the value of the knowledge sought,rather than the product's therapeutic activity.Stakeholders might already adjust their predictions in light of intuitions aboutvalidity or experiences with success or failure for similar agents. If so, they doso on the basis of private beliefs, and often without the data needed to make theseadjustments systematically. Our approach provides a more publicly accessible basisfor making and adjudicating risk-benefit predictions. We suggest that this wouldbetter cohere with a sage prescription offered by the National Commission:“there should first be a determination of the validity of the presuppositionsof the research…. The method of ascertaining risks should be explicit… Itshould also be determined whether an investigator's estimates of theprobability of harm or benefits are reasonable, as judged by known facts or otheravailable studies ”


Communication between neurons involves chemical and electric synapses. Electric synapses transmission is mediated by gap junctions providing direct communication between cells, allowing faster communication than chemical synapses. Electrical coupling between cells can be found in many parts of the nervous system.At the network level, electric synapses have several prominent effects such as neural synchronization, and generation of neural rhythms. Additionally, they are responsible for sharp peaks in the auto-correlation of ganglion cells in the retina. Dealing with spike population coding, interactions between neurons highly constrain the collective spike response of a neural assembly to stimuli. Thus, unveiling the respective effect of chemical and electric synapses on spike responses is a mandatory step towards a better understanding of spike coding.Can we have a reasonable idea of what is the spike train statistics and how it depends on stimulus and connectivity studying a neural network model considering chemical and electrical synapses? This work answers this question.In  we have This work suggest that electric synapses could have a strong influence in spike train statistics of biological neural networks, especially in the retina where gap junctions connections between several cells-type (e.g. amacrine and ganglion cells or amacrine-bipolar) are ubiquitous. The main observation is that considering gap junctions the probability of spike patterns does not factorize as a product of marginal, per-neuron, distributions. Therefore there is absolutely now way to defend that neurons in this model act as independent sources. Additionally, correlations mainly result from the chemical and electrical interactions , thus gap junctions play an important role in correlating the network even in absence of stimulus. This work provides a firm theoretical ground for recent studies attempting to describe experimental rasters in the retina as well as in the parietal cat cortex by Gibbs distributions using the maximum entropy principle.


Providing access to and utilization of medication assisted treatment (MAT) for the treatment of opioid abuse and dependence provides an important opportunity to improve public health. Access to health services comprising MAT in the community is fundamental to achieve broad service coverage. The type and placement of the health services comprising MAT and integration with primary medical care including human immunodeficiency virus (HIV) prevention, care and treatment services are optimal for addressing both substance abuse and co-occurring infectious diseases. As an HIV prevention intervention, integrated  MAT with HIV prevention, care and treatment programs provides the best “one stop shopping” approach for health service utilization. Alternatively, MAT, medical and HIV services can be separately managed but co-located to allow convenient utilization of primary care, MAT and HIV services. A third approach is coordinated care and treatment, where primary care, MAT and HIV services are provided at distinct locations and case managers, peer facilitators, or others promote direct service utilization at the various locations. Developing a continuum of care for patients with opioid dependence throughout the stages MAT enhances the public health and Recovery from opioid dependence. As a stigmatized and medical disenfranchised population with multiple medical, psychological and social needs, people who inject drugs and are opioid dependent have difficulty accessing services and navigating medical systems of coordinated care. MAT programs that offer comprehensive services and medical care options can best contribute to improving the health of these individuals thereby enhancing the health of the community. Drug abuse and dependence is a growing public health problem . Most siSubstance use disorders are defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition  as substExposure to addictive substances is widespread, but vulnerability to substance abuse and dependence is behaviorally complex, being a function of biological, psychological and environmental interactions and influences –14. AlthDrug users transition from non-injecting drug use to injection drug use because injecting drug use is considerably more cost effective and provides a more intense drug effect compared to non-injection of drugs –17. In aThe transition from non-injection drug use to injection drug use presents a formidable public health risk for the transmission of both HIV and hepatitis virus infections . The proHowever, injection drug users are not solely at–risk. Non-injection drug users are at-increased risk of death due to drug overdose, and sexually transmitted diseases, including HIV ,27. In cIn the United States, the use of pharmacotherapies in combination with counseling and behavior therapies to provide a comprehensive therapeutic approach to the treatment of opioid abuse and dependence is termed “Medication Assisted Treatment” or MAT. Federally supported research studies have developed and shown that the most efficacious treatments for opioid abuse and dependence comprise MAT and include psychosocial counseling, financial, legal, educational services as well as wrap around social services . FederalCurrently, the US Food and Drug Administration (FDA) has approved four medications for the use in the treatment of opioid abuse and dependence see . Methadohttp://buprenorphine.samhsa.gov/bwns_locator/. In addition, CSAT/SAMHSA provides a state-by-state profile of the locations of physicians with waivers to prescribe buprenorphine. Buprenorphine treatment of opioid abuse and dependence is reviewed in Treatment Improvement Protocol 40 [The Buprenorphine Initiative: An Evaluation of Innovative Methods for Integrating Buprenorphine Opioid Abuse Treatment in HIV Primary Care”. This five year initiative, which began in September 2004, comprises 10 demonstration sites coordinated by a technical assistance/evaluation center that works collaboratively to refine planned interventions, addresses state-of-the-art treatment and policy issues relating to the use of buprenorphine opioid abuse treatment in HIV primary care settings, and conducts local and multi-site evaluations and disseminate findings. A special issue of the Journal of the Acquired Immune Deficiency Syndrome (JAIDS) has been published providing a comprehensive analysis of the projects [Buprenorphine is a Schedule III partial opioid agonist which allows for qualified and specially licensed physicians to treat patients with opioid addiction in a primary care setting. The Division of Pharmacologic Therapies at CSAT/SAMHSA provides an online physician and treatment program locator at: tocol 40 . Buprenotocol 40 . Buprenotocol 40 . The HIVprojects .Naltrexone is a non-narcotic long-acting, opioid antagonist that blocks opioids binding to the mu opioid receptor. Unlike methadone, there is no negative reinforcement  upon discontinuation. Due to naltrexone’s opioid antagonism, patients must abstain from opioids for a minimum of seven days prior to starting treatment to avoid the precipitation of opioid withdrawal. The effectiveness of naltrexone treatment depends upon patient motivation and social support system . Thus, iVivitrol is an injectable extended-release naltrexone preparation that has recently been approved for the treatment of opioid abuse and dependence. Vivitrol addresses the concern of medication adherence as a monthly injectable formulation and this extended formulation has been shown to be more effective than oral naltrexone . This waHealth service programs deliver MAT in a regulatory environment where both the federal government and state/local government provide a regulatory framework for the access to and delivery of medications that are controlled by international convention . In the The MAT federal regulations regulate health service models restricting the dispensing of methadone to OTPs, but allows buprenorphine to be provided in an office base setting by registered and trained physicians. There are no prescribing restrictions for naltrexone and vivitrol, since these medications are not scheduled narcotics with federal controls. Federal regulations that allow the use of MAT in office based settings enhance access to MAT by providing additional venues where patients access pharmacotherapy for opioid dependence. The differing regulations for the use of methadone and buprenorphine in the treatment of opioid dependence result in differing treatment locations and treatment environments. There are a limited number of OTPs in the United States that dispense both methadone and buprenorphine, while there are only three OTPs that dispense exclusively buprenorphine. The highly regulated OTP where methadone is predominately used to treat opioid dependence are considered ‘strict” treatment environments with required daily appearance for medication and mandated urine tests for illicit drug use . Office The treatment environment and range of services provided either in OTPs or in OBOT are important in maintaining patients in care and treatment. Treatment programs that are patient centered, provide a supportive environment and meet the needs of the patient, regardless of the pharmacotherapy used in treatment, result in patients remaining in treatment for longer periods of time. Patients who remain in treatment have better treatment outcomes due to adherence compliance and persistence –47. ThesMedical treatment programs that provide MAT as part of a comprehensive set of services can interface substance abuse treatment services with primary medical care, infectious disease services, and social/rehabilitation services. That interface can be comprehensive through the integration of substance abuse treatment services, primary medical care, infectious disease prevention, care and treatment and social/rehabilitation services. An integrated care and treatment model where MAT services are provided within primary care uses a single medical record minimizes the stigma and discrimination associated with drug treatment services while improving overall health outcomes, particularly for patients with multiple health issues, in a cost-effective manner .For OTPs, methadone dispensing, primary medical care, infectious disease services, and social/rehabilitation services are integrated on-site in the structured environment where methadone is dispensed ,52. BaseBuprenorphine, an opioid agonist medication, is approved and regulated in the United States for OBOT. As noted earlier, an office based setting provides enhanced access to buprenorphine in a primary care environment, where health services can be integrated . MultiplNaltrexone is a non-narcotic and therefore non-controlled medication for the treatment of opioid abuse as well as alcohol abuse. Naltrexone integrated with mental health services, particularly psychosocial treatment has been shown to be an effective maintenance treatment for reducing heroin use after detoxification . In addiMedical service programs can connect substance abuse treatment services with primary medical care and social/rehabilitation services in a non-integrated but coordinated fashion. In these programs, MAT services work with primary medical care and social/rehabilitation services to provide good patient outcomes and enhance community health. MAT, health services and social/rehabilitation services can be separately managed with a different network of health care providers but co-located to allow convenient utilization of primary care, MAT and other services. An additional coordinated approach provides primary care, MAT and other services at distinct locations through differing network of health care providers. A recent study has shown twice as many patients retained in MAT when the MAT services were provided at single location compared to referral of MAT to a distant location . HoweverA unique Induction/Maintenance model for buprenorphine is the model where a substance abuse treatment specialist provides the initial treatment (induction) with buprenorphine until the patient is stabilized. Then the patient is transferred/referred to a primary care physician who then provides maintenance buprenorphine treatment and medical primary care. This so called ‘wheel and spoke model’ allows for substance abuse treatment specialists to manage the more difficult portion of buprenorphine treatment (early treatment –or induction phase) while the primary care medical program manages the long term maintenance phase of buprenorphine treatment . This moCoordinated MAT for patients seeking relapse prevention interventions after detoxification for opioid can be provided by naltrexone or the recently approved longer acting, extended release vivitrol. As noted earlier, naltrexone it is not widely prescribed for the treatment of opioid dependence in the United States, but is provided as an office based treatment for opioid dependence after detoxification. In addition, studies have shown that the extended release formulations are effective in reducing opioid use and retaining patients in care after detoxification ,69.The stages or phase of MAT are shown in The recovery process is the way in which a person actively manages their substance use disorder with efforts to reclaim a full and meaningful life in the community. Recovery is a personal process of growth and change which embraces hope, autonomy and the elements that results in re-establishing a satisfying and productive life. MAT becomes a recovery oriented system of care when its services and integration with other medical, social and rehabilitative services support the individual’s and family’s long term efforts to reclaim full and meaningful lives in the community. Important in recovery is the provision of comprehensive services in the context of MAT but also a supportive, enabling environment that fosters individual responsibility over one’s health and empowerment to change to a healthy lifestyle . PromotiMAT as a recovery orientated system of care has four phases, as shown in The use of pharmacotherapies in the treatment of opioid dependence in the form of medication assisted treatment is an important tool to enhance public health. Integrating the substance abuse treatment services that comprise medication assisted treatment with other medical, social and community services provides the best platform for promoting recovery from opioid dependence.


Medical student attitudes toward psychiatry form the foundation of their future interactions with psychiatric patients and their decision-making process regarding pursuing psychiatry as a career . RelatedN=166, response rate 92%) and fourth-year students . Our students’ attitudes were generally consistent with other studies, revealing a positive view of psychiatry overall. In fact, most (91% either strongly or moderately agreed) students believed that psychiatric research has made good strides in advancing care of the major mental disorders. In addition, most (88% either strongly or moderately) agreed that psychiatric consultation in a clinical setting is fruitful and that treatment is most often helpful to most people who receive it (81%).We looked at medical student attitudes at our own institution, the University of Medicine and Dentistry of New Jersey – New Jersey Medical School. The questionnaire used with permission was designed by Balon et al. and consists of 23 questions assessing the perceived merits of psychiatry, efficacy, role definition and functioning, possible abuse, and career and personal reward (Interestingly, comparisons between first- and fourth-year medical students showed no statistically significant differences in any of the 23 questions compared. These results were in contrast to our expectation to find more significant differences between first- and fourth-year student opinions, particularly since first-year medical students were assessed at the onset of their formal medical education and fourth-year students after completing their core clerkships, including psychiatry. It is possible that by observing relapses and readmissions among patients with chronic psychiatric illnesses, students felt discouraged about the value of psychiatric treatment. Also, it is plausible that the fourth-year students’ impressions of psychiatry were negatively impacted by medical professionals in other specialties – a consideration consistent with a study by Ndetei et al. in Kenya, which found that first years with no exposure to psychiatry had the most positive attitude toward psychiatry compared to other students (These findings led us to consider the role medical education plays in changing the attitudes of students toward psychiatry. Can medical education impact all aspects of student views or are some views reflective of societal opinions against psychiatry, and, therefore, less modifiable by medical school experience? It may be presumed that medical students would be better informed, and thus, less biased than the general populace. However, some authors hypothesize that medical school selection criterion are inherently prejudiced against students interested in psychiatry . StudiesRegardless, it appears that stigma against psychiatry remain despite efforts by educators and advances in the field of psychiatry. Future studies should focus on the full experience of medical school as an influencing factor rather than just the psychiatry clerkship. Also, studies must distinguish between factors that medical schooling can modify versus factors that reflect more deeply ingrained beliefs reflective of societal perceptions. The latter may be addressable by medical school admission policy changes.


Skeletal muscle makes up approximately 40% of the total body mass, providing structural support and enabling the body to maintain posture, to control motor movements and to store energy. It therefore plays a vital role in whole body metabolism. Skeletal muscle displays remarkable plasticity and is able to alter its size, structure and function in response to various stimuli; an essential quality for healthy living across the lifespan. Exercise is an important stimulator of extracellular and intracellular stress signals that promote positive adaptations in skeletal muscle. These adaptations are controlled by changes in gene transcription and protein translation, with many of these molecules identified as potential therapeutic targets to pharmacologically improve muscle quality in patient groups too ill to exercise. MicroRNAs (miRNAs) are recently identified regulators of numerous gene networks and pathways and mainly exert their effect by binding to their target messenger RNAs (mRNAs), resulting in mRNA degradation or preventing protein translation. The role of exercise as a regulatory stimulus of skeletal muscle miRNAs is now starting to be investigated. This review highlights our current understanding of the regulation of skeletal muscle miRNAs with exercise and disease as well as how they may control skeletal muscle health. Maintaining skeletal muscle metabolism, size and contractile function are prerequisites for whole body health throughout life. Skeletal muscle is highly sensitive to extracellular and intracellular signals elicited by contractions from endurance and resistance exercise. These signals are the catalyst for numerous physiological adaptations including enhanced substrate metabolism, mitochondrial biogenesis, angiogenesis, muscle growth and regeneration Hawke, . In contExtracellular and intracellular signals, activated by exercise or disease and inactivity, influence transcriptional and translational regulation of genes encoding proteins that control skeletal muscle metabolism, growth, regeneration and contraction  transcription in the nucleus. The pri-miRNA is cleaved by the RNase-III type endonuclease Drosha associated with Pasha  into a precursor molecule referred to as the pre-miRNA. The pre-miRNA is then exported into the cytoplasm by exportin 5 (XPO5) and cleaved a second time by Dicer  or exposure to microgravity during space flights decreases muscle mass  is the most common and severe form of muscular dystrophy characterized by the absence of the structural membrane protein dystrophin. The muscle-enriched miR-206 is downregulated in in vitro that miR-23a negatively regulates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)  and is associated with a downregulation of the MRTF-SRF axis -let-7 varies slightly from human (has)-let-7b and hsa-let-7e and this difference may be sufficient to confer different mRNA targets for these three miRNAs. Caution must be taken when comparing the expression of miRNAs between different species. MiRNAs have historically been named in the same order as they have been discovered. However, occasional discrepancies exist between species; therefore, a direct comparison between correspondingly named miRNAs cannot always be made. In addition, the mRNAs targeted by a same miRNA can differ between species, although their biological function can be conserved. The function of the let-7 family of miRNAs is similar in both C. elegans and humans. The primary role of the let-7 miRNAs appears to be anti-proliferative, as observed in human cancer cells  and therefore their presence and potential stability in blood (Chen et al., mdx mouse when compared to wild-type controls (Roberts et al., The existence and stability of miRNAs in circulation has led to the search for miRNA biomarkers for various diseases such as cancer, type 2 diabetes, hepatic diseases and coronary diseases (Chen et al., 2max when compared to individuals with high VO2max (Bye et al., Changes in plasma and whole blood miRNA profiles have been observed following acute and chronic exercise and in association with training-induced changes in muscle performance (Baggish et al., An ideal miRNA biomarker candidate for muscle disease or adaptation to exercise should not be expressed by hematopoietic cells but rather be predominantly expressed in the tissue of interest, such as miR-133a (Callis et al., in vivo is now required to significantly advance this exciting field.MiRNAs are positive regulators of myogenesis. Their expression levels change following a single bout of exercise and exercise training and following nutritional interventions. A dysregulation of various miRNAs occurs in myopathies, in chronic diseases associated with muscle atrophy as well as with ageing. These observations suggest that skeletal muscle miRNAs play an important role in muscle adaptation and maladaptation. The identification of circulating miRNAs and their regulation following exercise and in disease suggests that they may be useful biomarkers of health and adaptation to treatment interventions. These observations also imply that miRNAs might be amenable to therapeutic intervention. However, at present we have little knowledge relating to how changes in skeletal muscle or circulating miRNAs influence, either directly or indirectly, changes in skeletal muscle regeneration, size, function, metabolism and consequently whole body health. Establishing the causal roles of skeletal muscle miRNAs The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The concept of “diastolic” heart failure grew out of the                    observation that many patients who have the symptoms and signs of heart failure                    had an apparently normal left ventricular (LV) ejection fraction. Thus it was                    assumed that since systolic function was “preserved” the problem                    must lie in diastole, although it is not clear by whom or when this assumption                    was made. Nevertheless, many guidelines followed on how to diagnose                    “diastolic” heart failure backed up by indicators of diastolic                    dysfunction derived from Doppler echoardiography. Diastolic heart failure is                    associated with a lower annual mortality rate of approximately 8% as compared to                    annual mortality of 19% in heart failure with systolic dysfunction, however,                    morbidity rate can be substantial. Thus, diastolic heart failure is an important                    clinical disorder mainly seen in the elderly patients with hypertensive heart                    disease. Early recognition and appropriate therapy of diastolic dysfunction is                    advisable to prevent further progression to diastolic heart failure and death.                    There is no specific therapy to improve LV diastolic function directly. Medical                    therapy of diastolic dysfunction is often empirical and lacks clear-cut                    pathophysiologic concepts. Nevertheless, there is growing evidence that calcium                    channel blockers, beta-blockers, ACE-inhibitors and ARB as well as nitric oxide                    donors can be beneficial. Treatment of the underlying disease is currently the                    most important therapeutic approach.                             Heart failure is most commonly associated with impaired LV systolic function.                However, as many as 30-40% of all patients with typical symptoms of congestive heart                failure, have a normal or slightly reduced ejection fraction. In these patients,                diastolic dysfunction is implicated as a major contributor, if not the primary cause                of congestive heart failure , 2. The             Primary diastolic dysfunction is typically seen in patients with hypertension and or                restrictive cardiomyopathy but can also occur in a variety of other clinical                disorders and has a particularly high prevalence in the elderly population , 4.                Although diastolic heart failure is common in clinical practice worldwide, its                existence has been questioned for several reasons . Firstly            Doubts regarding diastolic heart failure are cast especially because the diagnosis of                heart failure is partly clinical and prone to error. When the left ventricular                ejection fraction is low the diagnosis of heart failure is seldom                questioned-clinicians seem more willing to accept a diagnosis of systolic heart                failure. Fortunately the advent of biomarkers such as plasma B-type natriuretic                peptides should help confirm the presence of heart failure in patients with                suspected diastolic heart failure.            A second area of controversy is that while investigators may agree that some patients                with heart failure do have a normal ejection fraction, they doubt if the underlying                mechanism is truly left ventricular diastolic dysfunction, as implied by the term                diastolic heart failure. Some of these patients have subtle abnormalities of                systolic function . In some                case series the relations between left ventricular pressure and volume on cardiac                catheterization do not conform to a classical pattern of diastolic dysfunction                    . The evi                            The patho-physiology of diastolic heart failure is characterized by a low cardiac                output that results typically from a ventricle that has thick walls but a small                cavity (increased left ventricular mass/volume ratio) . When th                            The symptoms , signs , and radiographic evidence  of heart failure                (HF) occur with equal frequency in patients with diastolic heart failure when                compared with patients with systolic heart failure . Therefo                                It is now clearly recognized that all patients with HF have abnormalities in both                systolic and diastolic function. However, the coexistence of these functional                abnormalities does not necessarily mean that SHF and DHF are part of a single                continuum. There are significant differences between SHF and DHF that justify their                separation into two different groups.            There is no doubt that a normal EF does not necessarily indicate the presence of                normal myocardial or even ventricular contractility , 16. The                            The diagnosis of diastolic heart failure requires three conditions to be                simultaneously satisfied : 1), Pre            Patients with shortness of breath on exertion, pulmonary rales, or gallop sound but                with near normal systolic function are usually diagnosed with DHF .            Several non-invasive techniques have been used for assessing diastolic function                    in patients with coronary, valvular or myocardial heart disease. The most                    commonly used methods are 2D- and Doppler-echocardiography, Doppler-tissue                    imaging, radionuclide ventriculography, MR myocardial tagging and MR imaging                        .                M-mode echocardiography has been used to assess the dimensional changes and                        its first derivates during diastolic filling. The presence of LV myocardial                        fibers oriented in the longitudinal direction and located in the trabecular,                        subendocardial, and papillary muscle regions has led to an increasing                        interest in echocardiographic assessment of the LV long axis function. As                        displacement of the atrioventricular plane towards the apex is a direct                        reflection of longitudinal fiber contraction, its measurement by M mode                        echocardiography provides additional information regarding global and                        regional systolic and diastolic function. As shown by Henein and Gibson,                        delayed onset of lengthening can effectively suppress early diastolic                        trans-mitral flow, even though the minor axis increases and mitral cusps                        separate normally .                    During the last 2 decades Doppler-echocardiography has emerged as an                        important clinical tool providing reliable and useful data on diastolic                        performance. Three different approaches are routinely used in the assessment                        of diastolic dysfunction: measurement of trans-mitral and pulmonary venous                        flow as well as intra-ventricular filling patterns (Doppler flow                        propagation) .                    The trans-mitral velocity pattern remains the starting point of                        echocardiographic assessment of LV diastolic function; since it is easy to                        acquire and can rapidly categorize patients with normal or abnormal                        diastolic function by E/A ratio (early to late filling velocity) , 21. In                     Color Doppler M-mode provides a unique window into the fluid dynamics of flow                        across the mitral valve. The speed of propagation is enhanced with rapid                        relaxation and LV suction. Clinical and experimental studies have                        demonstrated that the inverse correlation to t is relatively independent of                        left atrial pressure .                           Doppler tissue imaging yields information on intra-myocardial velocity,                        providing a unique insight into LV mechanics during iso-volumic contraction                        and relaxation. In normal persons the mitral annular motion is almost a                        mirror image of the trans-mitral flow pattern, but in patients with pseudo                        normal or restrictive filling pattern, annular motion is abnormally low,                        implying that it is relatively independent of preload , 25.                    It has been shown that relaxation velocities in the myocardium are inversely                        correlated with t, so that a non-invasively calculation of the time constant                        of relaxation seems to be possible , 27. Thr                                                    This technique has been shown to be of considerable use in the morphologic                        assessment of the heart, but functional assessment can also be obtained.                        However, their clinical relevance remains to be demonstrated . Additio                                                    This technique may be used to study the rapid filling phase of diastole, the                        duration of the iso-volumic relaxation phase, the relative contribution of                        rapid filling to total diastolic filling, and the relation between regional                        non-uniformity of left ventricular function and global filling properties                            . However                                                                            Cardiac catheterization with simultaneous pressure and volume measurements is the                    ‘gold’ standard for assessing LV diastolic function.                    Prerequisites are high-fidelity pressure recordings with simultaneous angio- or                    echocardiography or the use of the conductance technique. The rate of LV                    relaxation, rate and timing of diastolic filling as well as myocardial and                    chamber stiffness can be determined .                                                        Despite the large number of individuals suffering from diastolic dysfunction, there                is a paucity of recommendations available to help guide medical therapy in these                patients. The guidelines for the European Society of Hypertension (ESH) only briefly                touch on the subject of diastolic dysfunction and offer no specific recommendations                for its management, commenting that little information is available comparing the                effects of different antihypertensive agents on diastolic dysfunction . The Joi            Diastolic dysfunction may be present for several years before any symptoms occur and                may represent the first phase of diastolic heart failure. Thus, it is important to                detect diastolic dysfunction early and to start treatment before irreversible                structural alterations and systolic dysfunction have occurred.            Four treatment goals have been advocated for the therapy of diastolic dysfunction:                1), Reduction of central blood volume (diuretics); 2), Improvement of LV relaxation                ; 3), Regression of LV hypertrophy                ;                4), Maintenance of atrial contraction and control of heart rate (beta-blockers and                antiarrhythmic).            Diuretics are effective in reducing pulmonary congestion in patients with                    diastolic dysfunction, shifting the pressure-volume relation downwards. However,                    their positive effect on LV chamber stiffness is indirect, caused particularly                    by a reduction in systemic blood volume and the lowering of right atrial blood                    volume with a decrease in pericardial constraint. However, they must be used                    judiciously because the volume sensitivity of patients with diastolic                    dysfunction bears the risk that excessive diuresis results in sudden drop of                    stroke volume . The ste                                        Beta-blockers have long been theorized to provide benefit to patients with                    diastolic dysfunction. By slowing the heart rate to allow more time for LV                    filling and lowering blood pressure to improve LV compliance, beta- blockers can                    improve diastolic function .                                               Calcium channel blockade is thought to improve diastolic function by several                    mechanisms, including attenuating calcium homeostasis, reducing blood pressure,                    promoting LV hypertrophy regression, and slowing the heart rate . Benefit                                        ACE inhibitors and ARB’s show not only an effect on blood pressure but                    elicit a direct effect on the myocardium via the local renin-angiotensin system.                    These effects are essential for the regression of LV hypertrophy, and the                    improvement in the elastic properties of the myocardium , 51. Sev                                        Digitalis should not be used in patients with diastolic dysfunction, except in                    those with atrial fibrillation. When atrial fibrillation occurs, restoration of                    sinus rhythm is mandatory and is best achieved with electric conversion. For                    prophylaxis of recurrence, beta-blockers, especially sotalol, which exerts a                    class III antiarrhythmic effect and amiodarone are the most suitable.


Low neighborhood-level socioeconomic status has been associated with poorer health, reduced physical activity, increased psychological stress, and less neighborhood-based social support. These outcomes are correlates of late life cognition, but few studies have specifically investigated the neighborhood as a unique source of explanatory variance in cognitive aging. This study supplemented baseline cognitive data from the ACTIVE  study with neighborhood-level data to investigate (1) whether neighborhood socioeconomic position (SEP) predicts cognitive level, and if so, whether it differentially predicts performance in general and specific domains of cognition and (2) whether neighborhood SEP predicts differences in response to short-term cognitive intervention for memory, reasoning, or processing speed. Neighborhood SEP positively predicted vocabulary, but did not predict other general or specific measures of cognitive level, and did not predict individual differences in response to cognitive intervention. The neighborhood has emerged as a prominent level of analysis in studies of contextual influences on health and wellbeing in human development. This owes to the social organization of life within neighborhoods, and to the availability of data at neighborhood-like levels of analysis . Neighborhood context has also received greater attention due to ecological psychology's conceptualization of human development as the product of a dynamic interaction between the individual and multiple nested environments, of which the neighborhood is one of the most immediate environments . ContempNeighborhood socioeconomic status (SES) is the most consistently reported neighborhood-level predictor of cognitive outcomes—certainly in childhood, and potentially across the life span . SES is While neighborhood effects on late life cognition have received less attention, neighborhood effects on early-life cognitive development are relatively well documented. Neighborhood SES is positively correlated with cognitive development across the entire spectrum of child development, from the prenatal stages  and Four recent studies explored relationships between late life cognition and the neighborhood context on a broad scale. Wight and colleagues  found thstatus , but did not investigate the effect of neighborhood on different cognitive domains  is a simplistic approach to a complex and dynamic cognitive system ).The specific association of neighborhood SEP with vocabulary suggests neighborhood influences cognition more through sociocultural mechanisms, as vocabulary captures crystallized cognitive abilities, the dimension of cognition related to stored verbal knowledge, developed over a lifetime of engaging with culture . VocabulNeighborhood may influence vocabulary by facilitating or constraining one's capacity for, and influencing the results of, sociocultural engagement in the community. It may do so by providing resources or facilities  encouragWhile vocabulary is related to current neighborhood SEP, it is important to consider that vocabulary is also highly correlated with childhood cognitive level . VocabulFinally, it was reported in the results that there were catchment site-level differences in mean SEP. Clearly, an individual's neighborhood SEP is also part of the general SEP of the region in which that individual lived; the interaction between neighborhood and regional SEP may influence how a neighborhood's SEP relates to cognition. For example, in regions with lower overall SEP, it may be more “normal” to live in a lower-SEP neighborhood; this experience might differ from the experience of living in a low-SEP neighborhood within a high-SEP region, and might differently affect cognition. Such issues have been explored on the level of individual SES-to-neighborhood SES interactions , but neThis study was limited in several ways due to its nature as a secondary analysis. Several covariates would ideally have been included had they been collected in the parent study, including individual-level income and occupation  and the length of time lived at current residence. As a consequence, this study included only a single measure of individual-level socioeconomic status. This is an important limitation, as the observed neighborhood association may be attributable, partially or completely, to unmeasured differences in individual-level socioeconomic status. The possibility that the relationship between vocabulary and neighborhood SEP can be explained by childhood neighborhood SEP must also remain speculation, as this data was not originally collected in ACTIVE. This study therefore was unable to examine measures of childhood socioeconomic status . It is likely that childhood SEP is associated with both vocabulary and late life SEP, in which case vocabulary's relationship with current neighborhood SEP would be expected to diminish or disappear if childhood SEP was accounted for in the study. The cross-sectional nature of effects also limits discussion to relationships among variables at a particular time rather than to causal or temporal relationships between variables. Longitudinal assessment of these relationships is an important next step that will be attempted in future studies. At the time this study was conducted, ACTIVE collected its 10th annual follow-up testing occasion, allowing examination of the interaction between 2000 neighborhood and cognition with 2010 neighborhood and cognition. Future studies will also attempt to examine (a) neighborhood effects on change trajectories, and (b) whether there were neighborhood moves for participants, and whether such moves were associated with functional changes. Furthermore, at this follow-up data was collected documenting participant's county of primary schooling. National historical data will allow investigators to use county information to explore whether and how distal environmental influences  might predict contextual neighborhood characteristics and cognitive outcomes later in life. This paper adds to the body of research examining neighborhood-cognition associations in late life, and extends previous findings by looking beyond general cognition or cognitive status to examine effects of neighborhood across specific cognitive domains. The finding that neighborhood SEP predicts crystallized cognitive abilities  suggests that neighborhood effects may be most related to sociocultural influences on cognitive development. There was a lack of association between neighborhood SEP and fluid cognitive abilities, as well as between neighborhood SEP and immediate cognitive change following training. As discussed above, future research should investigate how associations between early life neighborhood context and cognitive development may influence cognitive function and neighborhood selection in late life.