Mark Corson

By M. Sinikar. Golden Gate University. 2018.

In addition buy famciclovir 250mg with mastercard, our method employs an exhaustive approach to analyze the structural features of ligands discount famciclovir 250mg with amex. Frequent substructure mining considers all possible substructures that occur in the ligands and is therefore unbiased generic 250 mg famciclovir with visa, i. However, in the present study less ‘obvious’ substructures such as ethyl or isobutyl are also considered [Chapter 3; ref 21]. For a complete discussion on substructure generation and evaluation, see chapter 2 or ref. For instance, it can be applied to the realm of enzymes to complement other 47 chemogenomics analyses. Targets were analyzed based on the substructure profiles of their ligands using an unbiased approach. The overall organization of the sequence tree and the substructure tree was similar; however, substantial differences were also discovered. Thus, receptor similarities that signal for potential off-target effects, such as for the serotonergic receptors, are readily identified. A reported affinity in one of these source databases classifies a compound as active, independent of the reported binding affinity. Ligands are annotated with an activity type, namely: full agonist, partial agonist, agonist, antagonist or inverse agonist. In the present study, we focused only on binding affinity and not on the activity type. For the same reason, we removed two singleton targets (targets that are the only member in a subfamily), the gonadotrophin-releasing hormone receptor and the ghrelin receptor. This was accomplished by using the frequent subgraph-mining 54 23 algorithm, which finds all frequent substructures in a set of molecular graphs. For a description and a quantitative comparison of recent substructure mining algorithms, 55 see. Briefly, starting from the smallest substructure, namely the single atoms, the algorithm finds the number of molecules in which the substructure occurs. If this occurrence is above a user-defined minimum, the minimum support value, the substructure is stored. Stored substructures are stepwise extended, and tested in a systematic manner, with the aim of testing all possible substructures that have at least one of the stored substructures as their basis. The algorithm seeks ways to test only those substructures that actually occur in the set, and that have a frequency above the set minimum. An important concept of frequent substructure mining is the a priori 56 principle, originating from frequent item set mining. Algorithms based on the a priori principle exploit that the frequency of a substructure will be equal or lower than the frequency of the substructures it contains. Structures were represented as labeled graphs with a special type for aromatic bonds. In this study, the minimum support value was set to 30% of the number of ligands in each activity set. At this value, the algorithm provided a large group of substructures while still being computationally feasible to work with. In addition, molecular structures were sorted in ascending order according to the number of bonds. This allowed the algorithm to prune scarce, complicated substructures that consisted of a large number of bonds, thereby reducing memory requirements. If the set of generated substructures is disproportionately large (more than 1000 times larger) compared to the majority of the other classes, the generated substructures are discarded except for those that also occur in other classes. This step was performed in order to prevent single targets from dominating the analysis. Since in practice most classes generated sets of less than 1000 substructures, a cut-off of 1M substructures was used. The frequent substructures of all classes were merged into one set, removing any duplicates. For all substructures in this set, the frequency in each subfamily was determined. To calculate the correlation between two targets, we used the substructure frequencies as features for that target. A correlation matrix was constructed by calculating the Pearson correlation coefficient for each pair of targets. Finally, a distance matrix was constructed by subtracting the values of the correlation matrix from unity and normalizing the results linearly to the interval [0;1]. Phylogenetic trees built from distance matrices facilitate tree comparison across domains. The number of branches between two leaves in the tree grows with dissimilarity of these two leaves. Both the sequence-based and ligand-based phylogenetic trees were constructed using the neighbor. Tree construction might be influenced by the order in which targets are provided to the tree constructor. To minimize the influence on the resulting phylogenetic tree, target input order was randomized 10 times and 10 new trees were generated. Trees were rooted on the mid-points, that is, a root is placed at the mid- point of the longest distance between two taxa of the unrooted tree.

Resistance to conversion probably can be increased through insuring that the individual remains well informed and understands his own opinions and attitudes sufficiently well to express them clearly discount famciclovir 250 mg without prescription. Future Research Directions A number of limiting factors make generalizations from laboratory situations to life difficult buy discount famciclovir 250mg on line. Real Life Situations Laboratory situations are relatively bland as far as involvement is concerned generic 250mg famciclovir otc, at least in comparision with lifelike settings where the personal stakes connected with conformity, compliance, and conversion are higher. Because of the limited investment a laboratory situation usually evokes in an individual, direct or absolute comparisons between results obtained in it and actual life settings are likely to be treacherous. There is a need for the type of research that provides the experimenter with the opportunity to control and manipulate variables under realistic operating circumstances. Current knowledge of relevant variables should make it possible to design experiments for lifelike settings with a minimum of trial and error. Significant Issues Many of the experiments reviewed in this study have employed tasks requiring adjustments of individuals under conformity or conversion conditions that are extremely artificial. As a result, conformity or resistance may develop under conditions that bear little resemblance -268- to actual situations. Future laboratory investigations can benefit from employing tasks that arouse deeper personal commitment and stronger group loyalties. Empiricism and Intuition Even a cursory examination of the principal reports summarized here shows that much of the work in this area has been designed according to empirical understanding, intuition, and "hunch. Such theoretical statements can serve to bring order to an otherwise chaotic field of endeavor. Single Variable Designs Results from more recent experiments give substantial support to the view that conformity, compliance, and conversion are complex matters of adjustment that occur when a host of circumstances, rather than a single factor, are favorable. Critical factors include the nature of the task, the circumstances of the situation within which the behavior occurs, and the characteristics of the individual on whom pressures are exerted. Each possible source of influence needs to be varied simultaneously within the design of a single experiment, if we are to obtain a more nearly accurate picture of the dynamics of conformity. In terms of present understanding, it can be stated that the interaction of sources of influence is not additive, but that true interaction among variables occurs. Replication experiments are needed to insure that conclusions from single studies will stand. Conversion Over 90 per cent of work in this area has been concerned with conformity, yet the conditions under which changes induced by conformity -269- pressures extend into future behavior are of critical concern. For the most part, they represent an extension of the conditions already used in studying conformity to secure measurements of the residual effects of conformity pressures. Great progress in the understanding of both conformity and conversion phenomena may be expected from investigations designed to measure the persistence of conversion over time. Group discussion, decision, public commitment, and perceived unanimity as factors in the effectiveness of "group decision. An experimental investigation of the effectiveness of the "big lie" in shifting attitudes. Screening tests, lie scales, observational and interview procedures have all been devised with the primary intent of unmasking the potentially or actually disturbed individual who masquerades behind a front of defensiveness and superficial social conformity. Murphy (65) has written an excellent history of malingering and has shown that the problem of simulation has been present since Early Greek and Biblical times. Although the simulation of psychosis or of epilepsy has a long history, more attention has been given in the past to the feigning of diseases of single organs, and the development of laboratory techniques which would differentiate the sick from the well. The malingerer, on his part, has shown amazing resourcefulness in keeping abreast of the literature and in devising counter counter-measures. The simulation of mental illness by captured prisoners of war is a potential, and perhaps effective, technique for evading interrogation. In almost all cultures, the mentally ill person cannot be held accountable for his actions, is considered incompetent, and is not -277- expected to give a rational account of himself, his past, or his environment. The prisoner of war, faced with coercive interrogation, and reluctant to betray his country and friends, might choose this as an honorable alternative which favors self-preservation. Certainly this has become more frequent among persons charged with serious crimes in courts of law. This chapter is not concerned with the moral or ethical aspects of this problem, but rather is directed toward understanding how malingering may become a factor in situations involving the interrogation of a resistant source by a captor. Because of the focus of interest, it seems feasible to limit the scope of this chapter to the feigning of those illnesses which would render the person mentally incompetent. Although a person may malinger a paralysis of the arms or legs, blindness, or a low back pain, none of these symptoms would make it impossible for him to testify or reveal information. However, psychosis, mental deficiency, or amnesia would more than likely lead an interrogator or examiner to the conclusion that the person is not a reliable source of information who can be expected to report events accurately and realistically. Thus, the primary aim of this behavior is evasion rather than the financial gain which is often the motivation for simulating physical disease. More specifically, it is an evasion of responsibility, the responsibility for past acts or for future acts, as related to the giving of information. In this chapter, then, malingering refers to the planned and deliberate simulation of mental symptoms for the purpose of evading responsibility. The bulk of it is impressionistic and subjective, and at times there is more disagreement than agreement among the writers. Much of the polemics revolve around issues such as the moral reprehensibility of malingering; whether or not the malingerer is, by definition, an emotionally disturbed person; the differentiation of malingering from the Ganser syndrome; whether or not the Ganser syndrome is an hysterical or psychotic reaction; and the difficulties of detecting malingering. For the most part, it appears that those who are optimistic about detecting malingering might do well to share some of the pessimism of their colleagues.

Nayyar and colleagues used the same criteria to categorize samples from sub-Saharan African countries (Nayyar et al purchase famciclovir 250mg on line. Forty-fve percent of the studies reported active ingredient test results buy 250 mg famciclovir with visa, fnding that 121 (15 percent) had low active ingredient and 3 percent had excessive active ingre- dient (Nayyar et al cheap famciclovir 250mg online. Only one study reported packaging analysis, and it found 36 percent failure (Nayyar et al. Nayyar and colleagues had fewer African samples (n = 389) from which to calculate the percentage of falsifed drugs; they found 20 percent falsifed (see Table 3-7) (Nayyar et al. A consistent problem with all convenience surveys of drug quality is that they tend to sample heavily from the formal market: licensed phar- macies and dispensaries. Results of these studies will likely underestimate the burden of falsifed and substandard drugs in places where much of the population buys essential medicines in unregulated bazaars. Sampling from these vendors is diffcult, but a convenience sample of informal and private medicine sellers in Guyana and Surinam found 58 percent of the antimalarial samples from Guyana and all the samples from Surinam to be falsifed or substandard (Evans et al. In a Burkina Faso study, Tipke and colleagues compared antimalarial drug quality in licit and illicit vendors. They found that 90 percent of samples from street vendors and open markets were substandard, and only 10 percent of samples from legal vendors were substandard (Tipke et al. This section presents the results of a few population-based random surveys of drug quality. Kaur and colleagues analyzed antimalarial quality in drugs drawn from a systematic, random sample of a range of Tanzanian retail outlets, including drug stores, general stores, street hawkers, and medicine kiosks Copyright © National Academy of Sciences. Investigators stratifed districts according to their par- ticipation in a national bed net program, chose districts at random from among the strata, and then surveyed 30 percent of wards in each study district (Kaur et al. They divided wards into major and nonmajor trading centers and drew half the samples from each type of market (Kaur et al. Between May and September 2005, investigators collected 1,080 samples from 2,474 vendors, one from each store that had them in stock on the day of the study visit (Kaur et al. After excluding 166 expired samples and 32 with no labeled expiry date, investigators had 882 samples, from which they systematically chose 301 for chemical analysis (Kaur et al. Taylor and colleagues collected 581 drugs from 35 randomly selected registered pharmacies in urban Nigeria (Taylor et al. They found 42 percent of antimalarials, 41 percent of antibacterials, and 54 percent of antituberculosis drugs outside of British Pharmacopoeia limits (Taylor et al. A stratifed random sample of medicine shops and licensed pharmacies in Laos found 90 percent of artesunate samples failed quality testing (Sengaloundeth et al. Researchers in southeast Nigeria attempted to include unlicensed private medicine dealers in their sample of antimalarial drug quality (Onwujekwe et al. They collected samples of a range of antimalari- als from patent medicine dealers, pharmacies, public and private hospitals, and primary health care centers (Onwujekwe et al. Pharmacopeia specifcations, by either not containing the active ingredient listed or containing it in low doses (Onwujekwe et al. Among the failed samples, 60 percent came from low-level shops, mostly the patent-medicine shops (Onwujekwe et al. Though most epidemiologically rigorous research on drug quality has tested antimicrobial drugs, there is some information about other essential medicines. In a 2012 study, Stanton and colleagues prepared an exhaus- tive sampling frame of formal and informal drug sellers in three districts in Ghana (Stanton et al. They chose 75 vendors at random from the sampling frame, from which patient actors collected 101 samples of ergometrine and oxytocin, the thermally unstable, uterotonic drugs used to treat postpartum hemorrhage (Stanton et al. A total of 89 percent of samples failed pharmacopeial testing; none of the ergometrine samples and only 26 percent of oxytocin samples met pharmacopeial specifcations (Stanton et al. All oxytocin samples (n = 46) were from unregistered manufacturers, though 18 were from manufacturers with registration pend- ing; 69 percent of ergometrine samples (n = 38) came from unregistered manufacturers, though 11 were from manufacturers with registration pend- ing (Stanton et al. A Need for More Field Surveys The best estimates of the scope of the drug supply affected come from systematic, random sampling and testing of medicines drawn from a rep- Copyright © National Academy of Sciences. The expense of required assays, discussed further in Chapter 6, is one barrier, but a large part of the problem is logistical. The frst step in drawing a systematic random sample of drugs is identifying the sampling frame, the list of every drug vendor in a given area. In developed coun- tries, registered pharmacies and dispensaries are the only place most of the population gets medicine. In low- and middle-income countries, however, there is often an extensive pharmaceutical gray market. Identifying all the vendors is diffcult and can be further complicated by the blurry lines be- tween licit and illicit commerce (Seear et al. Health workers may supplement their incomes by selling medicine informally (Peters and Bloom, 2012); peddlers may trade medicines occasionally, along with any number of dry goods, at bazaars and fea markets. Without formative research to catalogue the sampling frame, research on medicines quality is vulnerable to bias. Samples should be bought by patient actors, local study staff posing as shoppers who conceal from the vendor that they are working on an epidemiological investigation. Without taking steps to protect study validity, the researchers risk wast- ing time and money on a study that does not produce reliable estimates. For example, in 2009 the Indian government conducted a massive survey of drug quality across the country, estimating that only 0. Questions about the methodological rigor of the survey, particularly the choice of sampling frame and methods for sample collection, have called these results into question both within India and internationally (Bate, 2009, 2010; Pandeya, 2009). The committee supports the guidelines on feld surveys of medicine quality that Newton and colleagues proposed in March 2009 (Newton et al. They provide a standard protocol for collecting medicines samples and concrete advice on sampling techniques (Newton et al. More research adhering to the checklist in Table 3-8 would allow for a better understanding of the burden of falsifed and substandard drugs, and it would facilitate valid comparisons of the problem among countries and over time.