Idiosyncratic Events Research Articles

Variance partitioning of deconstructed periphyton communities: does the use of biological traits matter?

The use of species traits offers a promising approach to the understanding of the main processes underlying metacommunity patterns. We analyzed samples of periphytic algae in 30 environments of the Upper Parana River floodplain in southeastern Brazil, to test the hypotheses that variation in species composition of algal groups with low dispersal abilities would be mainly explained by spatial variables; on the other hand, algal groups with higher dispersal abilities would be better explained by environmental variables. The variation in community structure was mainly correlated with environmental variables. This result is in line with a growing body of evidence indicating a predominant role of species-sorting processes. The more-refined prediction that the spatial variables would gradually become more important across a gradient of adherence or size was, however, not supported by our analyses. Also, the large unexplained variation suggested that these periphytic communities were assembled by idiosyncratic events, or that other variables that are often neglected in studies of aquatic metacommunities needed to be included.

Mechanisms of Innovation in the Space and Defense Sector

Despite a rich legacy of space sector technological achievements, agencies are increasingly being criticized for their inability to deliver on their innovative promises. Although the phenomenon of innovation has received substantial attention across multiple disciplines, it has largely focused on relatively simple products in nearly competitive markets, making its applicability to the space system context suspect. This paper reviews the economic, political science/strategic, business and operational literatures most relevant to complex product innovation in government markets. It categorizes their insights in terms of the sources of innovation as – external political-level leadership, internal bureaucratic politics, structure of the system, new technologies and user innovations – to illustrate the overlap and gaps among the disciplinary insights. It argues that past studies have over emphasized innovations that were generated by idiosyncratic events and have not adequately addressed the architectural dimension of complex product innovation. If useful prescriptions are to be developed, the process of normal complex product innovation in monopsony markets must be examined as a whole. To this end, the paper suggests several priorities for future work.

The Generation, Detection, and Effects of Reactive Drug Metabolites

The decline in approval of new drugs during the past decade has led to a close analysis of the drug discovery process. One of the main reasons for attrition is preclinical toxicity, frequently attributed to the generation of protein-reactive drug metabolites. In this review, we present a critique of such reactive metabolites and evaluate the evidence linking them to observed toxic effects. Methodology for the characterization of reactive metabolites has advanced greatly in recent years, and is summarized first. Next, we consider the inhibition of key metabolic enzymes by electrophilic metabolites, as well as unfavorable drug-drug interactions that may ensue. One important class of protein-reactive metabolites, not linked conclusively to a toxic event, is acyl glucuronides. Their properties are discussed in light of the safety characteristics of carboxylic acid containing drugs. Many adverse drug reactions (ADRs) are known collectively as idiosyncratic events, that is, not predictable from knowledge of the pharmacology and pharmacokinetics of the parent compound. Observed ADRs may take various forms. Specific organ injury, particularly of the liver, is the most direct: we examine this in some detail. Moving to the cellular level, we also consider the upregulation of induced cellular processes. The related, but distinct, issue of hypersensitivity or allergic reactions to drugs and their metabolites, possibly via the immune system, is considered next. Finally, we discuss the impact of such data on the drug discovery process, both through early detection of reactive metabolites and informed synthetic design, which eliminates unfavorable functionality from drug candidates.

Safety and Tolerability of Antiepileptic Drug Treatment in Children with Epilepsy

The aim of treating epilepsy is to control or at least decrease seizures without producing unacceptable adverse effects that impair quality of life. Antiepileptic drugs (AEDs) have been considered amongst the drugs most frequently associated with fatal suspected adverse drug reactions. Physicians must therefore be as familiar with safety and tolerability data of AEDs as they are with the expected therapeutic effects. AEDs may cause dose-related adverse effects (i.e. drowsiness, fatigue, dizziness, blurry vision and incoordination) that, in most cases, may be obviated by lowering the dosage, reducing the number of drugs or switching to a better tolerated AED. AEDs also have the potential of precipitating idiosyncratic adverse effects (i.e. serious cutaneous, haematological and hepatic events), which are more common in children and usually require withdrawal of the AED. Although occurrence of idiosyncratic adverse effects can only rarely be predicted or prevented, there are known risk factors that can help in identifying patients at high risk. Occurrence of an idiosyncratic event in a close relative, a concomitant autoimmune disease, co-treatment with specific drugs, history of a previous allergic drug reaction, starting treatment with high doses and rapid titration have all been associated with a higher risk of idiosyncratic adverse effects. New AEDs have been developed in the last two decades with the aim of improving the benefit-risk balance of AED therapy. Available evidence suggests that the newer AEDs are no more effective but may be somewhat better tolerated than older molecules. We performed a literature review with the aim of evaluating safety and tolerability of second- and third-generation AEDs in children. A PubMed search was conducted with the purpose of identifying English-language studies published between 1 January 1989 and 1 January 2011 that reported any adverse event having occurred in children with epilepsy in whom second- and third-generation AEDs were administered.

Abstract 1743: Phase 1 clinical trial of the base-excision repair inhibitor Methoxyamine-HCl (TRC102; MX) in combination with Temozolomide (TMZ) in patients with solid tumors

Abstract Background: MX is the first base excision repair (BER) inhibitor evaluated in humans. MX blocks the BER pathway by covalently binding to apurinic/pymidinic (AP) sites in DNA. In several preclinical studies, improved therapeutic efficacy has been demonstrated with various chemotherapeutic agents. Final results of the phase I clinical trial of pemetrexed and oral MX have been published (GJ Weiss et al). Initial results and correlative studies of the alkylating agent TMZ and MX were previously presented (AACR Annual Meeting 2009, abstract#5433). As initial PK analyses on patient samples revealed a distinct and prolonged half life in humans, 10-fold greater than estimated in dogs, this report reflects the protocol amendment from MX administration as a 5-day intravenous continuous infusion to a 1-hour intravenous infusion. Methods: This phase I dose-escalation trial investigates the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile of MX given as an one-hour intravenous infusion in combination with daily times 5 TMZ. PD markers, including analysis of abasic sites measured on DNA extracted from patients’ mononuclear cells (PBMCs) as well as DNA strand breaks determined by comet assay at multiple time points over 5-days. Results: 23 patients have enrolled, at dose-levels (DL) 1 and 2 (TMZ 150 mg/m2/day, days 1-5 and MX 15 mg/m2 and 30 mg/m2 respectively) in two cohorts. In cohort A (patients with no-CNS disease, n =13 at DL1 and n=4 at DL2) primary tumors include lung, breast, pancreatic, colon, esophageal, ovarian, oropharyngeal, salivary gland, skin adnexal tumors. In cohort B (patients with CNS tumors, n =3 at DL1 and n=3 at DL2) primary tumors include brain, pancreatic, head and neck.The combination of MX and TMZ has been well-tolerated. For the non-CNS involvement cohort, one DLT was observed at DL1; grade 3 psychosis in a patient with progressive disease on increasing doses of opioids. A grade 3 allergic reaction classified as an idiosyncratic event resulted in further expansion to 10 evaluable patients with no additional DLTs observed. To date no DLTs have been observed at DL2 and in the CNS-involved cohort. Three patients had stable disease (lung, ovarian, head and neck) with extended dosing periods of 7, 10 and 11 months. The PK results will be presented separately. In all patients evaluated, abasic sites were blocked by MX resulting in an increase in DNA strand breaks. No significant anemia (the DLT observed in the MX and pemetrexed trial) has been observed at DL1 and 2 to date; possibly because of lower MX dose administered.Conclusions: MX has a distinct PK profile in humans, which has allowed us to move to a convenient one-hour infusion regimen. Ongoing data in this phase I clinical trial demonstrate that the combination of MX with TMZ is well tolerated and hits its target, interrupting base excision repair in all patients. Trial remains open to accrual. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1743. doi:1538-7445.AM2012-1743

The Limits of Electoral and Legislative Reform in Addressing Polarization

Professor Richard Pildes provides a very thorough and persuasive overview of the key arguments about the causes of partisan polarization in the United States. I am especially sympathetic to his argument that deep macro historical factors such as the partisan alignment of the South—rather than idiosyncratic events, elections, and personalities—bare the primary blame. But I remain quite skeptical that a political-reform agenda such as the one he outlines will go very far in ameliorating partisan conflicts. Given that the forces that produce polarized politics are deeply embedded in the American political system, opening primaries, eliminating gerrymandering, reforming Congress, and regulating campaign finance are unlikely to provide much relief. Each of the reforms proposed by Professor Pildes may have many salutary effects, but political science research casts much doubt about their ability to reduce polarization or ameliorate its consequences. Before responding to the specifics of Professor Pildes's excellent Article, let me briefly introduce some of the sources of evidence on which this Essay is based. This evidence is displayed in Figure 1, which contains a pair of time

Amoxicillin-induced aseptic meningoencephalitis

Meningitis is usually produced by an infectious agent, but there are multiple noninfectious causes. Drug-induced aseptic meningitis (DIAM) is an important entity and has been reported as an uncommon adverse reaction with numerous agents. Thus, DIAM constitutes a diagnostic and patient management challenge. We present a patient with three episodes of aseptic meningitis due to amoxicillin, and then review the literature on this rare idiosyncratic event which may occur after local or systemic drug administration. A 77-year-old man was admitted to our hospital with fever, headache, and neck stiffness. Seven days before admission he had a dental and gingival inflammation. He was treated with two oral doses of 500 mg daily of amoxicillin for one week. The seventh day he awoke with the complaints that prompted hospital admittance. Amoxicillin was stopped 1 day before his admission. From his history we knew of two similar episodes: The first episode was after a dental procedure 3 months before this incident. He had received a 1-week course of postprocedure amoxicillin of 500 mg daily and had similar headache, fever, and chills during the entire course of treatment. He wasn't admitted to the hospital, because he stopped taking amoxicillin and he felt spontaneous pain relief after taking symptomatic pain treatment. The second episodes was 6 months after his first admission, he had been admitted to our hospital with the same symptoms. Amoxicillin was stopped and changed with intravenous (IV) ceftriaxone (CTRX) for 10 days due to suspected partial untreated meningitis. The patient improved rapidly within 2 days and was discharged from the hospital. On the basis of these three confirmed episodes of meningitis after recurrent exposure to amoxicillin, with repetitive negative testing for viral, bacterial, and mycobacterial micro-organisms, we diagnosed aseptic meningitis induced by amoxicillin. To our knowledge, this is the seventh well documented publication of such a severe side effect of a commonly used antibiotic.

Modelling the default risk in large credit portfolios

We propose a reduced-form model for credit risk in a multivariate setting. The default intensities are linear combinations of three independent affine jump-diffusion processes representing the intensities of general, sectoral and idiosyncratic credit events. The model can be efficiently calibrated to term structures of default probabilities and conditional probabilities of default given the occurrence of common credit events. We analyse the correlation of defaults and formulate an algorithm for the exact simulation of default scenarios.

No Evidence of Renal Toxicity in Either Male or Female Subjects After Oral Sodium Phosphate Purgative Prior to Colonoscopy: A Randomized, Prospective Study

Background and Aims: Oral sodium phosphate solution (OSPS) is an effective agent for preparing the bowel prior to colonoscopy (C) examination. However, rare cases of nephrocalcinosis have been associated with the use of OSPS. Of the 21 cases reported in a retrospective series by Markowitz et al (J A Soc Nephrol 2005; 16: 3389) and of the 5 cases reported by Ori et al (A J Med Sci 2008; 336: 309), 80% were female. Thus gender may be a risk factor for phosphate induced nephropathy. However, there have been no randomized, prospective studies carried out to study this issue. Methods: Female (F) and male (M) subjects requiring C were randomized to receive either OSPS or PEG for bowel preparation. OSPS (Fleets PhosphoSoda) was given in 2 doses of 45 ml each, the day prior to C and on the morning of procedure. Adequate hydration was stressed. 240 ml of PEG (Colyte) was given every 10 minutes until 4L were ingested the night prior to C. Renal toxicity was assessed by measuring serum creatinine (Cr, mg/dL), GFR, (ml/min) and spot urine NAG (IU/mg cr) (N-acetyl-D-glucosamine is a urinary enzyme which increases after renal tubular injury) one week prior to, on the day of and one week after C. The efficacy of the bowel preparation was assessed using the Ottawa Score (OS, 0-14), the time to reach cecum and the number of polyps detected. Results: Twenty F and 40 M subjects completed the study. The mean age of F and M subjects was 52 ± 9 y and 54 ± 6 y, respectively. Of the 60 subjects, 42 received OSPS (14 F+ 28 M) and 18 received PEG (6 F+ 12 M). Administration of OSPS did not cause any significant difference in the % change in Cr (-7.2%, + 2.2%, P= 0.7 in F and M, respectively), % change in eGFR (+1%, +12%, P=0.12 in F and M, respectively) and urinary excretion of NAG (+2%, -7%, P=0.7 in F and M, respectively) when compared to baseline. Additionally, these parameters were not altered 1 week post C. Similarly, administration of the PEG did not make a significant difference in % change in either Cr or eGFR or urinary NAG excretion in either M or F subjects when compared to baseline. Bowel cleansing with both OSPS and PEG produced acceptable preparations (OS < 3 irrespective of gender). Furthermore, the time to reach the cecum (PEG 14 ± 3 min, OSPS 18 ± 4 min) and the number of polyps removed were not statistically different irrespective of the bowel preparations employed in both gender groups. Conclusion: In this prospective, randomized study, there was no clinically significant renal toxicity when comparing M and F subjects regardless of the type of C preparation. The present study, however, was not powered to detect idiosyncratic events of renal toxicity.

Widespread resistance of Mediterranean island ecosystems to the establishment of three alien species

ABSTRACTAlthough some invasive plants are cosmopolitan, not all ecosystems are invaded to the same degree. Yet there is little experimental work on how ecosystem resistance to invasion at the establishment phase differs among ecosystems. We conducted two field sowing experiments in two consecutive years to examine establishment of the deciduous tree Ailanthus altissima, the succulent subshrub Carpobrotus spp. and the annual geophyte Oxalis pes‐caprae in coastal dunes, shrublands and oldfields in more than 200 sites across six Mediterranean Basin islands differing in climatic conditions and local species richness.Establishment success (i.e. percentage of plots with at least one seedling) and rates (i.e. seedling to sown seed ratio) were low, especially for Ailanthus even when accounting for differences in seed viability. Oxalis was capable of producing a new cohort of seedlings the year following planting. By contrast, all Ailanthus seedlings and half the Carpobrotus seedlings died following the first summer. Differences in establishment success and rates among ecosystems were species‐, island‐ and year‐dependent.Differences in precipitation and mean temperature were associated with differences in establishment rates across sites. Establishment rates tended to be positively correlated with cumulative precipitation and negatively with mean Ta. Unexpectedly, native species richness was not a good predictor of seedling establishment, except for higher Oxalis establishment success in species rich habitats.By conducting field sowing tests at multiple sites across a region we found that except for Oxalis, Mediterranean island ecosystems are quite resistant to invader establishment. These results suggest that differences in the degree of invasion between ecosystems and islands might be more dependent upon the influence of invasion event factors (e.g. propagule pressure) or factors acting at a later life‐history stages rather than differences in the resistance imposed by ecosystems to invader recruitment. Moreover, our results support the notion that in Mediterranean ecosystems invasions are highly idiosyncratic events and strongly dependent on water availability conditions.

How to Tell a Life: The Development of the Cultural Concept of Biography

Extending research on age norms in adults, the development of the knowledge of two components of the cultural concept of biography, biographical salience of and age norms for life events was studied from late childhood to early adulthood in Study 1 and across adulthood in Study 2. The largest increase in knowledge was found between ages 8 and 12, with knowledge reaching its maximum at age 16. Across adulthood knowledge was relatively stable, with a small decline in older adults. In addition, across adolescence, personal memories increasingly corresponded to norms of biographical salience, although idiosyncratic events continued to dominate. The acquisition of knowledge of the cultural concept of biography may parallel developments in autobiographical memory, reminiscing, and life narratives.

How to Tell a Life: The Development of the Cultural Concept of Biography

Extending research on age norms in adults, the development of the knowledge of two components of the cultural concept of biography, biographical salience of and age norms for life events was studied from late childhood to early adulthood in Study 1 and across adulthood in Study 2. The largest increase in knowledge was found between ages 8 and 12, with knowledge reaching its maximum at age 16. Across adulthood knowledge was relatively stable, with a small decline in older adults. In addition, across adolescence, personal memories increasingly corresponded to norms of biographical salience, although idiosyncratic events continued to dominate. The acquisition of knowledge of the cultural concept of biography may parallel developments in autobiographical memory, reminiscing, and life narratives.

Use of Repeated Measures to Interpret Genetic and Environmental Correlations in Animal Research

A method for partitioning environmental correlations into two distinct sources of covariation--lifetime rearing effects and idiosyncratic stimulus events occurring during testing ("noise")--is presented. The method, which is based on structural equation modeling of repeated tests, is demonstrated using correlations obtained from pairs of sessions in an Open Field Test and in a Light-Dark Test. Heritabilities of most behaviors are low, but genetic correlations between- and within-test sessions are high and thus substantively influence phenotypic correlations, including test-retest reliability. Testing "noise" is usually the primary source of environmental covariance among pairs of measures, although some instances of rearing environment being the sole source of E correlations were observed. Effects of Session 1 testing and/or the additional experience between S1 and S2 test sessions produce some significant differences between S1 and S2 within-session correlations, but these are usually not large. Although varying in size, the genetic, the rearing environment and the test environment correlations between a pair of variables were always consistent in sign. The analysis demonstrates the value of incorporating some of the contemporary research and analytic strategies used in the human individual differences field into animal studies.

A Price of Total Risk for Managing against a Benchmark

A new model for capital budgeting is derived from a manager's optimizing behavior that, unlike the capital asset pricing model (CAPM), prices total risk. Manager risk preferences are characterized by a constraint on the probability of ruin, otherwise known as a Value-at-Risk or Telser constraint. More generally, the manager picks a floor value to the firm or fund, which may be stochastic, and his maximum tolerable probability that the floor value is breached. Subject to this constraint, he maximizes the firm's expected value. The manager uses his reservation price of risk, which is a contract's expected payoff or its expected payoff given that the firm's value equals the floor. This price is applicable to continuous distributions with well-defined expectations and conditional expectations, and the model has a simple pricing formula like the CAPM that reduces to the security market line equation as a special case. However the model differs significantly from the CAPM in eight other ways. For example, a manager using this model need not be classifiable as variance averse; and the model can be used with distributions that have infinite variances. Also unlike models that price only systematic risk, this model does not imply that some significant markets for insurance policies on idiosyncratic events should not exist. Models that price only systematic risk assign risk-neutral prices to policies with idiosyncratic payouts, so unless buying insurance lowers net expected losses, these models imply that markets for policies on idiosyncratic events should not exist.

Voluntary Regional Councils and the New Regionalism

This article compares the opposite fates of two voluntary regional councils in similar substate regions of Michigan and evaluates their effectiveness as planning mechanisms of the new regionalism. Organizational development strategies and consensus building drove the survival and partial success of one council but reduced its policy effectiveness. A climate of mistrust emanating from virulent localism and idiosyncratic events undercut the other council’s organizational capacity and policy effectiveness and led to its demise. Implications of these cases as “weak” examples of new regionalism are discussed.

Informational Contagion of Sudden Stops in a Global Games Framework

This paper highlights the cross-country spread of self-fulfilling financial crises through an informational channel. It sets up a two-country framework of investment with strategic complementarities and incomplete information about economic fundamentals. Each market may be subject to sudden stops, triggered by agents preemptively withdrawing their investments for fear others do so. After observing a massive capital outflow from one country, agents downgrade common fundamentals, and therefore have higher requirements regarding factors specific to the other country. This in turn may induce a crisis in the latter, which is not justified by idiosyncratic events or economic interdependence.

Testable implications of consumption-based asset pricing models with incomplete markets

This paper studies the testable implications of consumption-based asset pricing models with incomplete markets when idiosyncratic income shocks are permanent. It is shown that the theory places no testable restrictions (beyond absence of arbitrage) on either the macroeconomic data or the first N moments of the cross-sectional distribution of consumption growth even if the one-period utility function (degree of risk aversion) is known. More precisely, this paper shows that any “observed” joint process of aggregate consumption, arbitrage-free asset returns, and N moments of the cross-sectional distribution of consumption growth is an equilibrium outcome for some pure discount factor and some process of individual income. The proof is based on the construction of a personal-disaster process (process of extreme idiosyncratic events) which allows for arbitrary variations in idiosyncratic risk without affecting the first N moments of the cross-sectional distribution of consumption growth.

Asset Returns in an Endogenous Growth Model with Incomplete Markets

This paper studies the testable implications of consumption-based asset pricing models with incomplete markets when idiosyncratic income shocks are permanent and not lognormally distributed. It is shown that the theory places no testable restrictions (beyond absence of arbitrage) on either the macroeconomic data or the first N moments of the cross-sectional distribution of consumption (income) growth. More precisely, this paper shows that any observed joint process of aggregate consumption, arbitrage-free asset returns, and N moments of the cross-sectional distribution of consumption growth is an equilibrium outcome for some incomplete-markets economy (some pure discount factor and process of individual income). The proof is based on the construction of a personal-disaster process (process of extreme idiosyncratic events) which allows for arbitrary variations in idiosyncratic risk without affecting the first N moments of the cross-sectional distribution of consumption growth.

Lithium revisited.

To review lithium's utility in the treatment of mood disorders. We reviewed the safety, tolerability, teratogenicity, optimal dosing regimens, and mortality-lowering effects of lithium. Clinical relevance and scientific rigour determined which articles we selected for review. Lithium is the paradigmatic treatment for bipolar disorder (BD). In treating BD, optimal maintenance plasma levels may be approximately 0.75 to 0.85 mEq/L. Although nephrogenic diabetes insipidus is not uncommon, irreversible renal failure due to lithium appears to be a rare, idiosyncratic event. Lithium-induced cardiovascular teratology appears to be less common than previously thought. Optimal lithium dosing may be once daily, this agent appears to bestow a robust suicide-lowering effect, and emerging data hint at neurotrophic and neuroprotective effects. Lithium remains an effective and integral agent in the treatment of BD. Its ability to lower suicide rates in persons with BD warrants clinical attention.

Firm Size, Innovation, and Market Share Instability: the Role of Negative Feedback and Idiosyncratic Events

An evolutionary model is built which uses structural and random factors to account for the emergence of market share instability and industry concentration. The structural factors are studied through the relationship between firm size and innovation (dynamic returns to scale) while the random factors are studied through the effect of shocks on this feedback relationship. We find that market share instability is the highest under the negative feedback regime, when the industry specific level of technological opportunity is intermediate, and when shocks are neither very large nor very small.