Recurrent Events Models

Benign paroxysmal vertigo of childhood (BPV) is a paroxysmal, non-epileptic, recurrent event characterized by subjective or objective vertigo that occurs in neurologically intact children. We recorded the history and the clinical aspects of 19 cases presenting with neurological problems to the outpatient clinic at the Pediatrics Department of Padova University between 1987 and 1998 and re-examined in 1999. Details were collected on the characteristics of their vertigo: age at onset, mode of onset, trigger factors, duration, frequency and recurrence of episodes, duration of symptoms in time and age at disappearance. An attempt was also made to establish any family history of migraine and kinetosis and the most important data were compared, when possible, with those reported in the literature. Differential diagnosis and pathogenetic hypothesis were also reported. It is worth emphasizing that it is important for pediatricians to be aware of these benign events to ensure a correct diagnostic approach, avoiding the child and family any pointless anxiety or costly and sometimes invasive diagnostic procedures. q

Introduction: Various psychosocial studies on health related lifestyles lay emphasis on the fact that the
perception one has of himself as being at risk of HIV/AIDS infection was a necessary condition for preventive
behaviors to be adopted. Hierarchical Multiple Regression models was used to examine the relationship between
eight independent variables and one dependent variable to isolate predictors which have significant influence on
behavior and sexual practices.
Methods: A Cross-sectional design was used for the study. Structured close-ended interviewer-administered
questionnaire was used to collect primary data. Multistage stratified technique was used to sample views from
380 students from Takoradi Polytechnic, Ghana. A Hierarchical multiple regression model was used to ascertain
the significance of certain predictors of sexual behavior and practices.
Results: The variables that were extracted from the multiple regression were; for the constant;  =14.202,
t=2.279, p=0.023, variable is significant; for the marital status;  =0.092, t=1.996, p<0.05, variable is
significant; for the knowledge on AIDs;  = 0.090, t=1.996, p<0.05, variable is significant; for the attitude
towards HIV/AIDs;  =0.486, t=10.575, p<0.001, variable is highly significant. Thus, the best fitting model for
predicting behavior and sexual practices was a linear combination of the constant, one’s marital status,
knowledge on HIV/AIDs and Attitude towards HIV/AIDs.,
0 1 2
3
( ) ( ) ( / )
( / ).
Y Behavior and sexual practices Marital status Knowledge on HIV AIDs issues
Attitude towards HIV AIDs issues
  

  

β0, β1, β2 and β3 are respectively 14.201, 2.038, 0.148 and 0.486; the higher the better.
Conclusions: Attitude and behavior change education on HIV/AIDs should be intensified in the institution so
that students could adopt better lifestyles.
Keywords: attitudes, hierarchical regressions, knowledge, sex education, sexual practices

Introduction: Various psychosocial studies on health related lifestyles lay emphasis on the fact that the perception one has of himself as being at risk of HIV/AIDS infection was a necessary condition for preventive behaviors to be adopted. Hierarchical Multiple Regression models was used to examine the relationship between eight independent variables and one dependent variable to isolate predictors which have significant influence on behavior and sexual practices.

In studies of recurrent events, such as epileptic seizures, there can be a large amount of information about a cohort over a period of time, but current methods for these data are often unable to utilize all of the available information. The paper considers data which include posttreatment survival times for individuals experiencing recurring events, as well as a measure of the base-line event rate, in the form of a pre-randomization event count. Standard survival analysis may treat this pre-randomization count as a covariate, but the paper proposes a parametric joint model based on an underlying Poisson process, which will give a more precise estimate of the treatment effect.

COX&#x27;S REGRESSION MODEL 1101 intensity given by (1.1), ie we include the possibility of the event considered being recurrent, but not more than one event may happen at a given time. We have had several motivations for undertaking this study. First of all, much effort has been ...

In many biomedical studies, subjects may experience the outcome of interest more than once over a period of observation; outcomes of this sort have been termed recurrent events. A model that is becoming increasingly popular for modeling association between recurrent survival times is the use of a frailty model. In recent years a number of papers appeared, extending the survival models to models that are suitable to handle more complex survival data as recurrent events. We present here frailty model extensions to analyze recurrent events data: cure frailty models for a mixture of susceptible and insusceptible subjects for the event of interest; nested frailty models when data are clustered at several hierarchical levels and joint frailty models for the joint analysis of recurrent events and death. We performed a semi-parametric penalized likelihood approach to estimate the different parameters. Those different models can be fitted using the R package ''frailtypack''.

Recurrent falls are usually defined as two or more falls in a 12-month period (1). Given their high prevalence and incidence in older adults as well as their serious consequences, recurrent falls are a major public health issue (1-6). Around 25% of adults aged over 75 years suffer at least two falls a year (1, 3, 4, 7-10). Recurrent falls usually occur during basic activities of daily living such as walking and body transfer positions from sit-to-stand or stand-to-sit positions (5-8). Compared to single fall, recurrent falls lead to more injuries, hospitalizations and nursing home admissions, which impose high costs on public health and social services (1-10). These fall-related consequences are in part explained by underlying comorbidities and age-related decline. This context can turn a simple fall into a milestone that will accelerate loss of independence, and may result in death.

Frailty models are very useful for analysing correlated survival data, when observations are clustered into groups or for recurrent events. The aim of this article is to present the new version of an R package called frailtypack. This package allows to fit Cox models and four types of frailty models (shared, nested, joint, additive) that could be useful for several issues within biomedical research. It is well adapted to the analysis of recurrent events such as cancer relapses and/or terminal events (death or lost to follow-up). The approach uses maximum penalized likelihood estimation. Right-censored or left-truncated data are considered. It also allows stratification and time-dependent covariates during analysis.

Correlated survival outcomes occur quite frequently in the biomedical research. Available software is limited, particularly if we wish to obtain smoothed estimate of the baseline hazard function in the context of random effects model for correlated data.

Hasta la década de los años ochenta, los estudios de supervivencia se habían realizado consideran-do sólo una única ocurrencia del evento por unidad de estudio. Hoy en día, estos modelos son conocidos como modelos clásicos; entre los más conocidos, se encuentran: el modelo actuarial de Cutler-Ederer[1], el

We propose a general class of semiparametric transformation models with random effects to formulate the effects of possibly time-dependent covari- ates on clustered or correlated failure times. This class encompasses all commonly used transformation models, including proportional hazards and proportional odds models, and it accommodates a variety of random-effects distributions, particularly Gaussian distributions. We show that the nonparametric maximum likelihood

SUMMARY The observation of repeated events for subjects in cohort studies could be terminated by loss to follow- up, end of study, or a major failure event such as death. In this context, the major failure event could be correlated with recurrent events, and the usual assumption of noninformative censoring of the recurrent event process by death, required by most

In survival analysis a large literature using frailty models, or models with unobserved heterogeneity, exist. In the growing literate on multiple spell multiple states duration models, or multistate models, modeling this issue is only at its infant phase. Ignoring unobserved heteogeneity can, however, produce incorrect results. This paper presents how unobserved heterogeneity can be incorporated into multistate models, with an emphasis on semi-Markov multistate models with a mixed proportional hazard structure. First, the aspects of frailty modeling in univariate (proportional hazard, Cox) duration models are addressed and some important models with unobserved heterogeneity are discussed. Second, the domain is extended to modeling of parallel/clustered multivariate duration data with unobserved heterogeneity. The implications of choosing shared or correlated unobserved heterogeneity is highlighted. The relevant differences with recurrent events data is covered next. They include the...

The impact of Varroa destructor Anderson & Trueman (Mesostigmata: Varroidae) on colonies of Apis mellifera L. (Hymenoptera: Apidae) in southern Louisiana was evaluated by analyzing changes in swarming and longevity of colonies for 17 yr. Swarming rates were calculated from yearly captures of swarms in bait hives placed in Þve areas of Louisiana from 1991 to 2006. Colony longevity was monitored in 104 swarms established from 1990 to 2000 and followed until 2004. In the Þrst years, before V. destructor, average swarm capture rates ranged from 0.85 to 0.95 swarms per bait hive-year, and survival of colonies established from swarms averaged 14 mo. In years immediately after the arrival of V. destructor (1993Ð1996), swarming rates and colony longevity decreased to 0.36 Ð 0.60 swarms per bait hive-year and 10 mo, respectively. After Ϸ5 yr in the presence of V. destructor, both rates recovered to levels at least as high as those seen before varroa arrived; swarm capture rates were 0.75Ð1.04 swarms per bait hive-year and average longevity was 26 mo. Analysis of varroa infestations in three colonies established from swarms in 1997 showed the presence of varroa at oscillating densities for 5 to 8 yr. Possible causes for this apparent recovery are natural selection for resistance in honey bees, introgression of selected resistant genetic material or reduced virulence of the mites.

Background: Antiretroviral treatment (ART) has been effective in reducing HIV/AIDS related morbidity and mortality. However, the use and uptake of ART has resulted in adverse reactions, due mainly to the medicine's toxicity and interactions with other medicines. The timing of adverse drug reactions (ADRs) among these patients is a critical public health issue for antiretroviral (ARV) treatment adherence and retention. Reliable monitoring of HIV patients on ART is through a structured pharmacovigilance surveillance system. However, recurrent nature of these data pose challenges in their analyses. This study aimed at modelling the timing of ADR events in HIV patients on ART using correlated time-to-event models.

Background-Limited data describe the cardiovascular benefit of HMG-CoA reductase inhibitors (statins) in people with moderate chronic kidney disease (CKD). The objective of this analysis was to determine whether pravastatin reduced the incidence of cardiovascular events in people with or at high risk for coronary disease and with concomitant moderate CKD. Methods and Results-We analyzed data from the Pravastatin Pooling Project (PPP), a subject-level database combining results from 3 randomized trials of pravastatin (40 mg daily) versus placebo. Of 19 700 subjects, 4491 (22.8%) had moderate CKD, defined by an estimated glomerular filtration rate of 30 to 59.99 mL/min per 1.73 m 2 body surface area. The primary outcome was time to myocardial infarction, coronary death, or percutaneous/surgical coronary revascularization. Moderate CKD was independently associated with an increased risk of the primary outcome (adjusted HR 1.26, 95% CI 1.07 to 1.49) compared with those with normal renal function. Among the 4491 subjects with moderate CKD, pravastatin significantly reduced the incidence of the primary outcome (HR 0.77, 95% CI 0.68 to 0.86), similar to the effect of pravastatin on the primary outcome in subjects with normal kidney function (HR 0.78, 95% CI 0.65 to 0.94). Pravastatin also appeared to reduce the total mortality rate in those with moderate CKD (adjusted HR 0.86, 95% CI 0.74 to 1.00, Pϭ0.045). Conclusions-Pravastatin reduces cardiovascular event rates in people with or at risk for coronary disease and concomitant moderate CKD, many of whom have serum creatinine levels within the normal range. Given the high risk associated with CKD, the absolute benefit that resulted from use of pravastatin was greater than in those with normal renal function.

Despite significant advances in the management of coronary heart disease, myocardial infarction (MI) is still associated with a mortality rate of 45%. Acetylsalicylic acid (ASA) has been the oral antiplatelet drug of choice until recently. Thienopyridines such as clopidogrel have been shown to provide significant benefits in the management of acute coronary syndromes (ACS), either as an alternative to or in combination with ASA therapy. The purpose of this article was to review the available scientific literature evaluating the use of clopidogrel in the management of ACS. Relevant published data were identified through searches of the English-language literature indexed on MEDLINE and International Pharmaceutical Abstracts through April 2003. Search terms included thienopyridines, platelet aggregation inhibitors, clopidogrel, ticlopidine, acute coronary syndrome, myocardial infarction, and percutaneous coronary intervention. Pertinent conference abstracts were also included. The results of 3 large clinical trials-Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), Effect of Pretreatment with Clopidogrel and Aspirin Followed by Long-Term Therapy in Patients Undergoing Percutaneous Coronary Intervention (PCI-CURE), and Clopidogrel for the Reduction of Events During Observation (CREDO)-support prolonged use of clopidogrel (up to 12 months) in combination with ASA in patients with non-ST-segment elevation MI and patients undergoing a percutaneous coronary intervention (PCI). A significant increase in bleeding events was observed in the group that received clopidogrel plus ASA compared with ASA alone in the CURE (major bleeding, P = 0.001; minor bleeding, P &amp;amp;amp;amp;amp;lt; 0.001) and PCI-CURE (minor bleeding, P = 0.03) trials. Use of the combination of clopidogrel and ASA with other antiplatelet and/or anticoagulant agents has not been studied extensively. Use of the combination of clopidogrel and ASA for up to 9 months is recommended for the medical management of non-ST-segment elevation MI and after a PCI. The increased risk of bleeding must be taken into account, and use of this combination with other agents that affect bleeding risk should be considered carefully.

Introduction: Various psychosocial studies on health related lifestyles lay emphasis on the fact that the perception one has of himself as being at risk of HIV/AIDS infection was a necessary condition for preventive behaviors to be adopted. Hierarchical Multiple Regression models was used to examine the relationship between eight independent variables and one dependent variable to isolate predictors which have significant influence on behavior and sexual practices. Methods: A Cross-sectional design was used for the study. Structured close-ended interviewer-administered questionnaire was used to collect primary data. Multistage stratified technique was used to sample views from 380 students from Takoradi Polytechnic, Ghana. A Hierarchical multiple regression model was used to ascertain the significance of certain predictors of sexual behavior and practices. Results: The variables that were extracted from the multiple regression were; for the constant;  =14.202, t=2.279, p=0.023, variable is significant; for the marital status;  =0.092, t=1.996, p<0.05, variable is significant; for the knowledge on AIDs;  = 0.090, t=1.996, p<0.05, variable is significant; for the attitude towards HIV/AIDs;  =0.486, t=10.575, p<0.001, variable is highly significant. Thus, the best fitting model for predicting behavior and sexual practices was a linear combination of the constant, one's marital status, knowledge on HIV/AIDs and Attitude towards HIV/AIDs., Y Behavior and sexual practices Marital status Knowledge on HIV AIDs issues Attitude towards HIV AIDs issues         β 0 , β 1 , β 2 and β 3 are respectively 14.201, 2.038, 0.148 and 0.486; the higher the better. Conclusions: Attitude and behavior change education on HIV/AIDs should be intensified in the institution so that students could adopt better lifestyles.

This paper presents an exposition and synthesis of the theory and some applications of the so-called "indirect" method of inference. These ideas have been exploited in the field of econometrics, but less so in other fields such as biostatistics and epidemiology. In the indirect method, statistical inference is based on an intermediate statistic, which typically follows an asymptotic normal distribution, but is not necessarily a consistent estimator of the parameter of interest. This intermediate statistic can be a naive estimator based on a convenient but misspecified model, a sample moment, or a solution to an estimating equation. We review a procedure of indirect inference based on generalized method of moments, which involves adjusting the naive estimator to be consistent and asymptotically normal. The objective function of this procedure is shown to be interpretable as an 'indirect likelihood' based on the intermediate statistic. Many properties of the ordinary likelihood function can be extended to this indirect likelihood. This method is often more convenient computationally than maximum likelihood estimation when handling such model complexities as random effects and measurement error, for example; and it can also serve as a basis for robust inference and model selection, with less stringent assumptions on the data generating mechanism. Many familiar estimation techniques can be viewed as examples of this approach. We describe applications to measurement error, omitted covariates, and recurrent events. A data set concerning prevention of mammary tumors in rats is analyzed using a Poisson regression model with overdispersion. A second data set from an epidemiological study is analyzed using a logistic regression model with mismeasured covariates. A third data set of exam scores is used to illustrate robust covariance selection in graphical models.

I'hc effects of fire on forest structure and composition were studied in a severely firc-impacted landscape in the eastern Amazon. Extensive sampling of area forests was used to compare structure and compositional differences between burned and unburned forest stands.

In temporal networks, both the topology of the underlying network and the timings of interaction events can be crucial in determining how some dynamic process mediated by the network unfolds. We have explored the limiting case of the speed of spreading in the SI model, set up such that an event between an infectious and susceptible individual always transmits the infection. The speed of this process sets an upper bound for the speed of any dynamic process that is mediated through the interaction events of the network. With the help of temporal networks derived from large-scale time-stamped data on mobile phone calls, we extend earlier results that point out the slowing-down effects of burstiness and temporal inhomogeneities. In such networks, links are not permanently active, but dynamic processes are mediated by recurrent events taking place on the links at specific points in time. We perform a multi-scale analysis and pinpoint the importance of the timings of event sequences on individual links, their correlations with neighboring sequences, and the temporal pathways taken by the networkscale spreading process. This is achieved by studying empirically and analytically different characteristic relay times of links, relevant to the respective scales, and a set of temporal reference models that allow for removing selected time-domain correlations one by one.

Recognizing non-recurrent events in short-term traffic flow evolution is of ultimate importance in advanced transportation systems. The present paper proposes a methodological framework for the recognition and prediction of complex and irregular traffic flow patterns; an advanced nonlinear analysis is conducted in order to recognize patterns with respect to the statistical characteristics of their evolution. Following, patterns are predicted using a genetically-optimized probabilistic neural network. Results indicate the existence of three basic types of temporal patterns: (a) stable, (b) unstable, (c) non-recurrent (unique). Moreover, the developed probabilistic network provides accurate one-step ahead pattern predictions. The proposed model infers knowledge on the occurrence of patterns and transitions and can be a significant source of information in order to improve on short-term predictability of traffic flow.

The use of wireless location technology and mobile phone data appears to offer a broad range of new opportunities for sophisticated applications in traffic management and monitoring, particularly in the field of incident management. Indeed, due to the high market penetration of mobile phones, it allows the use of very detailed spatial data at lower costs than traditional data collection techniques. Albeit recent, the literature in the field is wide-ranging, although not adequately structured. The aim of this paper is to provide a systematic overview of the main studies and projects addressing the use of data derived from mobile phone networks to obtain location and traffic estimations of individuals, as a starting point for further research on incident and traffic management. The advantages and limitations of the process of retrieving location information and transportation parameters from cellular phones are also highlighted. The issues are presented by providing a description of the current background and data types retrievable from the GSM network. In addition to a literature review, the main findings on the so-called Current City project are presented. This is a test system in Amsterdam (The Netherlands) for the extraction of mobile phone data and for the analysis of the spatial network activity patterns. The main purpose of this project is to provide a full picture of the mobility and area consequences of an incident in near real time to create situation awareness. The first results from this project on how telecom data can be utilized for understanding individual presence and mobility in regular situations and during nonrecurrent events where regular flows of people are disrupted by an incident are presented. Furthermore, various interesting studies and projects carried out so far in the field are analyzed, leading to the identification of important research issues related to the use of mobile phone data in transportation applications. Relevant issues concern, on the one hand, factors that influence accuracy, reliability, data quality and techniques used for validation, and on the other hand, the specific role of private mobile companies and transportation agencies.

Abnormalities of 16q are important recurrent events in multiple myeloma (MM). We performed FISH on CD138 selected plasma cells from 701 newly diagnosed MM patients from the LRF UKMF cytogenetics database. Gene mapping, including paired normal controls, and gene expression analysis was performed on 55 cases using the Affymetrix Human Mapping 500K Array Set and U133 Plus 2.0 Arrays respectively. 16q deletion (del16q) was identified by FISH using probes for cMAF (Abbott Diagnostics) in 131/701 cases (18.7%) and was significantly associated with deletion 17p (16.5% vs. 8.9%, p=0.006), deletion 13 (60.8% vs. 48.5%, p=0.009), deletion of IgH (22.1% vs. 11.1%, p=0.0003) and non-hyperdiploid status (58.3% vs. 42.7%, p=0.006). Del16q showed a trend to poor overall survival, mean survival 43 vs. 61 months (p=0.09), and was associated with significantly worse survival in combination with t(4;14) compared with either t(4;14) or del16q alone, mean survival 15 vs. 26 vs. 45 months respectively (p=0.006). t(14;16) was identified by FISH in 31/701 cases (4.4%) and was associated with poor prognosis, mean survival 29 vs. 54 months (p=0.005). Mapping arrays revealed loss of heterozygosity (LOH) involving all or part of 16q in 20 of 55 cases (36%) in 3 distinct patterns: uniparental disomy (UPD) of chromosome 16 or 16q in 4/55 cases (7%); deletion of chromosome 16 or the whole of 16q in 11/55 cases (20%); and interstitial deletion of small regions of 16q in 5/55 cases (10%), focused on 16q12, the location of CYLD, and 16q23, the location of WWOX. 16q LOH was distributed across translocation groups but was identified in all 4 mapping cases containing 17p deletion, supporting the association identified by FISH. As WWOX is the site of the common fragile site FRA16D and deletions at common fragile sites have been associated with DNA instability in human cancers, we assessed this using gene mapping in these 55 MM cases. Although deletions spanning other common fragile sites were identified, they were not restricted to those with 16q LOH. However, in 2 t(14;16) cases, hemizygous deletions of approximately 100kb could be identified within WWOX at the presumed translocation breakpoint. One of the t(14;16) cases had a similar hemizygous deletion within FHIT, another tumor suppressor gene located within common fragile site FRA3B, consistent with findings in other cancer types. Cases with 16q LOH or t(14;16) all had significantly reduced WWOX expression relative to cases without 16q abnormalities, confirming gene inactivation by either LOH or translocation. Cases with 16q LOH also had significantly reduced expression of two other potential tumor suppressor genes located on 16q, CYLD and RBL2. In summary, our data confirms the adverse prognosis associated with 16q translocation or deletion. Array data reveals 16q LOH occurs due to deletion or UPD with two regions involved, one defined by CYLD and the other by WWOX. WWOX is also inactivated by translocation and is associated with interstitial deletions at this and other common fragile sites. WWOX is a likely candidate gene in MM pathogenesis because of its interaction with TP53 and CYLD via its effects on NF-B.

The impact of Varroa destructor Anderson & Trueman (Mesostigmata: Varroidae) on colonies of Apis mellifera L. (Hymenoptera: Apidae) in southern Louisiana was evaluated by analyzing changes in swarming and longevity of colonies for 17 yr. Swarming rates were calculated from yearly captures of swarms in bait hives placed in Þve areas of Louisiana from 1991 to 2006. Colony longevity was monitored in 104 swarms established from 1990 to 2000 and followed until 2004. In the Þrst years, before V. destructor, average swarm capture rates ranged from 0.85 to 0.95 swarms per bait hive-year, and survival of colonies established from swarms averaged 14 mo. In years immediately after the arrival of V. destructor (1993Ð1996), swarming rates and colony longevity decreased to 0.36 Ð 0.60 swarms per bait hive-year and 10 mo, respectively. After Ϸ5 yr in the presence of V. destructor, both rates recovered to levels at least as high as those seen before varroa arrived; swarm capture rates were 0.75Ð1.04 swarms per bait hive-year and average longevity was 26 mo. Analysis of varroa infestations in three colonies established from swarms in 1997 showed the presence of varroa at oscillating densities for 5 to 8 yr. Possible causes for this apparent recovery are natural selection for resistance in honey bees, introgression of selected resistant genetic material or reduced virulence of the mites.

Frailty models are very useful for analysing correlated survival data, when observations are clustered into groups or for recurrent events. The aim of this article is to present the new version of an R package called frailtypack. This package allows to fit Cox models and four types of frailty models (shared, nested, joint, additive) that could be useful for several issues within biomedical research. It is well adapted to the analysis of recurrent events such as cancer relapses and/or terminal events (death or lost to follow-up). The approach uses maximum penalized likelihood estimation. Right-censored or left-truncated data are considered. It also allows stratification and time-dependent covariates during analysis.

Background and Purpose-The goal of this study was to document the long-term outcome of ischemic stroke patients in a population with predominant intracranial atherosclerosis and risk factors for a recurrent event. Methods-Intracranial and extracranial arteries of consecutive patients with acute ischemic stroke were studied prospectively with transcranial Doppler and duplex ultrasound. All patients were followed up regularly for the development of recurrent stroke, cardiac event, or death. Results-We included 705 patients with acute ischemic stroke, of whom 345 were documented ultrasonographically as having large-artery lesions. The follow-up period was up to 42 months (mean, 28Ϯ5 months). One hundred seventeen patients (17%) died of any cause, and 199 (28%) suffered further cerebrovascular cardiac events. The 3.5-year cumulative mortality rate was 20.8%; for cerebrovascular event, it was 29.5%. The annual recurrent stroke rates during the first year were 10.9% for patients without vascular lesion, 17.1% for intracranial atherosclerosis only, and 24.3% for both intracranial and extracranial atherosclerosis; for the second year, the rates were 7.5%, 8.6%, and 7.7%, respectively. More occurrence of death (log rank, 5.19; Pϭ0.02) or cerebrovascular event (log rank, 9.68; Pϭ0.002) was found among patients with than those without vascular lesions. Patients with both intracranial and extracranial arterial lesions were at highest risk of death (log rank, 9.64; Pϭ0.008) and cerebrovascular event (log rank, 11.56; Pϭ0.003).

Background-Limited data describe the cardiovascular benefit of HMG-CoA reductase inhibitors (statins) in people with moderate chronic kidney disease (CKD). The objective of this analysis was to determine whether pravastatin reduced the incidence of cardiovascular events in people with or at high risk for coronary disease and with concomitant moderate CKD. Methods and Results-We analyzed data from the Pravastatin Pooling Project (PPP), a subject-level database combining results from 3 randomized trials of pravastatin (40 mg daily) versus placebo. Of 19 700 subjects, 4491 (22.8%) had moderate CKD, defined by an estimated glomerular filtration rate of 30 to 59.99 mL/min per 1.73 m 2 body surface area. The primary outcome was time to myocardial infarction, coronary death, or percutaneous/surgical coronary revascularization. Moderate CKD was independently associated with an increased risk of the primary outcome (adjusted HR 1.26, 95% CI 1.07 to 1.49) compared with those with normal renal function. Among the 4491 subjects with moderate CKD, pravastatin significantly reduced the incidence of the primary outcome (HR 0.77, 95% CI 0.68 to 0.86), similar to the effect of pravastatin on the primary outcome in subjects with normal kidney function (HR 0.78, 95% CI 0.65 to 0.94). Pravastatin also appeared to reduce the total mortality rate in those with moderate CKD (adjusted HR 0.86, 95% CI 0.74 to 1.00, Pϭ0.045). Conclusions-Pravastatin reduces cardiovascular event rates in people with or at risk for coronary disease and concomitant moderate CKD, many of whom have serum creatinine levels within the normal range. Given the high risk associated with CKD, the absolute benefit that resulted from use of pravastatin was greater than in those with normal renal function.

Background: In medical research, one common competing risks situation is the study of different types of events, such as disease recurrence and death. We focused on that situation but considered death under two aspects: "expected death" and "excess death", the latter could be directly or indirectly associated with the disease.

We analyzed the benefit of a 600-mg clopidogrel loading dose on platelet reactivity and clinical outcomes after stenting for non-ST-segment elevation acute coronary syndrome (NSTE ACS). BACKGROUND High post-treatment platelet reactivity (HPPR ϭ adenosine diphosphate 10 mol · l Ϫ1

Background-Although intravenous glycoprotein IIb/IIIa inhibitors are beneficial in patients with acute coronary syndromes, prolonged oral IIb/IIIa inhibition might provide an additional reduction in recurrent events. Methods and Results-Investigators at 888 hospitals in 29 countries enrolled 10 288 patients with acute coronary syndromes, which was defined as ischemic pain at rest within 72 hours of randomization, associated with positive cardiac markers, electrocardiographic changes, or prior cardiovascular disease. Patients received aspirin and were randomized to receive, for the duration of the trial, (1) 50 mg of orbofiban twice daily (50/50 group), (2) 50 mg of orbofiban twice daily for 30 days followed by 30 mg of orbofiban twice daily (50/30 group), or (3) a placebo. The primary composite end point was death, myocardial infarction, recurrent ischemia requiring rehospitalization, urgent revascularization, or stroke. The trial was terminated prematurely because of an unexpected increase in 30-day mortality in the 50/30 orbofiban group. Mortality through 10 months was 3.7% for the placebo group versus 5.1% in the 50/30 group (Pϭ0.008) and 4.5% in the 50/50 group (Pϭ0.11). There were no differences in the primary end point (22.9%, 23.1%, and 22.8%, for the placebo, 50/30, and 50/50 groups, respectively). Major or severe bleeding (but not intracranial hemorrhage) was higher with orbofiban; it occurred in 2.0%, 3.7% (Pϭ0.0004), and 4.5% (PϽ0.0001) of patients, respectively. Exploratory subgroup analyses found that patients who underwent percutaneous coronary intervention had a lower mortality and a significant reduction in the composite end point (Pϭ0.001) with orbofiban. Conclusions-Fixed-dose orbofiban failed to reduce major cardiovascular events and was associated with increased mortality in this broad population of patients with acute coronary syndromes; however, a benefit was observed among patients who underwent percutaneous coronary intervention. (Circulation. 2000;102:149-156.)

Tako-Tsubo cardiomyopathy (TTC) which is usually precipitated by profound emotional stress has been widely reported in the past. Recently, several co-morbidities have been found to be associated with this new cardiac entity. In this case we report from a female patient suffering from both, physical and emotional stress. After a persistent episode of severe abdominal pain due to acute cholecystitis and recurrent events of emotional stress, characteristic features of TTC could be documented. Histopathological analysis documented characteristic structural alterations including contraction band necrosis. Thus, this case confirms the hypothesis of an overstimulated sympthatoadrenergic system in TTC resulting from both, severe physical and emotional stress.

Background: In the setting of recurrent events, research studies commonly count only the first occurrence of an outcome in a subject. However this approach does not correctly reflect the natural history of the disease. The objective is to jointly identify prognostic factors associated with locoregional recurrences (LRR), contralateral breast cancer, distant metastases (DM), other primary cancer than breast and breast cancer death and to evaluate the correlation between these events. Methods: Patients (n = 919) with a primary invasive breast cancer and treated in a cancer center in South-Western France with breast-conserving surgery from 1990 to 1994 and followed up to January 2006 were included. Several types of non-independent events could be observed for the same patient: a LRR, a contralateral breast cancer, DM, other primary cancer than breast and breast cancer death. Data were analyzed separately and together using a random-effects survival model. Results: LRR represent the most frequent type of first failure (14.6%). The risk of any event is higher for young women (less than 40 years old) and in the first 10 years of follow-up after the surgery. In the combined analysis histological tumor size, grade, number of positive nodes, progesterone receptor status and treatment combination are prognostic factors of any event. The results show a significant dependence between these events with a successively increasing risk of a new event after the first and second event. The risk of developing a new failure is greatly increased (RR = 4.25; 95%CI: 2.51-7.21) after developing a LRR, but also after developing DM (RR = 3.94; 95% CI: 2.23-6.96) as compared to patients who did not develop a first event. Conclusion: We illustrated that the random effects survival model is a more satisfactory method to evaluate the natural history of a disease with multiple type of events.

This study sought to evaluate the long-term cost effectiveness of a clopidogrel loading strategy before percutaneous coronary intervention (PCI) followed by continued treatment for one year. BACKGROUND The Clopidogrel for the Reduction of Events During Observation (CREDO) trial, a randomized trial of 2,116 patients, showed the effectiveness of antiplatelet therapy with clopidogrel 300 mg before PCI and 75 mg daily for one year afterward compared with placebo load and placebo days 29 to 365 in reducing the combined risk of death, myocardial infarction, and stroke. All patients received clopidogrel on days 1 to 28 and aspirin on days 1 to 365.

Repeated events processes are ubiquitous across a great range of important health, medical, and public policy applications, but models for these processes have serious limitations. Alternative estimators often produce di erent inferences concerning treatment e ects due to bias and ine ciency. We recommend a robust strategy for the estimation of e ects in medical treatments, social conditions, individual behaviours, and public policy programs in repeated events survival models under three common conditions: heterogeneity across individuals, dependence across the number of events, and both heterogeneity and event dependence. We compare several models for analysing recurrent event data that exhibit both heterogeneity and event dependence. The conditional frailty model best accounts for the various conditions of heterogeneity and event dependence by using a frailty term, stratiÿcation, and gap time formulation of the risk set. We examine the performance of recurrent event models that are commonly used in applied work using Monte Carlo simulations, and apply the ÿndings to data on chronic granulomatous disease and cystic ÿbrosis.

van Balkom AJLM. Predictors of course in obsessivecompulsive disorder: logistic regression versus Cox regression for recurrent events. Objective: Two methods for predicting remissions in obsessivecompulsive disorder (OCD) treatment are evaluated. Y-BOCS measurements of 88 patients with a primary OCD (DSM-III-R) diagnosis were performed over a 16-week treatment period, and during three follow-ups. Method: Remission at any measurement was defined as a Y-BOCS score lower than thirteen combined with a reduction of seven points when compared with baseline. Logistic regression models were compared with a Cox regression for recurrent events model. Results: Logistic regression yielded different models at different evaluation times. The recurrent events model remained stable when fewer measurements were used. Higher baseline levels of neuroticism and more severe OCD symptoms were associated with a lower chance of remission, early age of onset and more depressive symptoms with a higher chance. Conclusion: Choice of outcome time affects logistic regression prediction models. Recurrent events analysis uses all information on remissions and relapses. Short-and long-term predictors for OCD remission show overlap.

Many neuropsychiatric symptom states are id iosyncratic, involuntary, randomly occurring, subjective, and transient. The brain states associated with these clin ically important mental states cannot be imaged directly with existing positron emission tomography (PET) tech niques. A new PET method that brings such mentallbrain states under experimental control for analysis in single subjects is described. It utilizes a slow bolus H2 150 three dimensional (3D) regional CBF imaging technique. The analysis focuses upon natural or experimentally induced variance in the temporal distribution of specific neuro psychological events over the course of a study session. For each scan, the amount of radioactivity entering the brain during these events is calculated to derive a score reflecting the contribution of the events to the image. A Regional CBF (rCBF) imaging of brain activity with H 2 150 positron emission tomography (PET) has provided valuable in vivo information about normal and abnormal human functional neuroanat omy. Most studies of this type are based upon within-group or between-group comparisons of rCBF images obtained at rest or during psycholog ical or pharmacological challenge (Posner et aI.,

Blooms of the toxic dinoflagellate Gymnodinium catenatum are annually recurrent events in south-east Tasmanian waters. Extensive blooms are preceded by a rainfall 'trigger' and the associated influx of dissolved organic matter (DOM; otherwise known as humic substances) from land runoff. Culture studies were conducted to investigate the potential nutritive influence of DOM on G. catenatum. Using a seawater-based growth medium (28‰ salinity), enriched with nutrients 29 but no DOM, the trace element selenium (as 10 M selenite) limited growth rate and biomass (cell density and chlorophyll a). Addition of standard humic acid (aquatic Suwannee River Humic Acid available from the International Humic Substances Society; SHA) caused a 5-25 and 30-90% decrease in G. catenatum growth and biomass, respectively. In contrast, growth and biomass of G. catenatum were increased by approximately 15 and 30-60%, respectively, when Suwannee River SHA and natural DOM (isolated from Huon River water, south-east Tasmania, by ultrafiltration) were added to cultures in the absence of any other chelators or associated trace metals. Under these conditions, biomass was limited by the macronutrients nitrate and phosphate suggesting that dissolved organic substances can change overall nutrient availability and / or uptake by G. catenatum, either by addition of nutrients (e.g. nitrogen and phosphorus) to the system, or by interaction with other nutrients (e.g. selenium). The importance of selenium for G. catenatum growth, its introduction into coastal systems in land runoff, and the interaction of selenium with DOM supports the widely accepted hypothesis that dissolved organic substances alter the supply of nutrients available for algal growth. From these observations it is clear that the outcome of DOM-nutrient interactions on algal growth is variable, and depends on the composition and amount of DOM, the concentration of nutrients in solution and the species-or strain-specific cellular nutrient requirements.

During their growth and evolution, oceanic hot-spot and arc shield volcanoes are destabilized and often dismantled by landslides. The origin of these phenomena can be found in the structure of volcanic islands marked by several low strength horizons such as a marine substratum, hyaloclastites, hydrothermally altered rocks, or volcaniclastic deltas, that weaken the edifice. We have tested the role of these Low Strength Layers (LSLs) with analogue modeling. We conclude that destabilization on these levels can lead to landslides or gravitational spreading. In our experiments, slides generated are only slump-type events, but they can evolve, in nature, into debris avalanches through mechanisms that could not be modeled in the laboratory. The role of fan-shaped volcaniclastic deltas included in the edifice structure is critical to slump formation. This process is more efficient if deltas are associated with another upper LSL, such as weak hyaloclastites or hydrothermally altered rocks. In this case, recurrent events generating collapses with increasing width are observed. Gravitational spreading of a volcanic island occurs when it is underlain by a ductile marine substratum, or includes an intra-edifice unconstrained hyaloclastic layer, 1/3 as thick as the height of the subaerial edifice. Spreading is characterized by edifice stretching and subsidence and does not generate major landslides. We also show that gravitational spreading on a marine substratum tends to inhibit slide generation, especially when the thickness of the sedimentary layer is larger than 1/10 of the edifice total height. However, if this value is lower, spreading occurs later and slumps can develop initially. We describe natural examples of oceanic hot-spot or arc shield volcanoes affected by both spreading and landslides, such as Reunion Island, Hawaii Island, James Ross Island (Antarctica) and Martinique Island (Antilles). The main structural features on these volcanoes can be explained solely by deformation on LSLs. We therefore propose a general model for the destabilization of volcanic islands that is applicable to all shield-like edifices. D

Background-Although intravenous glycoprotein IIb/IIIa inhibitors are beneficial in patients with acute coronary syndromes, prolonged oral IIb/IIIa inhibition might provide an additional reduction in recurrent events. Methods and Results-Investigators at 888 hospitals in 29 countries enrolled 10 288 patients with acute coronary syndromes, which was defined as ischemic pain at rest within 72 hours of randomization, associated with positive cardiac markers, electrocardiographic changes, or prior cardiovascular disease. Patients received aspirin and were randomized to receive, for the duration of the trial, (1) 50 mg of orbofiban twice daily (50/50 group), (2) 50 mg of orbofiban twice daily for 30 days followed by 30 mg of orbofiban twice daily (50/30 group), or (3) a placebo. The primary composite end point was death, myocardial infarction, recurrent ischemia requiring rehospitalization, urgent revascularization, or stroke. The trial was terminated prematurely because of an unexpected increase in 30-day mortality in the 50/30 orbofiban group. Mortality through 10 months was 3.7% for the placebo group versus 5.1% in the 50/30 group (Pϭ0.008) and 4.5% in the 50/50 group (Pϭ0.11). There were no differences in the primary end point (22.9%, 23.1%, and 22.8%, for the placebo, 50/30, and 50/50 groups, respectively). Major or severe bleeding (but not intracranial hemorrhage) was higher with orbofiban; it occurred in 2.0%, 3.7% (Pϭ0.0004), and 4.5% (PϽ0.0001) of patients, respectively. Exploratory subgroup analyses found that patients who underwent percutaneous coronary intervention had a lower mortality and a significant reduction in the composite end point (Pϭ0.001) with orbofiban. Conclusions-Fixed-dose orbofiban failed to reduce major cardiovascular events and was associated with increased mortality in this broad population of patients with acute coronary syndromes; however, a benefit was observed among patients who underwent percutaneous coronary intervention. (Circulation. 2000;102:149-156.)