State Legislation Monitoring Report FY 2005, February 2006

The Division of Criminal and Juvenile Justice Planning issued its first state legislation monitoring report in February 2002, covering the first six months’ impact of Senate File 543 (which enacted a number of sentencing changes) on the justice system; monitoring of the correctional impact of this bill was at the request of several members of the legislature. Since then, the Criminal and Juvenile Justice Planning Advisory Council has requested that CJJP monitor the correctional impact of enacted legislation of particular interest.

Prospective monitoring of cefepime in intensive care unit adult patients.

INTRODUCTION: Cefepime has been associated with a greater risk of mortality than other beta-lactams in patients treated for severe sepsis. Hypotheses for this failure include possible hidden side-effects (for example, neurological) or inappropriate pharmacokinetic/pharmacodynamic (PK/PD) parameters for bacteria with cefepime minimal inhibitory concentrations (MIC) at the highest limits of susceptibility (8 mg/l) or intermediate-resistance (16 mg/l) for pathogens such as Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus. We examined these issues in a prospective non-interventional study of 21 consecutive intensive care unit (ICU) adult patients treated with cefepime for nosocomial pneumonia. METHODS: Patients (median age 55.1 years, range 21.8 to 81.2) received intravenous cefepime at 2 g every 12 hours for creatinine clearance (CLCr) >or= 50 ml/min, and 2 g every 24 hours or 36 hours for CLCr < 50 ml/minute. Cefepime plasma concentrations were determined at several time-points before and after drug administration by high-pressure liquid chromatography. PK/PD parameters were computed by standard non-compartmental analysis. RESULTS: Seventeen first-doses and 11 steady states (that is, four to six days after the first dose) were measured. Plasma levels varied greatly between individuals, from two- to three-fold at peak-concentrations to up to 40-fold at trough-concentrations. Nineteen out of 21 (90%) patients had PK/PD parameters comparable to literature values. Twenty-one of 21 (100%) patients had appropriate duration of cefepime concentrations above the MIC (T>MIC >or= 50%) for the pathogens recovered in this study (MIC <or= 4 mg/l), but only 45 to 65% of them had appropriate coverage for potential pathogens with cefepime MIC >or= 8 mg/l. Moreover, 2/21 (10%) patients with renal impairment (CLCr < 30 ml/minute) demonstrated accumulation of cefepime in the plasma (trough concentrations of 20 to 30 mg/l) in spite of dosage adjustment. Both had symptoms compatible with non-convulsive epilepsy (confusion and muscle jerks) that were not attributed to cefepime-toxicity until plasma levels were disclosed to the caretakers and symptoms resolved promptly after drug arrest. CONCLUSIONS: These empirical results confirm the suspected risks of hidden side-effects and inappropriate PK/PD parameters (for pathogens with upper-limit MICs) in a population of ICU adult patients. Moreover, it identifies a safety and efficacy window for cefepime doses of 2 g every 12 hours in patients with a CLCr >or= 50 ml/minute infected by pathogens with cefepime MICs <or= 4 mg/l. On the other hand, prompt monitoring of cefepime plasma levels should be considered in case of lower CLCr or greater MICs.

Therapeutic monitoring of antidepressants in the era of pharmacogenetics studies.

As for other drugs, there is a large interindividual variability of the plasma concentrations of antidepressants for a given dose. Within the last 2 decades, a very large number of pharmacogenetic studies have made it possible to understand the importance of genetic factors on the disposition of drugs in the organism, many of them at the levels of drug metabolism. Polymorphism of CYP2D6 and of other drug-metabolizing enzymes may thus lead to very large differences in drug exposure between patients and possibly also to toxicity or ineffective drug concentrations in some subjects. In consequence, dose recommendations of antidepressants based on genotypes, justified by the principle of administering bioequivalent individualized drug doses, are now proposed. However, blood (and thus possibly brain) concentrations also depend on other factors than the genetic makeup of the patients. Therapeutic drug monitoring of antidepressants allows us to take into account the influence of factors such as comedications, diet, smoking habit, impaired organ function, and compliance. Therapeutic drug monitoring and genotyping are thus complementary, and their combined use contributes to improve pharmacotherapy with antidepressants and other drugs.

Effect of n-3 fatty acids on cerebral markers and the inflammatory response in sepsis

Introduction ICM+ software encapsulates our 20 years' experience in brain monitoring. It collects data from a variety of bedside monitors and produces time trends of parameters defi ned using confi gurable mathematical formulae. To date it is being used in nearly 40 clinical research centres worldwide. We present its application for continuous monitoring of cerebral autoregulation using near-infrared spectroscopy (NIRS). Methods Data from multiple bedside monitors are processed by ICM+ in real time using a large selection of signal processing methods. These include various time and frequency domain analysis functions as well as fully customisable digital fi lters. The fi nal results are displayed in a variety of ways including simple time trends, as well as time window based histograms, cross histograms, correlations, and so forth. All this allows complex information from bedside monitors to be summarized in a concise fashion and presented to medical and nursing staff in a simple way that alerts them to the development of various pathological processes. Results One hundred and fi fty patients monitored continuously with NIRS, arterial blood pressure (ABP) and intracranial pressure (ICP), where available, were included in this study. There were 40 severely headinjured adult patients, 27 SAH patients (NCCU, Cambridge); 60 patients undergoing cardiopulmonary bypass (John Hopkins Hospital, Baltimore) and 23 patients with sepsis (University Hospital, Basel). In addition, MCA fl ow velocity (FV) was monitored intermittently using transcranial Doppler. FV-derived and ICP-derived pressure reactivity indices (PRx, Mx), as well as NIRS-derived reactivity indices (Cox, Tox, Thx) were calculated and showed signifi cant correlation with each other in all cohorts. Errorbar charts showing reactivity index PRx versus CPP (optimal CPP chart) as well as similar curves for NIRS indices versus CPP and ABP were also demonstrated. Conclusions ICM+ software is proving to be a very useful tool for enhancing the battery of available means for monitoring cerebral vasoreactivity and potentially facilitating autoregulation guided therapy. Complexity of data analysis is also hidden inside loadable profi les, thus allowing investigators to take full advantage of validated protocols including advanced processing formulas.

Assessing the Functionality and Biocompatibility of a Wireless Contact Lens Sensor for 24 hour-intraocular Pressure Monitoring in Volunteers: Preliminary Results

Purpose: In vitro studies in porcine eyes have demonstrated a good correlation between induced intraocular pressure variations and corneal curvature changes, using a contact lens with an embedded microfabricated strain gauge. Continuous 24 hour-intraocular pressure (IOP) monitoring to detect large diurnal fluctuation is currently an unmet clinical need. The aims of this study is to evaluate precision of signal transmission and biocompatibility of 24 hour contact lens sensor wear (SENSIMED Triggerfish®) in humans. Methods: After full eye examination in 10 healthy volunteers, a 8.7 mm radius contact lens sensor and an orbital bandage containing a loop antenna were applied and connected to a portable recorder. Best corrected visual acuity and position, lubrication status and mobility of the sensor were assessed after 5 and 30 minutes, 4, 7 and 24 hours. Subjective comfort was scored and activities documented in a logbook. After sensor removal full eye examination was repeated, and the registration signal studied. Results: The comfort score was high and did not fluctuate significantly, except at the 7 hour-visit. The mobility of the contact lens was minimal but its lubrication remained good. Best corrected visual acuity was significantly reduced during the sensor wear and immediately after its removal. Three patients developed mild corneal staining. In all but one participant we obtained a registration IOP curve with visible ocular pulse amplitude. Conclusions: This 24 hour-trial confirmed the functionality and biocompatibility of SENSIMED Triggerfish® wireless contact lens sensor for IOP-fluctuation monitoring in volunteers. Further studies with a range of different contact lens sensor radii are indicated.

Benchmarking therapeutic drug monitoring software: A systematic evaluation of available computer tools

Introduction: Therapeutic drug monitoring (TDM) aims at optimizing treatment by individualizing dosage regimen based on measurement of blood concentrations. Maintaining concentrations within a target range requires pharmacokinetic and clinical capabilities. Bayesian calculation represents a gold standard in TDM approach but requires computing assistance. In the last decades computer programs have been developed to assist clinicians in this assignment. The aim of this benchmarking was to assess and compare computer tools designed to support TDM clinical activities.¦Method: Literature and Internet search was performed to identify software. All programs were tested on common personal computer. Each program was scored against a standardized grid covering pharmacokinetic relevance, user-friendliness, computing aspects, interfacing, and storage. A weighting factor was applied to each criterion of the grid to consider its relative importance. To assess the robustness of the software, six representative clinical vignettes were also processed through all of them.¦Results: 12 software tools were identified, tested and ranked. It represents a comprehensive review of the available software's characteristics. Numbers of drugs handled vary widely and 8 programs offer the ability to the user to add its own drug model. 10 computer programs are able to compute Bayesian dosage adaptation based on a blood concentration (a posteriori adjustment) while 9 are also able to suggest a priori dosage regimen (prior to any blood concentration measurement), based on individual patient covariates, such as age, gender, weight. Among those applying Bayesian analysis, one uses the non-parametric approach. The top 2 software emerging from this benchmark are MwPharm and TCIWorks. Other programs evaluated have also a good potential but are less sophisticated (e.g. in terms of storage or report generation) or less user-friendly.¦Conclusion: Whereas 2 integrated programs are at the top of the ranked listed, such complex tools would possibly not fit all institutions, and each software tool must be regarded with respect to individual needs of hospitals or clinicians. Interest in computing tool to support therapeutic monitoring is still growing. Although developers put efforts into it the last years, there is still room for improvement, especially in terms of institutional information system interfacing, user-friendliness, capacity of data storage and report generation.

Monitoring of biological markers indicative of doping: the athlete biological passport

The athlete biological passport (ABP) was recently implemented in anti-doping work and is based on the individual and longitudinal monitoring of haematological or urine markers. These may be influenced by illicit procedures performed by some athletes with the intent to improve exercise performance. Hence the ABP is a valuable tool in the fight against doping. Actually, the passport has been defined as an individual and longitudinal observation of markers. These markers need to belong to the biological cascade influenced by the application of forbidden hormones or more generally, affected by biological manipulations which can improve the performance of the athlete. So far, the haematological and steroid profile modules of the ABP have been implemented in major sport organisations, and a further module is under development. The individual and longitudinal monitoring of some blood and urine markers are of interest, because the intraindividual variability is lower than the corresponding interindividual variability. Among the key prerequisites for the implementation of the ABP is its prospect to resist to the legal and scientific challenges. The ABP should be implemented in the most transparent way and with the necessary independence between planning, interpretation and result management of the passport. To ensure this, the Athlete Passport Management Unit (APMU) was developed and the WADA implemented different technical documents associated to the passport. This was carried out to ensure the correct implementation of a profile which can also stand the challenge of any scientific or legal criticism. This goal can be reached only by following strictly important steps in the chain of production of the results and in the management of the interpretation of the passport. Various technical documents have been then associated to the guidelines which correspond to the requirements for passport operation. The ABP has been completed very recently by the steroid profile module. As for the haematological module, individual and longitudinal monitoring have been applied and the interpretation cascade is also managed by a specific APMU in a similar way as applied in the haematological module. Thus, after exclusion of any possible pathology, specific variation from the individual norms will be then considered as a potential misuse of hormones or other modulators to enhance performance.

Benchmarking therapeutic drug monitoring software: A systematic evaluation of available computer tools

Objectives: Therapeutic drug monitoring (TDM) aims at optimizing treatment by individualizing dosage regimen based on blood concentrations measurement. Maintaining concentrations within a target range requires pharmacokinetic (PK) and clinical capabilities. Bayesian calculation represents a gold standard in TDM approach but requires computing assistance. The aim of this benchmarking was to assess and compare computer tools designed to support TDM clinical activities.¦Methods: Literature and Internet were searched to identify software. Each program was scored against a standardized grid covering pharmacokinetic relevance, user-friendliness, computing aspects, interfacing, and storage. A weighting factor was applied to each criterion of the grid to consider its relative importance. To assess the robustness of the software, six representative clinical vignettes were also processed through all of them.¦Results: 12 software tools were identified, tested and ranked. It represents a comprehensive review of the available software characteristics. Numbers of drugs handled vary from 2 to more than 180, and integration of different population types is available for some programs. Nevertheless, 8 programs offer the ability to add new drug models based on population PK data. 10 computer tools incorporate Bayesian computation to predict dosage regimen (individual parameters are calculated based on population PK models). All of them are able to compute Bayesian a posteriori dosage adaptation based on a blood concentration while 9 are also able to suggest a priori dosage regimen, only based on individual patient covariates. Among those applying Bayesian analysis, MM-USC*PACK uses a non-parametric approach. The top 2 programs emerging from this benchmark are MwPharm and TCIWorks. Others programs evaluated have also a good potential but are less sophisticated or less user-friendly.¦Conclusions: Whereas 2 software packages are ranked at the top of the list, such complex tools would possibly not fit all institutions, and each program must be regarded with respect to individual needs of hospitals or clinicians. Programs should be easy and fast for routine activities, including for non-experienced users. Although interest in TDM tools is growing and efforts were put into it in the last years, there is still room for improvement, especially in terms of institutional information system interfacing, user-friendliness, capability of data storage and automated report generation.

Monitoring mortality as an indicator of influenza in Catalonia, Spain.

This study aimed to investigate the behaviour of two indicators of influenza activity in the area of Barcelona and to evaluate the usefulness of modelling them to improve the detection of influenza epidemics. DESIGN: Descriptive time series study using the number of deaths due to all causes registered by funeral services and reported cases of influenza-like illness. The study concentrated on five influenza seasons, from week 45 of 1988 to week 44 of 1993. The weekly number of deaths and cases of influenza-like illness registered were processed using identification of a time series ARIMA model. SETTING: Six large towns in the Barcelona province which have more than 60,000 inhabitants and funeral services in all of them. MAIN RESULTS: For mortality, the proposed model was an autoregressive one of order 2 (ARIMA (2,0,0)) and for morbidity it was one of order 3 (ARIMA (3,0,0)). Finally, the two time series were analysed together to facilitate the detection of possible implications between them. The joint study of the two series shows that the mortality series can be modelled separately from the reported morbidity series, but the morbidity series is influenced as much by the number of previous cases of influenza reported as by the previous mortality registered. CONCLUSIONS: The model based on general mortality is useful for detecting epidemic activity of influenza. However, because there is not an absolute gold standard that allows definition of the beginning of the epidemic, the final decision of when it is considered an epidemic and control measures recommended should be taken after evaluating all the indicators included in the influenza surveillance programme.

Monitoring of malaria parasite resistance to chloroquine and sulphadoxine-pyrimethamine in the Solomon Islands by DNA microarray technology.

BACKGROUND: Little information is available on resistance to anti-malarial drugs in the Solomon Islands (SI). The analysis of single nucleotide polymorphisms (SNPs) in drug resistance associated parasite genes is a potential alternative to classical time- and resource-consuming in vivo studies to monitor drug resistance. Mutations in pfmdr1 and pfcrt were shown to indicate chloroquine (CQ) resistance, mutations in pfdhfr and pfdhps indicate sulphadoxine-pyrimethamine (SP) resistance, and mutations in pfATPase6 indicate resistance to artemisinin derivatives. METHODS: The relationship between the rate of treatment failure among 25 symptomatic Plasmodium falciparum-infected patients presenting at the clinic and the pattern of resistance-associated SNPs in P. falciparum infecting 76 asymptomatic individuals from the surrounding population was investigated. The study was conducted in the SI in 2004. Patients presenting at a local clinic with microscopically confirmed P. falciparum malaria were recruited and treated with CQ+SP. Rates of treatment failure were estimated during a 28-day follow-up period. In parallel, a DNA microarray technology was used to analyse mutations associated with CQ, SP, and artemisinin derivative resistance among samples from the asymptomatic community. Mutation and haplotype frequencies were determined, as well as the multiplicity of infection. RESULTS: The in vivo study showed an efficacy of 88% for CQ+SP to treat P. falciparum infections. DNA microarray analyses indicated a low diversity in the parasite population with one major haplotype present in 98.7% of the cases. It was composed of fixed mutations at position 86 in pfmdr1, positions 72, 75, 76, 220, 326 and 356 in pfcrt, and positions 59 and 108 in pfdhfr. No mutation was observed in pfdhps or in pfATPase6. The mean multiplicity of infection was 1.39. CONCLUSION: This work provides the first insight into drug resistance markers of P. falciparum in the SI. The obtained results indicated the presence of a very homogenous P. falciparum population circulating in the community. Although CQ+SP could still clear most infections, seven fixed mutations associated with CQ resistance and two fixed mutations related to SP resistance were observed. Whether the absence of mutations in pfATPase6 indicates the efficacy of artemisinin derivatives remains to be proven.

Optimal fiscal policy in overlapping generations models

[eng] This paper provides, from a theoretical and quantitative point of view, an explanation of why taxes on capital returns are high (around 35%) by analyzing the optimal fiscal policy in an economy with intergenerational redistribution. For this purpose, the government is modeled explicitly and can choose (and commit to) an optimal tax policy in order to maximize society's welfare. In an infinitely lived economy with heterogeneous agents, the long run optimal capital tax is zero. If heterogeneity is due to the existence of overlapping generations, this result in general is no longer true. I provide sufficient conditions for zero capital and labor taxes, and show that a general class of preferences, commonly used on the macro and public finance literature, violate these conditions. For a version of the model, calibrated to the US economy, the main results are: first, if the government is restricted to a set of instruments, the observed fiscal policy cannot be disregarded as sub optimal and capital taxes are positive and quantitatively relevant. Second, if the government can use age specific taxes for each generation, then the age profile capital tax pattern implies subsidizing asset returns of the younger generations and taxing at higher rates the asset returns of the older ones.

Interiority of the optimal population growth rate with endogenous fertility

This paper analyzes the issue of the interiority of the optimal population growth rate in a two-period overlapping generations model with endogenous fertility. Using Cobb-Douglas utility and production functions, we show that the introduction of a cost of raising children allows for the possibility of the existence of an interior global maximum in the planner¿s problem, contrary to the exogenous fertility case

Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes.

Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.