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PubMed2002

Randomized, international study of cyclosporine microemulsion absorption profiling in renal transplantation with basiliximab immunoprophylaxis.

Increasing information suggests that absorption profiling may be superior to trough level monitoring for optimal concentration control of cyclosporine microemulsion (Neoral) therapy, and that CsA exposure early post-transplant may correlate significantly with reduced risk of acute graft rejection. This randomized, prospective, multicenter international concentration-controlled study was conducted in 21 renal transplant centers in 8 countries to test and compare the clinical feasibility, functionality, accuracy, precision and prediction of rejection by cyclosporine microemulsion absorption profiling to conventional trough-level drug monitoring. Primary or second renal allograft recipients treated with basiliximab, cyclosporine microemulsion and prednisone immunosuppression were randomized to two study groups in which cyclosporine microemulsion therapy was monitored using a multipointalgorithm or by trough levels. The two study arms were comparable in terms of baseline characteristics, treatment and clinical outcomes. Treatment failure, consisting of acute rejection, graft loss or death, occurred with equal incidence in the two groups (30% and 33%, respectively). Diagnostic feasibility, measured as the proportion of samples obtained within the designated time window, was marginally lower in area under the time-concentration curve (AUC) than in trough groups, but the therapeutic accuracy and precision were comparable or superior in the AUC group. Cox regression analysis performed across study groups showed a highly significant correlation between the predicted probability of acute rejection and cyclosporine (CsA) exposure measured by AUC over the entire 12-h dosage interval (AUC[0-12]) (p = 0.0068), AUC over the first 4 h of the 12-h dosage interval (AUC[0-4]) (p = 0.0014) or 2h post-dose (C2) CsA level (p = 0.0027). Day 3 dose- and weight-corrected C2 values (EMIT equivalent) separated patients into low (< 200 microg/L/mg/kg dose), intermediate (200-350 microg/L/mg/kg dose) and high absorber categories (> 350 microg/L/mg/kg dose), defining those at greatest risk. Within these categories, C2 values above approximately 1500 microg/L by day 3 post-transplant were associated with the lowest predicted probability of rejection. Comparable analysis by Cox regression using C0 levels did notreach statistical significance. Absorption profiling is a feasible, accurate and precise method for monitoring cyclosporine microemulsion therapy in clinical practice and, as shown in the companion article, may be simplified by the use of single-point C2 concentrations which accurately predict individual AUC[0-4] exposure levels. Both cyclosporine microemulsion relative absorption (i.e. dose- and weight-corrected exposure) and CsA exposure (measured by predicted AUC or C2 levels) are closely correlated with the risk of rejection, and define patients at high and low risk of acute graft rejection. Trough (C0) levels are not closely correlated with either CsA exposure or rejection risk, and should not be considered reliable for monitoring cyclosporine microemulsion therapy.

Adult↗
PubMed1996

Self-reported transient ischemic attack and stroke symptoms: methods and baseline prevalence. The ARIC Study, 1987-1989.

As part of the Atherosclerosis Risk in Communities (ARIC) Study assessment of the etiology and sequelae of atherosclerosis, a standardized questionnaire on transient ischemic attack (TIA) and nonfatal stroke and a computerized diagnostic algorithm simulating clinical reasoning were developed and tested at the four ARIC field centers: Forsyth County, North Carolina; Minneapolis, Minnesota; Jackson, Mississippi; and Washington County, Maryland. The diagnostic algorithm used participant responses to a series of questions about six neurologic trigger symptoms to identify symptoms of TIA or stroke and their vascular distribution. Among 12,205 ARIO participants reporting their lifetime occurrence of one or more symptoms probably due to cerebrovascular causes, nearly half (47%) reported the sudden onset of at least one symptom sometime prior to their ARIC examination. Of those with at least one symptom, only 12.9% were classified by the computer algorithm as having symptoms of TIA or stroke. Dizziness/loss of balance was the most frequently reported symptom (36%); 1.2% of these persons were classified by the algorithm as having a TIA/stroke event. Positive symptoms of speech dysfunction were classified most often (77.%) as being symptoms of TIA or stroke. Symptoms suggesting TIA were reported more frequently than symptoms suggesting stroke by both sexes. TIA or stroke-like phenomena were more frequent (p < 0.001) in females (7%) than in males (5%) and increased with age in both sexes (p = 0.13 for females; p = 0.02 for males). In Forsyth County, TIA and stroke symptoms were greater in African Americans than in Caucasians (p = 0.05, controlling for sex). The association of algorithmically defined symptoms of TIA or stroke with traditional cerebrovascular risk factors is the subject of a companion paper.

Algorithms↗
PubMed2004

Quantitative comparison of four brain extraction algorithms.

In a companion paper (Rehm et al., 2004), we introduced Minneapolis Consensus Strip (McStrip), a hybrid algorithm for brain/non-brain segmentation. In this paper, we compare the performance of McStrip and three brain extraction algorithms (BEAs) in widespread use within the neuroimaging community--Statistical Parametric Mapping v.2 (SPM2), Brain Extraction Tool (BET), and Brain Surface Extractor (BSE)--to the "gold standard" of manually stripped T1-weighted MRI brain volumes. Our comparison was based on quantitative boundary and volume metrics, reproducibility across repeat scans of a single subject, and assessments of performance consistency across datasets acquired on different scanners at different institutions. McStrip, a hybrid method incorporating warping to a template, intensity thresholding, and edge detection, consistently outperformed SPM2, BET, and BSE, all of which rely on a single algorithmic strategy.

Algorithms↗
PubMed2003

Simultaneous vs. sequential analysis for population PK/PD data II: robustness of methods.

A model can be fit to joint PK/PD data (concentration and effect) either simultaneously or sequentially. The results of a companion paper suggested that when the data-analytic and true models agree, a particular sequential approach is computationally faster than the simultaneous one, yet produces hardly less precise PD parameter estimates, and for suitable designs, about as accurate PD standard error estimates. In this paper, we compare the performance of various methods for the case that the data-analytic model is misspecified. We illustrate these methods by applying them to a set of real data. Using NONMEM, population PK/PD observations were simulated under various study designs according to a one- or two-compartment PK model and direct Emax or sigmoid Emax model. A one-compartment PK model and Emax PD model were fit to the simulated observations by simultaneous and sequential methods. Predictive performance (interpolation and extrapolation) of PD and the type-I error rate of a likelihood ratio test are compared. The real data set consists of PK and (more frequent) PD observations after administration of the muscle relaxant vecuronium. When only the PK data-analytic model is misspecified, the simultaneous method has greater precision than the sequential methods. However a sequential method that uses a non-parametric PK model performs better than both other methods when PK model misspecification is severe. When the PD data-analytic model is misspecified, sequential and simultaneous methods perform similarly. The analysis of the real data shows that the PK fitted with the simultaneous method can be quite sensitive to PD model misspecification, yielding a possible diagnostic for this type of misspecification.

Computer Simulation↗
PubMed2006

Increasing lanthanide luminescence by use of the RETEL effect.

BACKGROUND: Luminescent lanthanide complexes produce emissions with the narrowest-known width at half maximum; however, their significant use in cytometry required an increase in luminescence intensity. The companion review, Leif et al., Cytometry 2006;69A:767-778, described a new technique for the enhancement of lanthanide luminescence, the Resonance Energy Transfer Enhanced Luminescence (RETEL) effect, which increases luminescence and is compatible with standard slide microscopy. METHODS: The luminescence of the europium ion macrocyclic complex, EuMac, was increased by employing the RETEL effect. After adding the nonluminescent gadolinium ion complex of the thenoyltrifluoroacetonate (TTFA) ligand or the sodium salt of TTFA in ethanol solution, the EuMac-labeled sample was allowed to dry. Both a conventional arc lamp and a time-gated UV LED served as light sources for microscopic imaging. The emission intensity was measured with a CCD camera. Multiple time-gated images were summed with special software to permit analysis and effective presentation of the final image. RESULTS: With the RETEL effect, the luminescence of the EuMac-streptavidin conjugate increased at least six-fold upon drying. Nuclei of apoptotic cells were stained with DAPI and tailed with 5BrdUrd to which a EuMac-anti-5BrdU conjugate was subsequently attached. Time-gated images showed the long-lived EuMac luminescence but did not show the short-lived DAPI fluorescence. Imaging of DNA-synthesizing cells with an arc lamp showed that both S phase and apoptotic cells were labeled, and that their labeling patterns were different. The images of the luminescent EuMac and fluorescent DAPI were combined to produce a color image on a white background. This combination of simple chemistry, instrumentation, and presentation should make possible the inexpensive use of the lanthanide macrocycles, Quantum Dyes, as molecular diagnostics for cytological and histopathological microscopic imaging.

Acute Disease↗
PubMed1999

ACTH and cortisol release following intravenous desmopressin: a dose-response study.

OBJECTIVE: Desmopressin (DDAVP) is a synthetic analogue of AVP, the companion regulator of corticotrophin-releasing hormone (CRH) in the control of ACTH synthesis and release from the pituitary corticotrophs. The body of evidence from human studies suggests that DDAVP alone, unlike AVP, does not bring about ACTH release, although recent evidence suggests idiosyncracies of response in healthy subjects. We examined whether DDAVP exerted any consistent effect on ACTH and cortisol release, and also if this occurred in a dose-dependant manner. DESIGN AND SUBJECTS: A total of 18 subjects participated in the study. Saline, 5 microg, 10 microg and 15 microg DDAVP were administered as an intravenous bolus at 1300 h; 5, 7, 18 and 8 subjects, respectively, participated in each arm of the study. Plasma ACTH and cortisol responses were measured over a 120-minutes period. RESULTS: Significant between group comparisons were demonstrated for both ACTH (P < 0.05) and cortisol responses (P < 0. 005) measured as maximum increment from baseline. The ACTH response to 5, 10 and 15 microg DDAVP was significantly greater than saline at all three doses, whilst maximal responses were seen at 10 microg. The cortisol responses to 10 and 15 microg DDAVP doses, but not 5 microg, were significantly greater than following saline. 11/18 subjects were deemed 'responders' following 10microg DDAVP on the basis of both ACTH and cortisol output. CONCLUSIONS: This data suggests that DDAVP is capable of stimulating ACTH and cortisol release when administered alone as a bolus in over 50% of healthy subjects. This is in contrast to much of the extant literature. The mode of administration may be pertinent to this effect. This finding has implications for the recent focus on DDAVP as a diagnostic tool in disorders such as Cushing's Disease.

Adrenocorticotropic Hormone↗
PubMed2006

Developing evidence-based guidelines for management of alimentary mucositis: process and pitfalls.

INTRODUCTION: It is important yet difficult to maintain currency in clinical oncology practice. The emergence of new diagnostic technologies and new paradigms for cancer treatment combine to produce a rapidly changing clinical approach to patients aided by the increasing use of multidisciplinary care teams and development of evidence-based protocols. METHODS: Teams of experts review the literature in a given area and produce management guidelines and protocols for use by practicing clinicians. Traditionally within Hematology/Oncology, these guidelines have been directed to management of a given tumor type. However, in recent years, attention has increasingly turned to supportive oncology; for example, there are now management guidelines for conditions such as neutropenic fever [Hughes et al. Clinical Infectious Diseases 34(6):730-751, 2002], antiemetic (The Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer Annals of Oncology 17:20-28, 2006) and most recently, mucositis [Rubenstein et al. Cancer 100(9 Suppl):2026-2046, 2004]. It is critical that any guideline process should include education, evaluation, and timely update in its remit, because guidelines become highly compromised if their existence is not widely known, if they do not facilitate clinical practice, or if they are not reflective of contemporary medical literature. RESULTS: The Mucositis Study Group (MSG) of the Multinational Association for Supportive Care in Cancer/International Society for Oral Oncology was created in 1998 to specifically address the multiprofessional approach to clinical care, research, and education associated with mucosal injury in cancer patients. A specific outcome has been the development of evidence-based guidelines for the management of mucositis [Rubenstein et al. Cancer 100(9 Suppl):2026-2046, 2004; The Mucositis Study Group of MASCC/ISSO 2005]. The original guidelines [Rubenstein et al. Cancer 100(9 Suppl):2026-2046, 2004] and a companion paper discussing the science behind mucositis [Sonis et al. Cancer 100(9):1995-2025, 2004], were published in 2004. The MSG has recently updated the guidelines [The Mucositis Study Group of MASCC/ISSO 2005]. DISCUSSION: This paper discusses the process involved and the lessons learned that might help other groups planning to undertake a similar project.

Effect Modifier, Epidemiologic↗
PubMed2003

Risk of weight gain associated with antipsychotic treatment: results from the Canadian National Outcomes Measurement Study in Schizophrenia.

BACKGROUND: Antipsychotic-induced weight gain occurs in a substantial percentage of treated persons. There remains a paucity of naturalistic data that describe relative weight-gain liability with the available novel atypical antipsychotics (NAPs). This investigation describes comparative NAP-induced weight gain in a prospective naturalistic cohort of persons with schizophrenia and related psychotic disorders. METHODS: The Canadian National Outcomes Measurement Study in Schizophrenia (CNOMSS) is an ongoing prospective, longitudinal, naturalistic study involving 32 academic and community sites across Canada. Persons with DSM-IV-defined schizophrenia, schizophreniform or schizoaffective disorder, and psychosis not otherwise specified were consecutively enrolled. The overarching objectives of this initiative were to collect and compare global effectiveness, tolerability, safety, and humanistic outcomes in persons receiving commercially available NAPs in Canada. This analysis reports only weight change with the respective NAPs. Other outcomes were reported in separate companion papers. RESULTS: A spectrum of weight-gain liability was noted with quetiapine (QUE) (mean 7.55 kg, SD 9.20; P = 0.28), olanzapine (OLZ) (mean 3.72 kg, SD 0.56; P = 0.15), and risperidone (RIS) (mean 1.62 kg, SD 7.72; P = 0.43). Categorically defined weight gain (that is, over 7% of baseline weight) was observed in 55.6% of QUE patients, 24.1% of OLZ patients, and 23.7% of RIS patients. Adjusting for demographic and disease-specific confounding factors, QUE patients had greater odds of gaining over 7% of their baseline weight compared with RIS patients (odds ratio [OR] 3.62; 95% CI, 1.02 to 12.83; P = 0.05). No statistical difference was detected between OLZ patients and RIS patients for over 7% of baseline weight (OR 1.54; 95% CI, 0.63 to 3.75; P = 0.12) or over 10% weight gain (OR 1.44; 95% CI, 0.50 to 4.13; P = 0.58). CONCLUSION: Clinicians are reminded to monitor anthropometric and metabolic parameters in all NAP-treated persons. Clinically significant differences in weight gain liability exist among the available NAPs.

Adult↗
PubMed2003

Preventive care in the emergency department: should emergency departments conduct routine HIV screening? a systematic review.

OBJECTIVE: To perform a systematic review of the emergency medicine literature to assess the appropriateness of offering routine HIV screening to patients in the emergency department (ED). METHODS: The systematic review was conducted with the aid of a structured template, a companion explanatory guide, and a grading and methodological scoring system based on published criteria for critical appraisal. Two reviewers conducted independent searches using OvidR, PubMed, MD Consult, and Grateful Med. Relevant abstracts were reviewed; those most pertinent to the stated objective were selected for complete evaluation using the structured template. RESULTS: Fifty-two relevant abstracts were reviewed; of these, nine were selected for detailed evaluation. Seven ED-based prospective cross-sectional seroprevalence studies found HIV rates of 2-17%. Highest rates of infection were seen among patients with behavioral risks such as male homosexual activity and intravenous drug use. Two studies demonstrated feasibility of both standard and rapid HIV testing in the ED, with more than half of the patients approached consenting to testing by either method, consistent with voluntary testing acceptance rates described in other settings. Several cost-benefit analyses lend indirect support for HIV screening in the ED. CONCLUSIONS: Multiple ED-based studies meeting the Centers for Disease Control and Prevention Guideline threshold to recommend routine screening, in conjunction with limited feasibility trials and extrapolation from cost-benefit studies, provide evidence to recommend that EDs offer HIV screening to high-risk patients (i.e., those with identifiable risk factors) or high-risk populations (i.e., those where HIV seroprevelance is at least 1%).

AIDS Serodiagnosis↗
PubMed2002

Did he drown or was he murdered?

An unemployed, 60-year-old Singaporean gentleman died during a brief overseas trip to another South-East Asian country. He had, presumably, drowned in the bathtub of his hotel room, which he shared with his then 44-year-old companion, who was supposedly his nephew. The relevant public health and medico-legal authorities of the host country conducted an external examination of the body at the scene, whereupon they agreed with the police that his death was probably due to accidental drowning following an episode of syncope. It would appear that this verdict was based almost entirely on circumstantial and hearsay evidence. No autopsy was performed. In its place, considerable reliance was placed on the observation that abdominal compression resulted in the outflow of a small amount of water from the mouth, as being proof of drowning. A few days later, the body was cremated in the host country and the remains (ashes) were subsequently repatriated to Singapore. It later transpired that, shortly before they embarked on the ill-fated trip, the deceased's 'nephew' had purchased, on the former's behalf, travel insurance policies (covering accidental injury and death) amounting to a total of S$800,000 from five different insurance companies, as well as a separate life policy for a further S$100,000, most of which had been issued within the fortnight prior to their departure. Interestingly, the beneficiary (later the plaintiff in the ensuing civil trial some three years later) of all of these policies, was the ex-wife of the deceased's 'nephew', with whom he had, in fact, continued to live although they were officially divorced several years ago. Whilst the claim against the life policy had been settled, the first five insurers declined to issue payment on grounds of suspicion that the deceased had been the victim of a homicide, planned or executed by the 'nephew', wherein the beneficiary was a conspirator of sorts. The author was approached by defence counsel (representing the various insurers), for assistance in this matter. It was felt that a proper forensic review was seriously hampered by the lack of a full autopsy which would have been indispensable in ascertaining the actual cause of death and in eliminating other possibilities, apart from drowning, such as death from natural causes, other forms of injury, poisoning, or homicide. It was also emphasized that the mere presence of ingested water is not diagnostic of drowning. Eventually, after a protracted but unsuccessful attempt at mediation (in the course of which, the plaintiff rejected the offer of a reduced, although apparently sizable quantum), the matter came before the High Court, which found in favour of the defendants. It appeared that the judge was more than convinced that the deceased was indeed the victim of a homicide of which the plaintiff was a conspirator and her ex-husband, the perpetrator, as even a cursory perusal of the written judgement would indicate. Accordingly, the court ruled that the plaintiff (in her capacity as both the beneficiary of the insurance policies and executor of the estate) and her ex-husband had, effectively, deprived the insurers of their contractual right (as stipulated in the insurance policies) to have an autopsy conducted on the body of the deceased and they were, therefore, entitled to deny liability. This case illustrates the difficulties inherent in conducting an independent review of a putative instance of drowning, where convincing and reliable forensic evidence and documentation are largely wanting; this being compounded by its occurrence in a foreign jurisdiction whose medico-legal practices differ substantially from that to which one is accustomed. It may even be said that the corpus delecti was destroyed, in this instance, by cremation. It is also unusual in that a de-facto finding of murder was made in a civil court (whose standard of proof is that of a balance of probabilities) and that this had, subsequently, spurred the police to undertake a criminal investigation for conspiracy to murder. In the event, the civil appeal was dismissed by the Court of Appeal, but no charge was laid against any of the suspects for want of sufficient forensic or investigative evidence of a criminal offence having been committed.

Drowning↗
PubMed2002

Stabilization of mRNA expression in whole blood samples.

BACKGROUND: Accurate quantification of mRNA in whole blood is made difficult by the simultaneous degradation of gene transcripts and unintended gene induction caused by sample handling or uncontrolled activation of coagulation. This study was designed to compare a new blood collection tube (PAXgene Blood RNA System) and a companion sample preparation reagent set with a traditional sample collection and preparation method for the purpose of gene expression analysis. METHODS: We collected parallel blood samples from healthy donors into the new sample collection tubes and control EDTA tubes and performed serial RNA extractions on samples stored for 5 days at room temperature and for up to 90 days at 4 and 20 degrees C. Samples were analyzed by Northern blot analysis or reverse transcription-PCR (RT-PCR). RESULTS: Specific mRNA concentrations in blood stored in EDTA tubes at any temperature changed substantially, as determined by high-precision RT-PCR. These changes were eliminated or markedly reduced when whole blood was stored in PAXgene tubes. Loss of specific mRNAs, as measured by RT-PCR, reflected total RNA depletion as well as specific mRNA destruction demonstrated by Northern blot analysis. The salutary effects of PAXgene on mRNA stabilization extended to blood samples from eight unrelated donors. CONCLUSIONS: Compared with whole blood collected in EDTA tubes and extracted by an organic method, the PAXgene Blood RNA System reduced RNA degradation and inhibited or eliminated gene induction in phlebotomy whole blood samples. Storage of whole blood samples in PAXgene tubes can be recommended for clinically related blood samples that will be analyzed for total or specific RNA content.

Blood Specimen Collection↗