Modeling the forensic two-trace problem with Bayesian networks

The forensic two-trace problem is a perplexing inference problem introduced by Evett (J Forensic Sci Soc 27:375-381, 1987). Different possible ways of wording the competing pair of propositions (i.e., one proposition advanced by the prosecution and one proposition advanced by the defence) led to different quantifications of the value of the evidence (Meester and Sjerps in Biometrics 59:727-732, 2003). Here, we re-examine this scenario with the aim of clarifying the interrelationships that exist between the different solutions, and in this way, produce a global vision of the problem. We propose to investigate the different expressions for evaluating the value of the evidence by using a graphical approach, i.e. Bayesian networks, to model the rationale behind each of the proposed solutions and the assumptions made on the unknown parameters in this problem.

Seeing the Wood through the Trees: The Current State of Higher Systematics in the Strepsirhini.

Strepsirhines comprise 10 living or recently extinct families, ≥50% of extant primate families. Their phylogenetic relationships have been intensively studied, but common topologies have only recently emerged; e.g. all recent reconstructions link the Lepilemuridae and Cheirogaleidae. The position of the indriids, however, remains uncertain, and molecular studies have placed them as the sister to every clade except Daubentonia, the preferred sister group of morphologists. The node subtending Afro-Asian lorisids has been similarly elusive. We probed these phylogenetic inconsistencies using a test data set including 20 strepsirhine taxa and 2 outgroups represented by 3,543 mtDNA base pairs, and 43 selected morphological characters, subjecting the data to maximum parsimony, maximum likelihood and Bayesian inference analyses, and reconstructing topology and node ages jointly from the molecular data using relaxed molecular clock analyses. Our permutations yielded compatible but not identical evolutionary histories, and currently popular techniques seem unable to deal adequately with morphological data. We investigated the influence of morphological characters on tree topologies, and examined the effect of taxon sampling in two experiments: (1) we removed the molecular data only for 5 endangered Malagasy taxa to simulate 'extinction leaving a fossil record'; (2) we removed both the sequence and morphological data for these taxa. Topologies were affected more by the inclusion of morphological data only, indicating that palaeontological studies that involve inserting a partial morphological data set into a combined data matrix of extant species should be interpreted with caution. The gap of approximately 10 million years between the daubentoniid divergence and those of the other Malagasy families deserves more study. The apparently contemporaneous divergence of African and non-daubentoniid Malagasy families 40-30 million years ago may be related to regional plume-induced uplift followed by a global period of cooling and drying. © 2013 S. Karger AG, Basel.

HACEK infective endocarditis: characteristics and outcomes from a large, multi-national cohort.

The HACEK organisms (Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species) are rare causes of infective endocarditis (IE). The objective of this study is to describe the clinical characteristics and outcomes of patients with HACEK endocarditis (HE) in a large multi-national cohort. Patients hospitalized with definite or possible infective endocarditis by the International Collaboration on Endocarditis Prospective Cohort Study in 64 hospitals from 28 countries were included and characteristics of HE patients compared with IE due to other pathogens. Of 5591 patients enrolled, 77 (1.4%) had HE. HE was associated with a younger age (47 vs. 61 years; p<0.001), a higher prevalence of immunologic/vascular manifestations (32% vs. 20%; p<0.008) and stroke (25% vs. 17% p = 0.05) but a lower prevalence of congestive heart failure (15% vs. 30%; p = 0.004), death in-hospital (4% vs. 18%; p = 0.001) or after 1 year follow-up (6% vs. 20%; p = 0.01) than IE due to other pathogens (n = 5514). On multivariable analysis, stroke was associated with mitral valve vegetations (OR 3.60; CI 1.34-9.65; p<0.01) and younger age (OR 0.62; CI 0.49-0.90; p<0.01). The overall outcome of HE was excellent with the in-hospital mortality (4%) significantly better than for non-HE (18%; p<0.001). Prosthetic valve endocarditis was more common in HE (35%) than non-HE (24%). The outcome of prosthetic valve and native valve HE was excellent whether treated medically or with surgery. Current treatment is very successful for the management of both native valve prosthetic valve HE but further studies are needed to determine why HE has a predilection for younger people and to cause stroke. The small number of patients and observational design limit inferences on treatment strategies. Self selection of study sites limits epidemiological inferences.

Robust response transformations based on optimal prediction

Nonlinear regression problems can often be reduced to linearity by transforming the response variable (e.g., using the Box-Cox family of transformations). The classic estimates of the parameter defining the transformation as well as of the regression coefficients are based on the maximum likelihood criterion, assuming homoscedastic normal errors for the transformed response. These estimates are nonrobust in the presence of outliers and can be inconsistent when the errors are nonnormal or heteroscedastic. This article proposes new robust estimates that are consistent and asymptotically normal for any unimodal and homoscedastic error distribution. For this purpose, a robust version of conditional expectation is introduced for which the prediction mean squared error is replaced with an M scale. This concept is then used to develop a nonparametric criterion to estimate the transformation parameter as well as the regression coefficients. A finite sample estimate of this criterion based on a robust version of smearing is also proposed. Monte Carlo experiments show that the new estimates compare favorably with respect to the available competitors.

Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European Organisation for Research and Treatment of Cancer Brain Tumor Group Study.

PURPOSE: To evaluate the safety and the efficacy of imatinib in recurrent malignant gliomas. PATIENTS: AND METHODS: This was a single-arm, phase II study. Eligible patients had recurrent glioma after prior radiotherapy with an enhancing lesion on magnetic resonance imaging. Three different histologic groups were studied: glioblastomas (GBM), pure/mixed (anaplastic) oligodendrogliomas (OD), and low-grade or anaplastic astrocytomas (A). Imatinib was started at a dose of 600 mg/d with dose escalation to 800 mg in case of no toxicity; during the trial this dose was increased to 800 mg/d with escalation to 1,000 mg/d. Trial design was one-stage Fleming; both an objective response and 6 months of progression-free survival (PFS) were considered a successful outcome to treatment. RESULTS: A total of 112 patients (51 patients with GBM, 25 patients with A, and 36 patients with OD) were enrolled. Imatinib was in general well tolerated. The median number of cycles was 2.0 (range, 1 to 43 cycles). Five patients had an objective partial response, including three patients with GBM; all had 6 months of PFS. The 6-month PFS rate was 16% (95% CI, 8.0% to 34.0%) in GBM, 4.0% (95% CI, 0.3% to 15.0%) in OD, and 9% (95% CI, 2.0% to 25.0%) in A. The exposure to imatinib was significantly lower in patients using enzyme-inducing antiepileptic drugs. The presence of ABCG2 point mutations were not correlated with pharmacokinetic findings. No somatic activating mutations of KIT or platelet-derived growth factor receptor-A or -B were found. CONCLUSION: In the dose range of 600 to 1,000 mg/d, single-agent imatinib is well tolerated but has limited antitumor activity in patients with recurrent gliomas.

Cytochrome P450 2D6 genotype and methadone steady-state concentrations

A genetic polymorphism of cytochrome P450 2D6 has been described with the existence of poor (zero functional genes), extensive (one or two functional genes), and ultrarapid metabolizers (three or more functional genes). The authors measured the steady-state trough (R)- (i.e., the active enantiomer), (S)-, and (R,S)-methadone plasma levels in opiate-dependent patients receiving methadone maintenance treatment (MMT) and genotyped them for cytochrome P4502D6. The patients' medical records were reviewed to assess the outcome of the MMT with regard to the absence of illicit opiate consumption and to the absence of withdrawal complaints in ultrarapid and poor metabolizers. Of 256 patients included, 18 were found to be poor metabolizers, 228 to be extensive metabolizers, and 10 to be ultrarapid metabolizers. Significant differences were found between genotypes for (R)- (p = 0.024), (S)- (p = 0.033), and (R,S)-methadone (p = 0.026) concentrations to dose-to-weight ratios. For (R)-methadone, a significant difference was found between ultrarapid metabolizers and poor metabolizers (p = 0.009), with the median value in the former group being only 54% of the median value in the latter group. These results confirm the involvement of cytochrome P450 2D6 in methadone metabolism. Although the difference was nonsignificant (p = 0.103), 13 (72%) of the 18 poor metabolizers and only 4 (40%) of the 10 ultrarapid metabolizers were considered successful in their treatment. More studies are needed to examine the influence of the ultrarapid metabolizer status on the outcome of the MMT.

A genetic isolation gradient of populations of the Balearic green toad (Bufo balearicus) follows rising eastward fragmentation of the rural landscapes on the island of Menorca.

We present the first approach to the genetic diversity and structure of the Balearic toad (Bufo balearicus Boettger, 1880) for the island of Menorca. Forty-one individ- uals from 21 localities were analyzed for ten microsatellite loci. We used geo-refer- enced individual multilocus genotypes and a model-based clustering method for the inference of the number of populations and of the spatial location of genetic dis- continuities between those populations.¦Only six of the microsatellites analyzed were polymorphic. We revealed a northwest- ern area inhabited by a single population with several well-connected localities and another set of populations in the southeast that includes a few unconnected small units with genetically significant differences among them as well as with the individ- uals from the northwest of the island. The observed fragmentation may be explained by shifts from agricultural to tourism practices that have been taking place on the island of Menorca since the 1960s. The abandonment of rural activities in favor of urbanization and concomitant service areas has mostly affected the southeast of the island and is currently threatening the overall geographic connectivity between the different farming areas of the island that are inhabited by the Balearic toad.

B1-insensitive T2 preparation for improved coronary magnetic resonance angiography at 3 T.

At 3 T, the effective wavelength of the RF field is comparable to the dimension of the human body, resulting in B1 standing wave effects and extra variations in phase. This effect is accompanied by an increase in B0 field inhomogeneity compared to 1.5 T. This combination results in nonuniform magnetization preparation by the composite MLEV weighted T2 preparation (T2 Prep) sequence used for coronary magnetic resonance angiography (MRA). A new adiabatic refocusing T2 Prep sequence is presented in which the magnetization is tipped into the transverse plane with a hard RF pulse and refocused using a pair of adiabatic fast-passage RF pulses. The isochromats are subsequently returned to the longitudinal axis using a hard RF pulse. Numerical simulations predict an excellent suppression of artifacts originating from B1 inhomogeneity while achieving good contrast enhancement between coronary arteries and surrounding tissue. This was confirmed by an in vivo study, in which coronary MR angiograms were obtained without a T2 Prep, with an MLEV weighted T2 Prep and the proposed adiabatic T2 Prep. Improved quantitative and qualitative coronary MRA image measurement was achieved using the adiabatic T2 Prep at 3 T.

A deep dig-hindsight on Holocene plant composition from ancient environmental DNA

Want a glimpse at past vegetation? Studying pollen and other plant remains, which are preserved for example in lake sediments or mires for thousands of years, allows us to document regional occurrences of plant species over radiocarbon-dated time series. Such vegetation reconstructions derived from optical analyses of fossil samples are inherently incomplete because they only comprise taxa that contribute sufficient amounts of pollen, spores, macrofossil or other evidences. To complement optical analyses for paleoecological inference, molecular markers applied to ancient DNA (aDNA) may help in disclosing information hitherto inaccessible to biologists. Parducci etal. (2013) targeted aDNA from sediment cores of two lakes in the Scandes Mountains with generic primers in a meta-barcoding approach. When compared to palynological records from the same cores, respective taxon lists show remarkable differences in their compositions, but also in quantitative representation and in taxonomic resolution similar to a previous study (JOrgensen etal. 2012). While not free of assumptions that need critical and robust testing, notably the question of possible contamination, this study provides thrilling prospects to improve our knowledge about past vegetation composition, but also other organismic groups, stored as a biological treasure in the ground.

Evaluation of the Adolescent Drug Abuse Diagnosis instrument in a Swiss sample of drug abusers.

OBJECTIVE: The aim of this study was to evaluate a French language version of the Adolescent Drug Abuse Diagnosis (ADAD) instrument in a Swiss sample of adolescent illicit drug and/or alcohol users. PARTICIPANTS AND SETTING: The participants in the study were 102 French-speaking adolescents aged 13-19 years who fitted the criteria of illicit drug or alcohol use (at least one substance--except tobacco--once a week during the last 3 months). They were recruited in hospitals, institutions and leisure places. Procedure. The ADAD was administered individually by trained psychologists. It was integrated into a broader protocol including alcohol and drug abuse DSM-IV diagnoses, the BDI-13 (Beck Depression Inventory), life events and treatment trajectories. RESULTS: The ADAD appears to show good inter-rater reliability; the subscales showed good internal coherence and the correlations between the composite scores and the severity ratings were moderate to high. Finally, the results confirmed good concurrent validity for three out of eight ADAD dimensions. CONCLUSIONS: The French language version of the ADAD appears to be an adequate instrument for assessing drug use and associated problems in adolescents. Despite its complexity, the instrument has acceptable validity, reliability and usefulness criteria, enabling international and transcultural comparisons.

Carbamazepine augmentation in depressive patients non-responding to citalopram: a pharmacokinetic and clinical pilot study

Citalopram is a chiral antidepressant drug. Its eutomer, S-citalopram (escitalopram), has recently been introduced as an antidepressant. In an open pilot study, four outpatients and two inpatients with a major depressive episode (ICD-10), and who were nonresponders to a 4-week pretreatment with 40-60 mg/day citalopram, were comedicated for another 4-week period with carbamazepine (200-400 mg/day). Some of the patients suffered also from comorbidities: Phobic anxiety disorder with panic attacks (n=2), generalised anxiety disorder, alcohol abuse, dependent personality disorder, hypertension (n=1). After a 4-week augmentation therapy with carbamazepine, a significant (P<0.03) decrease of the plasma concentrations of S-citalopram and R-citalopram, by 27 and 31%, respectively, was observed. Apparently, the probable induction of CYP3A4 by carbamazepine results in a nonstereoselective increase in N-demethylation of citalopram. Moreover, there was a significant (P<0.03) decrease of the ratio S/R-citalopram propionic acid derivative, the formation of it being partly regulated by MAO-A and MAO-B. Already, within 1 week after addition of carbamazepine, there was a slight but significant (P<0.03) decrease of the MADRS depression scores, from 27.0+/-7.7 (mean+/-S.D.) to 23.3+/-6.6, and the final score on day 56 was 18.8+/-10.9. The treatment was generally well tolerated. There was no evidence of occurrence of a serotonin syndrome. After augmentation with carbamazepine, treatment related adverse events were: Nausea in one case, diarrhea in one case, and rash in two cases. In conclusion, the results of this pilot study suggest that carbamazepine augmentation of a citalopram treatment in previous nonresponders to citalopram may be clinically useful, but that in addition carbamazepine can lead to a decrease of the plasma concentrations of the active enantiomer escitalopram.

Bortezomib(Velcade (R))-Thalidomide-Dexamethasone (VTD) Is Superior to Thalidomide-Dexamethasone (TD) In Patients with Multiple Myeloma (MM) Progressing or Relapsing After Autologous Transplantation.

Introduction: The Thalidomide-Dexamethasone (TD) regimen has provided encouraging results in relapsed MM. To improve results, bortezomib (Velcade) has been added to the combination in previous phase II studies, the so called VTD regimen. In January 2006, the European Group for Blood and Marrow Transplantation (EBMT) and the Intergroupe Francophone du Myélome (IFM) initiated a prospective, randomized, parallel-group, open-label phase III, multicenter study, comparing VTD (arm A) with TD (arm B) for MM patients progressing or relapsing after autologous transplantation. Patients and Methods: Inclusion criteria: patients in first progression or relapse after at least one autologous transplantation, including those who had received bortezomib or thalidomide before transplant. Exclusion criteria: subjects with neuropathy above grade 1 or non secretory MM. Primary study end point was time to progression (TTP). Secondary end points included safety, response rate, progression-free survival (PFS) and overall survival (OS). Treatment was scheduled as follows: bortezomib 1.3 mg/m2 was given as an i.v bolus on Days 1, 4, 8 and 11 followed by a 10-Day rest period (days 12 to 21) for 8 cycles (6 months) and then on Days 1, 8, 15, 22 followed by a 20-Day rest period (days 23 to 42) for 4 cycles (6 months). In both arms, thalidomide was scheduled at 200 mg/Day orally for one year and dexamethasone 40 mg/Day orally four days every three weeks for one year. Patients reaching remission could proceed to a new stem cell harvest. However, transplantation, either autologous or allogeneic, could only be performed in patients who completed the planned one year treatment period. Response was assessed by EBMT criteria, with additional category of near complete remission (nCR). Adverse events were graded by the NCI-CTCAE, Version 3.0.The trial was based on a group sequential design, with 4 planned interim analyses and one final analysis that allowed stopping for efficacy as well as futility. The overall alpha and power were set equal to 0.025 and 0.90 respectively. The test for decision making was based on the comparison in terms of the ratio of the cause-specific hazards of relapse/progression, estimated in a Cox model stratified on the number of previous autologous transplantations. Relapse/progression cumulative incidence was estimated using the proper nonparametric estimator, the comparison was done by the Gray test. PFS and OS probabilities were estimated by the Kaplan-Meier curves, the comparison was performed by the Log-Rank test. An interim safety analysis was performed when the first hundred patients had been included. The safety committee recommended to continue the trial. Results: As of 1st July 2010, 269 patients had been enrolled in the study, 139 in France (IFM 2005-04 study), 21 in Italy, 38 in Germany, 19 in Switzerland (a SAKK study), 23 in Belgium, 8 in Austria, 8 in the Czech republic, 11 in Hungary, 1 in the UK and 1 in Israel. One hundred and sixty nine patients were males and 100 females; the median age was 61 yrs (range 29-76). One hundred and thirty six patients were randomized to receive VTD and 133 to receive TD. The current analysis is based on 246 patients (124 in arm A, 122 in arm B) included in the second interim analysis, carried out when 134 events were observed. Following this analysis, the trial was stopped because of significant superiority of VTD over TD. The remaining patients were too premature to contribute to the analysis. The number of previous autologous transplants was one in 63 vs 60 and two or more in 61 vs 62 patients in arm A vs B respectively. The median follow-up was 25 months. The median TTP was 20 months vs 15 months respectively in arm A and B, with cumulative incidence of relapse/progression at 2 years equal to 52% (95% CI: 42%-64%) vs 70% (95% CI: 61%-81%) (p=0.0004, Gray test). The same superiority of arm A was also observed when stratifying on the number of previous autologous transplantations. At 2 years, PFS was 39% (95% CI: 30%-51%) vs 23% (95% CI: 16%-34%) (A vs B, p=0.0006, Log-Rank test). OS in the first two years was comparable in the two groups. Conclusion: VTD resulted in significantly longer TTP and PFS in patients relapsing after ASCT. Analysis of response and safety data are on going and results will be presented at the meeting. Protocol EU-DRACT number: 2005-001628-35.

The Gene Ontology: enhancements for 2011.

The Gene Ontology (GO) (http://www.geneontology.org) is a community bioinformatics resource that represents gene product function through the use of structured, controlled vocabularies. The number of GO annotations of gene products has increased due to curation efforts among GO Consortium (GOC) groups, including focused literature-based annotation and ortholog-based functional inference. The GO ontologies continue to expand and improve as a result of targeted ontology development, including the introduction of computable logical definitions and development of new tools for the streamlined addition of terms to the ontology. The GOC continues to support its user community through the use of e-mail lists, social media and web-based resources.

Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial.

BACKGROUND: In alcohol withdrawal, fixed doses of benzodiazepine are generally recommended as a first-line pharmacologic approach. This study determines the benefits of an individualized treatment regimen on the quantity of benzodiazepine administered and the duration of its use during alcohol withdrawal treatment. METHODS: We conducted a prospective, randomized, double-blind, controlled trial including 117 consecutive patients with alcohol dependence, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, entering an alcohol treatment program at both the Lausanne and Geneva university hospitals, Switzerland. Patients were randomized into 2 groups: (1) 56 were treated with oxazepam in response to the development of signs of alcohol withdrawal (symptom-triggered); and (2) 61 were treated with oxazepam every 6 hours with additional doses as needed (fixed-schedule). The administration of oxazepam in group 1 and additional oxazepam in group 2 was determined using a standardized measure of alcohol withdrawal. The main outcome measures were the total amount and duration of treatment with oxazepam, the incidence of complications, and the comfort level. RESULTS: A total of 22 patients (39%) in the symptom-triggered group were treated with oxazepam vs 100% in the fixed-schedule group (P<.001). The mean oxazepam dose administered in the symptom-triggered group was 37.5 mg compared with 231.4 mg in the fixed-schedule group (P<.001). The mean duration of oxazepam treatment was 20.0 hours in the symptom-triggered group vs 62.7 hours in the fixed-schedule group (P<.001). Withdrawal complications were limited to a single episode of seizures in the symptom-triggered group. There were no differences in the measures of comfort between the 2 groups. CONCLUSIONS: Symptom-triggered benzodiazepine treatment for alcohol withdrawal is safe, comfortable, and associated with a decrease in the quantity of medication and duration of treatment.

Schizophrenia connectivity: correlation between cognitive deficits and reduced thalamo-cortical fibers

Introduction: Schizophrenia is associated with multiple neuropsychological dysfunctions, such as disturbances of attention, memory, perceptual functioning, concept formation and executive processes. These cognitive functions are reported to depend on the integrity of the prefrontal and thalamo-prefrontal circuits. Multiple lines of evidence suggest that schizophrenia is related to abnormalities in neural circuitry and impaired structural connectivity. Here, we report a preliminary case-control study that showed a correlation between thalamo-frontal connections and several cognitive functions known to be impaired in schizophrenia. Materials and Methods: We investigated 9 schizophrenic patients (DSM IV criteria, Diagnostic Interview for Genetic Studies) and 9 age and sex matched control subjects. We obtained from each volunteer a DT-MRI dataset (3 T, _ _ 1,000 s/mm2), and a high resolution anatomic T1. The thalamo- frontal tracts are simulated with DTI tractography on these dataset, a method allowing inference of the main neural fiber tracks from Diffusion MRI data. In order to see an eventual correlation with the thalamo-frontal connections, every subject performs a battery of neuropsychological tests including computerized tests of attention (sustained attention, selective attention and reaction time), working memory tests (Plane test and the working memory sub-tests of the Wechsler Adult Intelligence Scale), a executive functioning task (Tower of Hanoï) and a test of visual binding abilities. Results: In a pilot case-control study (patients: n _ 9; controls: n _ 9), we showed that this methodology is appropriate and giving results in the excepted range. Considering the relation of the connectivity density and the neuropsychological data, a correlation between the number of thalamo- frontal fibers and the performance in the Tower of Hanoï was observed in the patients (Pearson correlation, r _ 0.76, p _ 0.05) but not in control subjects. In the most difficult item of the test, the least number of fibers corresponds to the worst performance of the test (fig. 2, number of supplementary movements of the elements necessary to realize the right configuration). It's interesting to note here that in an independent study, we showed that schizophrenia patients (n _ 32) perform in the most difficult item of the Tower of Hanoï (Mann-Whitney, p _ 0.005) significantly worse than control subjects (n _ 29). This has been observed in several others neuropsychological studies. Discussion: This pilot study of schizophrenia patients shows a correlation between the number of thalam-frontal fibers and the performance in the Tower of Hanoï, which is a planning and goal oriented actions task known to be associated with frontal dysfonction. This observation is consistent with the proposed impaired connectivity in schizophrenia. We aim to pursue the study with a larger sample in order to determine if other neuropsychological tests may be associated with the connectivity density.