Inferring the degree of incipient speciation in secondary contact zones of closely related lineages of Palearctic green toads (Bufo viridis subgroup).

Reproductive isolation between lineages is expected to accumulate with divergence time, but the time taken to speciate may strongly vary between different groups of organisms. In anuran amphibians, laboratory crosses can still produce viable hybrid offspring >20 My after separation, but the speed of speciation in closely related anuran lineages under natural conditions is poorly studied. Palearctic green toads (Bufo viridis subgroup) offer an excellent system to address this question, comprising several lineages that arose at different times and form secondary contact zones. Using mitochondrial and nuclear markers, we previously demonstrated that in Sicily, B. siculus and B. balearicus developed advanced reproductive isolation after Plio-Pleistocene divergence (2.6 My, 3.3-1.9), with limited historic mtDNA introgression, scarce nuclear admixture, but low, if any, current gene flow. Here, we study genetic interactions between younger lineages of early Pleistocene divergence (1.9 My, 2.5-1.3) in northeastern Italy (B. balearicus, B. viridis). We find significantly more, asymmetric nuclear and wider, differential mtDNA introgression. The population structure seems to be molded by geographic distance and barriers (rivers), much more than by intrinsic genomic incompatibilities. These differences of hybridization between zones may be partly explained by differences in the duration of previous isolation. Scattered research on other anurans suggests that wide hybrid zones with strong introgression may develop when secondary contacts occur <2 My after divergence, whereas narrower zones with restricted gene flow form when divergence exceeds 3 My. Our study strengthens support for this rule of thumb by comparing lineages with different divergence times within the same radiation.

Identification of an RP1 Prevalent Founder Mutation and Related Phenotype in Spanish Patients with Early-Onset Autosomal Recessive Retinitis.

OBJECTIVE: To identify the genetic causes underlying early-onset autosomal recessive retinitis pigmentosa (arRP) in the Spanish population and describe the associated phenotype. DESIGN: Case series. PARTICIPANTS: A total of 244 unrelated families affected by early-onset arRP. METHODS: Homozygosity mapping or exome sequencing analysis was performed in 3 families segregating arRP. A mutational screening was performed in 241 additional unrelated families for the p.Ser452Stop mutation. Haplotype analysis also was conducted. Individuals who were homozygotes, double heterozygotes, or carriers of mutations in RP1 underwent an ophthalmic evaluation to establish a genotype-phenotype correlation. MAIN OUTCOME MEASURES: DNA sequence variants, homozygous regions, haplotypes, best-corrected visual acuity, visual field assessments, electroretinogram responses, and optical coherence tomography images. RESULTS: Four novel mutations in RP1 were identified. The new mutation p.Ser542Stop was present in 11 of 244 (4.5%) of the studied families. All chromosomes harboring this mutation shared the same haplotype. All patients presented a common phenotype with an early age of onset and a prompt macular degeneration, whereas the heterozygote carriers did not show any signs of retinitis pigmentosa (RP). CONCLUSIONS: p.Ser542Stop is a single founder mutation and the most prevalent described mutation in the Spanish population. It causes early-onset RP with a rapid macular degeneration and is responsible for 4.5% of all cases. Our data suggest that the implication of RP1 in arRP may be underestimated. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

A Typology of Identity-Related Crime

Identification is ever more important in the online world, and identity-related crime is a growing problem related to this. This new category of crime is not restricted to high-profile instances of identity 'theft' or identity fraud; it is wide-ranging and complex, ranging from identity deletion to unlawful identity creation and identity 'theft'. Commonly accepted definitions are lacking, thus blurring available statistics, and policies to combat this new crime are piecemeal at best. To assess the real nature and magnitude of identity-related crime, and to be able to discuss how it can be combated, identity-related crime should be understood in all its aspects. As a first key step, this article introduces a typology of identity-related crime, consisting of conceptual, technical and legal categories, that can be used as a comprehensive framework for future research, countermeasures and policies related to identity related crime.

A neuropsychological instrument measuring age-related cerebral decline in older drivers: development, reliability, and validity of MedDrive.

When facing age-related cerebral decline, older adults are unequally affected by cognitive impairment without us knowing why. To explore underlying mechanisms and find possible solutions to maintain life-space mobility, there is a need for a standardized behavioral test that relates to behaviors in natural environments. The aim of the project described in this paper was therefore to provide a free, reliable, transparent, computer-based instrument capable of detecting age-related changes on visual processing and cortical functions for the purposes of research into human behavior in computational transportation science. After obtaining content validity, exploring psychometric properties of the developed tasks, we derived (Study 1) the scoring method for measuring cerebral decline on 106 older drivers aged ≥70 years attending a driving refresher course organized by the Swiss Automobile Association to test the instrument's validity against on-road driving performance (106 older drivers). We then validated the derived method on a new sample of 182 drivers (Study 2). We then measured the instrument's reliability having 17 healthy, young volunteers repeat all tests included in the instrument five times (Study 3) and explored the instrument's psychophysical underlying functions on 47 older drivers (Study 4). Finally, we tested the instrument's responsiveness to alcohol and effects on performance on a driving simulator in a randomized, double-blinded, placebo, crossover, dose-response, validation trial including 20 healthy, young volunteers (Study 5). The developed instrument revealed good psychometric properties related to processing speed. It was reliable (ICC = 0.853) and showed reasonable association to driving performance (R (2) = 0.053), and responded to blood alcohol concentrations of 0.5 g/L (p = 0.008). Our results suggest that MedDrive is capable of detecting age-related changes that affect processing speed. These changes nevertheless do not necessarily affect driving behavior.

Rapid Improvement in Health-Related Quality of Life in Gouty Arthritis Patients Treated with Canakinumab (ACZ885) Compared to Triamcinolone Acetonide

Background: Gout patients initiating urate lowering therapy have an increased risk of flares. Inflammation in gouty arthritis is induced by interleukin (IL)-1b. Canakinumab inhibits IL-1b effectively in clinical studies. This study compared different doses of canakinumab vs colchicine in preventing flares in gout patients initiating allopurinol therapy.Methods: In this 24 wk double blind study, gout patients (20-79 years) initiating allopurinol were randomized (1:1:1:1:1:1:2) to canakinumab s.c. single doses of 25, 50, 100, 200, 300 mg, or 150mg divided in doses every 4 wks (50þ50þ25þ25mg [q4wk]) or colchicine 0.5mg p.o. daily for 16 wks. Primary outcome was to determine the canakinumab dose giving comparable efficacy to colchicine with respect to number of flares occurring during first 16 wks. Secondary outcomes included number of patients with flares and C-reactive protein (CRP) levels during the first 16 wks.Results: 432 patients were randomized and 391 (91%) completed the study. All canakinumab doses were better than colchicine in preventing flares and therefore, a canakinumab dose comparable to colchicine couldn't be determined. Based on a negative binomialmodel, all canakinumab groups, except 25 mg, reduced the flare rate ratio per patient significantly compared to colchicine group (rate ratio estimates 25mg 0.60, 50mg 0.34, 100mg 0.28, 200mg 0.37, 300mg 0.29, q4wk 0.38; p_0.05). Percentage of patients with flares was lower for all canakinumab groups (25mg 27.3%, 50mg 16.7%, 100mg 14.8%, 200mg 18.5%, 300mg 15.1%, q4wk 16.7%) compared to colchicine group (44.4%). All patients taking canakinumab were significantly less likely to experience at least one gout flare than patients taking colchicine (odds ratio range [0.22 - 0.47]; p_0.05 for all). Median baseline CRP levels were 2.86 mg/L for 25 mg, 3.42 mg/L for 50 mg, 1.76 mg/L for 100 mg, 3.66 mg/L for 200 mg, 3.21 mg/L for 300 mg, 3.23 mg/L for q4wk canakinumab groups and 2.69 mg/L for colchicine group. In all canakinumab groups with median CRP levels above the normal range at baseline, median levels declined within 15 days of treatment and were maintained at normal levels (ULN¼3 mg/L) throughout the 16 wk period. Adverse events (AEs) occurred in 52.7% (25 mg), 55.6% (50 mg), 51.9% (100 mg), 51.9% (200 mg), 54.7% (300 mg), 58.5% (q4wk) of patients on canakinumab vs 53.7% of patients on colchicine. Serious AEs (SAE) were reported in 2 (3.6%; 25 mg), 2 (3.7%, 50 mg), 3 (5.6%, 100 mg), 3 (5.6%, 200 mg), 3 (5.7%, 300 mg), 1 (1.9%, q4wk) patients on canakinumab and in 5 (4.6%) patients on colchicine. 1 fatal SAE (myocardial infarction, not related to study drug) occurred in colchicine group.Conclusions: In this randomized, double-blind active controlled study of flare prevention in gout patients initiating allopurinol therapy, treatment with canakinumab led to a statistically significant reduction in flares compared with colchicine and was well tolerated.Disclosure statement: U.A., A.B., G.K., D.R. and P.S. are employees of and have stock options or bold holdings with Novartis Pharma AG. E.M. is a principal investigator for Novartis Pharmaceuticals Corporation. E.N. has received consulting fees from Roche. N.S. has received research grants from Novartis Pharmaceuticals Corporation. A.S. has received consultancy fees from Novartis Pharma AG, Abbott, Bristol-Myers Squibb, Essex, Pfizer, MSD, Roche, UCB and Wyeth. All other authors have declared no conflicts of interest.

Response Prediction in Chronic Hepatitis C by Assessment of IP-10 and IL28B-Related Single Nucleotide Polymorphisms.

BACKGROUND: High baseline levels of IP-10 predict a slower first phase decline in HCV RNA and a poor outcome following interferon/ribavirin therapy in patients with chronic hepatitis C. Several recent studies report that single nucleotide polymorphisms (SNPs) adjacent to IL28B predict spontaneous resolution of HCV infection and outcome of treatment among HCV genotype 1 infected patients. METHODS AND FINDINGS: In the present study, we correlated the occurrence of variants at three such SNPs (rs12979860, rs12980275, and rs8099917) with pretreatment plasma IP-10 and HCV RNA throughout therapy within a phase III treatment trial (HCV-DITTO) involving 253 Caucasian patients. The favorable SNP variants (CC, AA, and TT, respectively) were associated with lower baseline IP-10 (P = 0.02, P = 0.01, P = 0.04) and were less common among HCV genotype 1 infected patients than genotype 2/3 (P<0.0001, P<0.0001, and P = 0.01). Patients carrying favorable SNP genotypes had higher baseline viral load than those carrying unfavorable variants (P = 0.0013, P = 0.029, P = 0.0004 respectively). Among HCV genotype 1 infected carriers of the favorable C, A, or T alleles, IP-10 below 150 pg/mL significantly predicted a more pronounced reduction of HCV RNA from day 0 to 4 (first phase decline), which translated into increased rates of RVR (62%, 53%, and 39%) and SVR (85%, 76%, and 75% respectively) among homozygous carriers with baseline IP-10 below 150 pg/mL. In multivariate analyses of genotype 1-infected patients, baseline IP-10 and C genotype at rs12979860 independently predicted the first phase viral decline and RVR, which in turn independently predicted SVR. CONCLUSIONS: Concomitant assessment of pretreatment IP-10 and IL28B-related SNPs augments the prediction of the first phase decline in HCV RNA, RVR, and final therapeutic outcome.

Affect-related synesthesias: A prospective view on their existence, expression and underlying mechanisms

The literature on developmental synaesthesia has seen numerous sensory combinations, with surprisingly few reports on synaesthesias involving affect. On the one hand, emotion, or more broadly affect, might be of minor importance to the synaesthetic experience (e.g. Sinke et al., 2012). On the other hand, predictions on how affect could be relevant to the synaesthetic experience remain to be formulated, in particular those that are driven by emotion theories. In this theoretical paper, we hypothesize that a priori studies on synaesthesia involving affect will observe the following. Firstly, the synaesthetic experience is not merely about discrete emotion processing or overall valence (positive, negative) but is determined by or even altered through cognitive appraisal processes. Secondly, the synaesthetic experience changes temporarily on a quantitative level according to i) the affective appraisal of the inducing stimulus or ii) the current affective state of the individual. These hypotheses are inferred from previous theoretical and empirical accounts on synaesthesia (including the few examples involving affect), different emotion theories, crossmodal processing accounts in synaesthetes and nonsynaesthetes, and the presumed stability of the synaesthetic experience. We hope that the current review will succeed in launching a new series of studies on "affective synaesthesias". We particularly hope that such studies will apply the same creativity in experimental paradigms as we have seen and still see when assessing and evaluating "traditional" synaesthesias.

Evaluation of C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as diagnostic parameters in sepsis-related fatalities.

The aims of this study were to investigate the usefulness of serum C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as postmortem markers of sepsis and to compare C-reactive protein and procalcitonin values in serum, vitreous humor, and cerebrospinal fluid in a series of sepsis cases and control subjects, in order to determine whether these measurements may be employed for the postmortem diagnosis of sepsis. Two study groups were formed, a sepsis group (eight subjects coming from the intensive care unit of two university hospitals, with a clinical diagnosis of sepsis in vivo) and control group (ten autopsy cases admitted to two university medicolegal centers, deceased from natural and unnatural causes, without elements to presume an underlying sepsis as the cause of death). Serum C-reactive protein and procalcitonin concentrations were significantly different between sepsis cases and control cases, whereas serum tumor necrosis factor alpha, interleukin-6, and interleukin-8 values were not significantly different between the two groups, suggesting that measurement of interleukin-6, interleukin-8, and tumor necrosis factor alpha is non-optimal for postmortem discrimination of cases with sepsis. In the sepsis group, vitreous procalcitonin was detectable in seven out of eight cases. In the control group, vitreous procalcitonin was clearly detectable only in one case, which also showed an increase of all markers in serum and for which the cause of death was myocardial infarction associated with multi-organic failure. According to the results of this study, the determination of vitreous procalcitonin may be an alternative to the serum procalcitonin for the postmortem diagnosis of sepsis.

Exotic taxa less related to native species are more invasive.

Some species introduced into new geographical areas from their native ranges wreak ecological and economic havoc in their new environment. Although many studies have searched for either species or habitat characteristics that predict invasiveness of exotic species, the match between characteristics of the invader and those of members of the existing native community may be essential to understanding invasiveness. Here, we find that one metric, the phylogenetic relatedness of an invader to the native community, provides a predictive tool for invasiveness. Using a phylogenetic supertree of all grass species in California, we show that highly invasive grass species are, on average, significantly less related to native grasses than are introduced but noninvasive grasses. The match between the invader and the existing native community may explain why exotic pest species are not uniformly noxious in all novel habitats. Relatedness of invaders to the native biota may be one useful criterion for prioritizing management efforts of exotic species.

Interdisciplinary intervention for work-related musculoskeletal disorders

The proposed research aims to address the work-related MSD management issue through an interdisciplinary intervention involving clinical and occupational health competencies (rheumatology, occupational medicine, ergonomics). Workers enduring MSD (especially back-pain) and absent from work are selected from volunteering companies (construction, hospitals, public transport, delivery networks). The workers are randomly placed into two groups : the control group benefits from an usual MSD management strategy and the intervention group benefits from a case-management strategy including workhardening treatment (work oriented reeducation) and ergonomic intervention in the workplace. The comparison of health and work-related variables prior and after intervention in the two groups will be used to assess the intervention efficiency and its economic benefits. We expect to produce new strategies for the management of MSD and workplace rehabilitation as well as guidelines for both authorities and companies.