Dissecting TCR-MHC/peptide complex interactions with A2/peptide multimers incorporating tumor antigen peptide variants: crucial role of interaction kinetics on functional outcomes.

Soluble peptide/MHC-class-I (pMHC) multimers have recently emerged as unique reagents for the study of specific interactions between the pMHC complex and the TCR. Here, we assessed the relative binding efficiency of a panel of multimers incorporating single-alanine-substituted variants of the tumor-antigen-derived peptide MAGE-A10(254-262) to specific CTL clones displaying different functional avidity. For each individual clone, the efficiency of binding of multimers incorporating MAGE-A10 peptide variants was, in most cases, in good although not linear correlation with the avidity of recognition of the corresponding variant. In addition, we observed two types of discrepancies between efficiency of recognition and multimer binding. First, for some peptide variants, efficient multimer binding was detected in the absence of measurable effector functions. Some of these peptide variants displayed antagonist activity. Second, when comparing different clones we found clear discrepancies between the dose of peptide required to obtain half-maximal lysis in CTL assays and the binding efficiency of the corresponding multimers. These discrepancies, however, were resolved when the differential stability of the TCR/pMHC complexes was determined. For individual clones, decreased recognition correlated with increased TCR/pMHC off-rate. TCR/pMHC complexes formed by antagonist ligands displayed off-rates faster than those of TCR/pMHC complexes formed with weak agonists. In addition, when comparing different clones, the efficiency of multimer staining correlated better with relative multimer off-rates than with half-maximal lysis values. Altogether, the data presented here reconcile and extend our previous results on the impact of the kinetics of interaction of TCR with pMHC complexes on multimer binding and underline the crucial role of TCR/pMHC off-rates for the functional outcome of such interactions.

Role of CCR5 genetic polymorphisms in clinical and histological outcomes of hepatitis C

Background: The CCR5 32-base deletion (CCR5D32), which results into the expression of a non-functioning receptor, has been associated with H CV c learance a nd may influence fibrosis progression i n hepatitis C . We a ssessed t he link between C CR5D32 and c linical outcomes o f HCV. Methods: Genomic D NA was isolated and analyzed b y PCR to i dentify C CR5D32 in 1 303 anti-HCV-positive persons (161 clearers and 1142 chronically infected, 1007 with a liver biopsy). Results: Overall, 200 (15.3%) w ere heterozygote a nd 16 (1.2%) homozygote for CCR5D32. H CV c learance (by univariate) was associated with m ale sex (OR 0.633, 9 5% C I 0.428-0.935, P=0.022), HCV acquisition by blood transfusion (OR 0.360, 95% CI 0.175-0.741, P =0.0056), polymorphisms at IL28B rs12979860 ( OR 0.482, 9 5% C I 0.277-0.839, P =0.0098) a nd rs8099917 ( OR 0.291, 95% CI 0.167-0.508, P=0.000014), but not with CCR5D32. However, CCR5D32 was associated with spontaneous HCV clearance when the 482 females only w ere considered, although the number of homozygotes was small (1/427 chronic vs 3/51 clearers) (OR 24.56, 95% C I 12.5-241.4, P =0.006). T he CCR5D32 deletion was not associated with liver grading and staging scores, fibrosis progression rate, or t herapy response. Conclusions: At v ariance w ith a p revious report (Nattermann et a l, 2011), suggesting that a n on-functional CCR5 m ay hamper H CV clearance, C CR5D32 appeared to b e associated with an increased spontaneous eradication in women (but not men). Given the small number of CCR5D32 homozygote persons, these data need further validation.

Does Warfare Matter? Severity, Duration, and Outcomes of Civil Wars

Importa si una guerra civil es combat com un conflicte irregular, convencional o simètric no convencional? En altres paraules, tenen les “tecnologies de la rebel·lió” un impacte sobre la gravetat d’una guerra, la seva durada o el seu resultat? Aquest treball mostra que els conflictes irregulars duren més que els altres tipus de conflicte, mentre els convencionals tendeixen a ser més greus en termes de letalitat al camp de batalla. D’altra banda, els conflictes irregulars tendeixen a ser guanyats pels governs, mentre els altres són més propensos a acabar en empat. Substancialment, aquests resultats ens ajuden a donar sentit a l’evolució de les guerres civils, les quals tendeixen a ser més curtes, més intenses i més difícils per als governs. Teòricament, aquests resultats donen suport a la importància de la tecnologia de rebel·lió a l’estudiar la gravetat, la durada i els resultats de les guerres civils; a més, contribueixen a una millor comprensió de la contribució històrica de la guerra irregular a la construcció de l’Estat i al canvi social.

Outcomes of patients on dual-boosted PI regimens : experience of the Swiss HIV cohort study

Rapport de SynthèseLa thérapie antirétrovirale a progressée de manière significative depuis te début de l'épidémie du syndrome d'immunodéficience acquise (SIDA). Durant les 20 dernières années, plusieurs combinaisons de traitements ont été utilisées avec succès menant à une réduction de la mortalité associée. Par contre, le traitement a aussi engendré des cas de résistances multiples avec comme résultat, le besoin d'utiliser plusieurs molécules en combinaison, et une augmentation des cas de toxicité. Une stratégie souvent employée fût la combinaison de deux molécules inhibitrices de la protéase en même temps en combinaison avec une troisième molécule, le ritonavir. (DBPI).La cohorte Suisse sur le VIH existe depuis 1987 et permet d'étudier de façon longitudinale les patients qui y sont inscrits. Pour ce travail de thèse, nous avons étudié les patients inscrits à la cohorte suisse de 1996 à 2007 qui ont reçu une combinaison DBPI.Pendant la période étudiée, un total de 405 patients ont reçu un traitement DBPI, dont 295 patients ont reçu le DBPI pour plus de 6 mois. La durée médiane du traitement était de 2.2 ans. Sur les 287 patients qui étaient en échec viral au début du traitement (défini comme HIV RNA>400 copies/ml), 64.1% ont réussi à supprimer la virémie et 54.4% ont eu une suppression dans les 24 semaines qui ont suivi le début de la thérapie. Les patients avaient reçu en moyenne 6 combinaisons de traitement différentes avant le début de la thérapie DBPi. Pour les patients qui ont arrêté le traitement DBPI, la cause principale de l'arrêt était due au souhait du patient (48.3%), à l'échec virologique (22.5%) et à la toxicité (15.8%). Les patients ayant reçu le traitement après 1999, ou ayant été traités avec une combinaison de Lopinavir-ritonvir/saquinavir ou lopinavir-ritonavir/atazanavir arrivaient à supprimer leur virémie plus souvent que ceux qui avaient reçu d'autres combinaisons.Cette étude constitue la plus grande étude publiée sur le sujet de l'utilisation des DBPI pour les patients à résistances multiples. Malgré le fait que c'est une étude observationnelle, nous pouvons attester que le taux de succès était de 64.4%, le taux de toxicité était relativement bas (15.8%) et que la plus part des patients ont toléré ces combinaisons, malgré le taux élevé d'effets secondaires souvent rapportés. En somme, cette approche pourrait être envisagée dans des situations ou les nouveaux traitements tels que les inhibiteurs de l'intégrase et du CCR5 ne sont pas encore disponibles.

Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS): a prospective registry study.

BACKGROUND: Treatment strategies for acute basilar artery occlusion (BAO) are based on case series and data that have been extrapolated from stroke intervention trials in other cerebrovascular territories, and information on the efficacy of different treatments in unselected patients with BAO is scarce. We therefore assessed outcomes and differences in treatment response after BAO. METHODS: The Basilar Artery International Cooperation Study (BASICS) is a prospective, observational registry of consecutive patients who presented with an acute symptomatic and radiologically confirmed BAO between November 1, 2002, and October 1, 2007. Stroke severity at time of treatment was dichotomised as severe (coma, locked-in state, or tetraplegia) or mild to moderate (any deficit that was less than severe). Outcome was assessed at 1 month. Poor outcome was defined as a modified Rankin scale score of 4 or 5, or death. Patients were divided into three groups according to the treatment they received: antithrombotic treatment only (AT), which comprised antiplatelet drugs or systemic anticoagulation; primary intravenous thrombolysis (IVT), including subsequent intra-arterial thrombolysis; or intra-arterial therapy (IAT), which comprised thrombolysis, mechanical thrombectomy, stenting, or a combination of these approaches. Risk ratios (RR) for treatment effects were adjusted for age, the severity of neurological deficits at the time of treatment, time to treatment, prodromal minor stroke, location of the occlusion, and diabetes. FINDINGS: 619 patients were entered in the registry. 27 patients were excluded from the analyses because they did not receive AT, IVT, or IAT, and all had a poor outcome. Of the 592 patients who were analysed, 183 were treated with only AT, 121 with IVT, and 288 with IAT. Overall, 402 (68%) of the analysed patients had a poor outcome. No statistically significant superiority was found for any treatment strategy. Compared with outcome after AT, patients with a mild-to-moderate deficit (n=245) had about the same risk of poor outcome after IVT (adjusted RR 0.94, 95% CI 0.60-1.45) or after IAT (adjusted RR 1.29, 0.97-1.72) but had a worse outcome after IAT compared with IVT (adjusted RR 1.49, 1.00-2.23). Compared with AT, patients with a severe deficit (n=347) had a lower risk of poor outcome after IVT (adjusted RR 0.88, 0.76-1.01) or IAT (adjusted RR 0.94, 0.86-1.02), whereas outcomes were similar after treatment with IAT or IVT (adjusted RR 1.06, 0.91-1.22). INTERPRETATION: Most patients in the BASICS registry received IAT. Our results do not support unequivocal superiority of IAT over IVT, and the efficacy of IAT versus IVT in patients with an acute BAO needs to be assessed in a randomised controlled trial. FUNDING: Department of Neurology, University Medical Center Utrecht.

Pregnancy outcomes following use of escitalopram: a prospective comparative cohort study.

Escitalopram is a serotonin reuptake inhibitor prescribed for depression and anxiety. There is a paucity of information regarding safety in pregnancy. The objective of this study was to determine whether escitalopram is associated with an increased risk for major malformations or other adverse outcomes following use in pregnancy. The authors analyzed pregnancy outcomes in women exposed to escitalopram (n = 212) versus other antidepressants (n = 212) versus nonteratogenic exposures (n = 212) and compared the outcomes. Among the escitalopram exposures were 172 (81%) live births, 32 (15%) spontaneous abortions, 6 (2.8%) therapeutic abortions, 3 stillbirths (1.7%), and 3 major malformations (1.7%). The only significant differences among groups was the rate of low birth weight (<2500 g) and overall mean birth weight (P = .225). However, spontaneous abortion rates were higher in both antidepressant groups (15% and 16%) compared with controls (8.5%; P = .066). There were lower rates of live births (P = .006), lower overall birth weight (P < .001), and increased rates of low birth weight (<2500 g; P = .009) with escitalopram. Spontaneous abortion rates were nearly double in both antidepressant groups (15% and 16%) compared with controls (8.5%) but not significant (P = .066). Escitalopram does not appear to be associated with an increased risk for major malformations but appears to increase the risk for low birth weight, which was correlated with the increase in infants weighing <2500 g. In addition, the higher rates of spontaneous abortions in both antidepressant groups confirmed previous findings.

Effects of recommended levels of physical activity on pregnancy outcomes.

OBJECTIVE: We sought to examine the relation between recommended levels of physical activity during pregnancy and pregnancy outcomes. STUDY DESIGN: We conducted an observational study with energy expenditure, aerobic fitness, and sleeping heart rate measured in 44 healthy women in late pregnancy. Medical records were examined for pregnancy outcome. RESULTS: Active women, who engaged in > or = 30 minutes of moderate physical activity per day, had significantly better fitness and lower sleeping heart rate compared to the inactive. Duration of second stage of labor was 88 and 146 minutes in the active vs inactive women, respectively (P = .05). Crude odds ratio of operative delivery in the inactive vs the active was 3.7 (95% confidence interval, 0.87-16.08). Birthweight, maternal weight gain, and parity adjusted odds ratio was 7.6 (95% confidence interval, 1.23-45.8). Neonatal condition and other obstetric outcomes were similar between groups. CONCLUSION: Active women have better aerobic fitness as compared to inactive women. The risk for operative delivery is lower in active women compared to inactive, when controlled for birthweight, maternal weight gain, and parity. Further studies with larger sample size are required to confirm the association between physical activity and pregnancy outcomes.

Conditional and syllogistic deductive tasks dissociate functionally during premise integration.

Deduction allows us to draw consequences from previous knowledge. Deductive reasoning can be applied to several types of problem, for example, conditional, syllogistic, and relational. It has been assumed that the same cognitive operations underlie solutions to them all; however, this hypothesis remains to be tested empirically. We used event-related fMRI, in the same group of subjects, to compare reasoning-related activity associated with conditional and syllogistic deductive problems. Furthermore, we assessed reasoning-related activity for the two main stages of deduction, namely encoding of premises and their integration. Encoding syllogistic premises for reasoning was associated with activation of BA 44/45 more than encoding them for literal recall. During integration, left fronto-lateral cortex (BA 44/45, 6) and basal ganglia activated with both conditional and syllogistic reasoning. Besides that, integration of syllogistic problems additionally was associated with activation of left parietal (BA 7) and left ventro-lateral frontal cortex (BA 47). This difference suggests a dissociation between conditional and syllogistic reasoning at the integration stage. Our finding indicates that the integration of conditional and syllogistic reasoning is carried out by means of different, but partly overlapping, sets of anatomical regions and by inference, cognitive processes. The involvement of BA 44/45 during both encoding (syllogisms) and premise integration (syllogisms and conditionals) suggests a central role in deductive reasoning for syntactic manipulations and formal/linguistic representations.

Iowa Juvenile Crime Prevention Community Grant Fund Outcomes Report and FY 2002 Juvenile Justice Youth Development Program Summary, 2002

This document contains two related, but separate reports. The Juvenile Crime Prevention Community Grant Fund Outcomes Report is a summary of outcomes from services and activities funded through the Juvenile Crime Prevention Community Grant Fund in FY2001. The Juvenile Justice Youth Development Program Summary describes Iowa communities current prevention and sanction programs supported with funding from the Division of Criminal and Juvenile Justice Planning (CJJP) during FY2002.

Juvenile Crime Prevention Community Grant Fund Outcomes Report and FY 2002 Juvenile Justice Youth Development Program Summary, 2002

This document contains two related, but separate reports. The Juvenile Crime Prevention Community Grant Fund Outcomes Report is a summary of outcomes from services and activities funded through the Juvenile Crime Prevention Community Grant Fund in FY 2001. The Juvenile Justice Youth Development Program Summary describes Iowa communities’ current prevention and sanction programs supported with funding from the Division of Criminal and Juvenile Justice Planning (CJJP) during FY 2002.

Iowa Juvenile Crime Prevention Community Grant Fund Outcomes Report, 2000

The following Outcome Reports are derived from the Iowa Juvenile Crime Prevention Community Grant Fund 1999-2000 Report compiled by the Division of Criminal and Juvenile Justice Planning, Department of Human Rights. The report includes background information on the Community Grant Fund and more detailed information on the individual community programs (community collaboration, program overview, contact information, and budget).

Defining responses to therapy and study outcomes in clinical trials of invasive fungal diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer consensus criteria.

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.

Feasibility and clinical outcomes when using practice guidelines for evaluation of fever in returning travelers and migrants : a validation study.

BACKGROUND: Practice guidelines for examining febrile patients presenting upon returning from the tropics were developed to assist primary care physicians in decision making. Because of the low level of evidence available in this field, there was a need to validate them and assess their feasibility in the context they have been designed for. OBJECTIVES: The objectives of the study were to (1) evaluate physicians' adherence to recommendations; (2) investigate reasons for non-adherence; and (3) ensure good clinical outcome of patients, the ultimate goal being to improve the quality of the guidelines, in particular to tailor them for the needs of the target audience and population. METHODS: Physicians consulting the guidelines on the Internet (www.fevertravel.ch) were invited to participate in the study. Navigation through the decision chart was automatically recorded, including diagnostic tests performed, initial and final diagnoses, and clinical outcomes. The reasons for non-adherence were investigated and qualitative feedback was collected. RESULTS: A total of 539 physician/patient pairs were included in this study. Full adherence to guidelines was observed in 29% of the cases. Figure-specific adherence rate was 54.8%. The main reasons for non-adherence were as follows: no repetition of malaria tests (111/352) and no presumptive antibiotic treatment for febrile diarrhea (64/153) or abdominal pain without leukocytosis (46/101). Overall, 20% of diversions from guidelines were considered reasonable because there was an alternative presumptive diagnosis or the symptoms were mild, which means that the corrected adherence rate per case was 40.6% and corrected adherence per figure was 61.7%. No death was recorded and all complications could be attributed to the underlying illness rather than to adherence to guidelines. CONCLUSIONS: These guidelines proved to be feasible, useful, and leading to good clinical outcomes. Almost one third of physicians strictly adhered to the guidelines. Other physicians used the guidelines not to forget specific diagnoses but finally diverged from the proposed attitudes. These diversions should be scrutinized for further refinement of the guidelines to better fit to physician and patient needs.