Mirroring everyday clinical practice in clinical trial design: a new concept to improve the external validity of randomized double-blind placebo-controlled trials in the pharmacological treatment of major depression

Background: Randomized, double-blind, placebo-controlled trials constitute the gold standard in clinical research when testing the efficacy of new psychopharmacological interventions in the treatment of major depression. However, the blinded use of placebo has been found to influence clinical trial outcomes and may bias patient selection. Discussion: To improve clinical trial design in major depression so as to reflect clinical practice more closely we propose to present patients with a balanced view of the benefits of study participation irrespective of their assignment to placebo or active treatment. In addition every participant should be given the option to finally receive the active medication. A research agenda is outlined to evaluate the impact of the proposed changes on the efficacy of the drug to be evaluated and on the demographic and clinical characteristics of the enrollment fraction with regard to its representativeness of the eligible population. Summary: We propose a list of measures to be taken to improve the external validity of double-blind, placebocontrolled trials in major depression. The recommended changes to clinical trial design may also be relevant for other psychiatric as well as medical disorders in which expectations regarding treatment outcome may affect the outcome itself

Antigen expression determines adenoviral vaccine potency independent of IFN and STING signaling

Recombinant adenoviral vectors (rAds) are lead vaccine candidates for protection against a variety of pathogens, including Ebola, HIV, tuberculosis, and malaria, due to their ability to potently induce T cell immunity in humans. However, the ability to induce protective cellular immunity varies among rAds. Here, we assessed the mechanisms that control the potency of CD8 T cell responses in murine models following vaccination with human-, chimpanzee-, and simian-derived rAds encoding SIV-Gag antigen (Ag). After rAd vaccination, we quantified Ag expression and performed expression profiling of innate immune response genes in the draining lymph node. Human-derived rAd5 and chimpanzee-derived chAd3 were the most potent rAds and induced high and persistent Ag expression with low innate gene activation, while less potent rAds induced less Ag expression and robustly induced innate immunity genes that were primarily associated with IFN signaling. Abrogation of type I IFN or stimulator of IFN genes (STING) signaling increased Ag expression and accelerated CD8 T cell response kinetics but did not alter memory responses or protection. These findings reveal that the magnitude of rAd-induced memory CD8 T cell immune responses correlates with Ag expression but is independent of IFN and STING and provide criteria for optimizing protective CD8 T cell immunity with rAd vaccines

Campionamento biologico delle catture commerciali Sezione III.C - Variabili biologiche relative al mestiere e dei parametri biologici Sezione III.E - Variabili biologiche relative agli stock del Programma Nazionale Sub-area Geografica (GSA16) – Stretto di Sicilia Anno 2015

Il campionamento biologico delle catture/sbarcati commerciali, sezione C – Relative al mestiere ed E – Relative agli stock, nell’ambito del Programma Nazionale per la Raccolta Dati Alieutici (PNRDA) (Reg. Ce. N°199/2008; N°665/2008 e decisione della commissione N°949/2008), ha l’obiettivo di valutare la composizione in taglia e/o età del pescato ed ottenere altre informazioni sulla biologia delle specie bersaglio, quali le chiavi età/lunghezza, la relazione lunghezza/peso, i parametri di crescita, la composizione in sesso e le condizioni di maturità sessuale. Il campionamento delle catture/sbarchi commerciali (campionamento biologico - CAMPBIOL) risulta di grande importanza per conoscere come agisce il prelievo dei diversi ”metiers” sulle diverse specie, in termini di variazioni dell’abbondanza e struttura demografica delle risorse da pesca. Il campionamento biologico risponde, quindi, principalmente alle seguenti esigenze: 1. Ricostruire il pattern di sfruttamento dei diversi ”métiers” per le diverse specie. 2. Ricostruire la struttura demografica delle catture commerciali/sbarchi di ogni specie (in taglia/età), considerando tutti i ”métiers” che incidono significativamente sull’ammontare globale delle catture. 3. Consentire lo studio dei fenomeni biologici rilevanti, quali la crescita ed il ciclo sessuale, che variano nel corso dell’anno. 4. Acquisire informazioni sulla struttura demografica con specifico riferimento allo stadio di maturazione gonadica (maturità/taglia-età) ed alla relazione fra lunghezza e peso corporeo (taglia-peso/età). Il Programma Nazionale prevede il rilievo dei parametri significativi ai fini della caratterizzazione biologica del prodotto della pesca, principalmente nell’ambito di due differenti moduli: Modulo di valutazione del settore della pesca Sezione C – “Variabili biologiche relative al mestiere” Sezione E – “Variabili biologiche relative agli stock

Protective CD8+ T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation.

Induction of antigen-specific CD8(+) T cells offers the prospect of immunization against many infectious diseases, but no subunit vaccine has induced CD8(+) T cells that correlate with efficacy in humans. Here we demonstrate that a replication-deficient chimpanzee adenovirus vector followed by a modified vaccinia virus Ankara booster induces exceptionally high frequency T-cell responses (median >2400 SFC/10(6) peripheral blood mononuclear cells) to the liver-stage Plasmodium falciparum malaria antigen ME-TRAP. It induces sterile protective efficacy against heterologous strain sporozoites in three vaccinees (3/14, 21%), and delays time to patency through substantial reduction of liver-stage parasite burden in five more (5/14, 36%), P=0.008 compared with controls. The frequency of monofunctional interferon-γ-producing CD8(+) T cells, but not antibodies, correlates with sterile protection and delay in time to patency (P(corrected)=0.005). Vaccine-induced CD8(+) T cells provide protection against human malaria, suggesting that a major limitation of previous vaccination approaches has been the insufficient magnitude of induced T cells

Campionamento biologico delle catture commerciali Sezione III.C - Variabili biologiche relative al mestiere e dei parametri biologici Sezione III.E - Variabili biologiche relative agli stock del Programma Nazionale

Il campionamento biologico delle catture/sbarcati commerciali, sezione C – Relative al mestiere ed E – Relative agli stock (Campbiol), nell’ambito del Programma Nazionale per la Raccolta Dati Alieutici (PNRDA) (Reg. Ce. N°199/2008; N°665/2008 e decisione della commissione N°949/2008) risulta di grande importanza per conoscere come agisce il prelievo dei diversi ”metiers” sulle diverse specie, in termini di variazioni dell’abbondanza e struttura demografica delle risorse da pesca. Il campionamento biologico risponde, quindi, principalmente alle seguenti esigenze: 1. Ricostruire la struttura demografica delle catture commerciali/sbarchi di ogni specie (in taglia/età), considerando tutti i ”métiers” che incidono significativamente sull’ammontare globale delle catture. 2. Ricostruire il pattern di sfruttamento dei diversi ”métiers” per le diverse specie. 3. Consentire lo studio dei fenomeni biologici rilevanti, quali la crescita ed il ciclo sessuale, che variano nel corso dell’anno. 4. Acquisire informazioni sulla struttura demografica con specifico riferimento allo stadio di maturazione gonadica (maturità/taglia-età) ed alla relazione fra lunghezza e peso corporeo (taglia-peso/età). Il Programma Nazionale prevede il rilievo dei parametri significativi ai fini della caratterizzazione biologica del prodotto della pesca, principalmente nell’ambito di due differenti moduli: Modulo di valutazione del settore della pesca Sezione C – “Variabili biologiche relative al mestiere” Sezione E – “Variabili biologiche relative agli stock

The placebo effect: from concepts to genes

Despite its initial treatment as a nuisance variable, the placebo effect is now recognized as a powerful determinant of health across many different diseases and encounters. This is in light of some remarkable findings ranging from demonstrations that the placebo effect significantly modulates the response to active treatments in conditions such as pain, anxiety, Parkinson’s disease, and some surgical procedures. Here, we review pioneering studies and recent advances in behavioural, neurobiological, and genetic influences on the placebo effect. Based on a previous developed conceptual framework, the placebo effect is presented as the product of a general expectancy learning mechanism in which verbal, conditioned, observational, and social cues are centrally integrated to change behaviours and outcomes. Examples of the integration of verbal and conditioned cues, such as instructed reversal of placebo effects are also incorporated into this model. We discuss neuroimaging studies that using well-established behavioral paradigms have identified key brain regions and modulatory mechanisms underlying placebo effects. Finally, we present a synthesis of recent genetics studies on the placebo effect, highlighting a promising link between genetic variants in the dopamine, opioid, serotonin, and endocannabinoid pathways and placebo responsiveness. Greater understanding of the behavioural, neurobiological, and genetic influences on the placebo effect is critical for evaluating medical interventions and may allow health professionals to tailor and personalize interventions in order to maximise treatment outcomes in clinical settings

The placebo effect: from concepts to genes

Despite its initial treatment as a nuisance variable, the placebo effect is now recognized as a powerful determinant of health across many different diseases and encounters. This is in light of some remarkable findings ranging from demonstrations that the placebo effect significantly modulates the response to active treatments in conditions such as pain, anxiety, Parkinson’s disease, and some surgical procedures. Here, we review pioneering studies and recent advances in behavioural, neurobiological, and genetic influences on the placebo effect. Based on a previous developed conceptual framework, the placebo effect is presented as the product of a general expectancy learning mechanism in which verbal, conditioned, observational, and social cues are centrally integrated to change behaviours and outcomes. Examples of the integration of verbal and conditioned cues, such as instructed reversal of placebo effects are also incorporated into this model. We discuss neuroimaging studies that using well-established behavioral paradigms have identified key brain regions and modulatory mechanisms underlying placebo effects. Finally, we present a synthesis of recent genetics studies on the placebo effect, highlighting a promising link between genetic variants in the dopamine, opioid, serotonin, and endocannabinoid pathways and placebo responsiveness. Greater understanding of the behavioural, neurobiological, and genetic influences on the placebo effect is critical for evaluating medical interventions and may allow health professionals to tailor and personalize interventions in order to maximise treatment outcomes in clinical settings