Which placebo to cure depression? A thought-provoking network meta-analysis

BACKGROUND: Antidepressants are often considered to be mere placebos despite the fact that meta-analyses are able to rank them. It follows that it should also be possible to rank different placebos, which are all made of sucrose. To explore this issue, which is rather more epistemological than clinical, we designed an unusual meta-analysis to investigate whether the effects of placebo in one situation are different from the effects of placebo in another situation. METHODS: Published and unpublished studies were searched for by three reviewers on Medline, the Cochrane Library, Embase, clinicaltrials.gov, Current Controlled Trial, in bibliographies, and by mailing key organizations. The following studies in first-line treatment for major depressive disorder were considered to construct an “evidence network”: 1) randomized controlled trials (RCTs) versus placebo on fluoxetine, venlafaxine and 2) fluoxetine versus venlafaxine head-to-head RCTs. Two network meta-analyses were run to indirectly compare response and remission rates among three different placebos: 1) fluoxetine placebo, 2) venlafaxine placebo, and 3) venlafaxine/fluoxetine placebo (that is, placebo compared to both venlafaxine and fluoxetine). Publication biases were assessed using funnel plots and statistically tested. RESULTS: The three placebos were not significantly different in terms of response or remission. The antidepressant agents were significantly more efficacious than the placebos, and venlafaxine was more efficacious than fluoxetine. The funnel plots, however, showed a major publication bias. CONCLUSION: The presence of significant levels of publication bias indicates that we cannot even be certain of the conclusion that sucrose equals sucrose in trials of major depressive disorder. This result should remind clinicians to step back to take a more objective view when interpreting a scientific result. It is of crucial importance for their practice, far more so than ranking antidepressant efficacy

Antidepressant Response in Major Depressive Disorder: A Meta-Regression Comparison of Randomized Controlled Trials and Observational Studies

To compare response to antidepressants between randomized controlled trials (RCTs) and observational trials.Published and unpublished studies (from 1989 to 2009) were searched for by 2 reviewers on Medline, the Cochrane library, Embase, clinicaltrials.gov, Current Controlled Trial, bibliographies and by mailing key organisations and researchers. RCTs and observational studies on fluoxetine or venlafaxine in first-line treatment for major depressive disorder reported in English, French or Spanish language were included in the main analysis. Studies including patients from a wider spectrum of depressive disorders (anxious depression, minor depressive episode, dysthymia) were added in a second analysis. The main outcome was the pre-/post-treatment difference on depression scales standardised to 100 (17-item or 21-item Hamilton Rating Scale for Depression or Montgomery and Åsberg Rating Scale) in each study arm. A meta-regression was conducted to adjust the comparison between observational studies and RCTs on treatment type, study characteristics and average patient characteristics. 12 observational studies and 109 RCTs involving 6757 and 11035 patients in 12 and 149 arms were included in the main analysis. Meta-regression showed that the standardised treatment response in RCTs is greater by a magnitude of 4.59 (2.61 to 6.56). Study characteristics were related to standardised treatment response, positively (study duration, number of follow-up assessments, outpatients versus inpatients, per protocol analysis versus intention to treat analysis) or negatively (blinded design, placebo design). At patient level, response increased with baseline severity and decreased with age. Results of the second analysis were consistent with this.Response to antidepressants is greater in RCTs than in observational studies. Observational studies should be considered as a necessary complement to RCTs

Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity

ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1 has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized. International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing. We identified 13 individuals with heterozygous likely pathogenic variants in ARFGEF1. These individuals displayed congruent clinical features of developmental delay, behavioral problems, abnormal findings on brain magnetic resonance image (MRI), and epilepsy for almost half of them. While nearly half of the cohort carried de novo variants, at least 40% of variants were inherited from mildly affected parents who were clinically re-evaluated by reverse phenotyping. Our in silico predictions and in vitro assays support the contention that ARFGEF1-related conditions are caused by haploinsufficiency, and are transmitted in an autosomal dominant fashion with variable expressivity. We provide evidence that loss-of-function variants in ARFGEF1 are implicated in sporadic and familial cases of developmental delay with or without epilepsy

The 16th Data Release of the Sloan Digital Sky Surveys: First Release from the APOGEE-2 Southern Survey and Full Release of eBOSS Spectra

This paper documents the 16th data release (DR16) from the Sloan Digital Sky Surveys (SDSS), the fourth and penultimate from the fourth phase (SDSS-IV). This is the first release of data from the Southern Hemisphere survey of the Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2); new data from APOGEE-2 North are also included. DR16 is also notable as the final data release for the main cosmological program of the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), and all raw and reduced spectra from that project are released here. DR16 also includes all the data from the Time Domain Spectroscopic Survey and new data from the SPectroscopic IDentification of ERosita Survey programs, both of which were co-observed on eBOSS plates. DR16 has no new data from the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey (or the MaNGA Stellar Library "MaStar"). We also preview future SDSS-V operations (due to start in 2020), and summarize plans for the final SDSS-IV data release (DR17)

The 16th Data Release of the Sloan Digital Sky Surveys: First Release from the APOGEE-2 Southern Survey and Full Release of eBOSS Spectra

This paper documents the 16th data release (DR16) from the Sloan Digital Sky Surveys (SDSS), the fourth and penultimate from the fourth phase (SDSS-IV). This is the first release of data from the Southern Hemisphere survey of the Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2); new data from APOGEE-2 North are also included. DR16 is also notable as the final data release for the main cosmological program of the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), and all raw and reduced spectra from that project are released here. DR16 also includes all the data from the Time Domain Spectroscopic Survey and new data from the SPectroscopic IDentification of ERosita Survey programs, both of which were co-observed on eBOSS plates. DR16 has no new data from the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey (or the MaNGA Stellar Library "MaStar"). We also preview future SDSS-V operations (due to start in 2020), and summarize plans for the final SDSS-IV data release (DR17)

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance.

Investment in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing in Africa over the past year has led to a major increase in the number of sequences that have been generated and used to track the pandemic on the continent, a number that now exceeds 100,000 genomes. Our results show an increase in the number of African countries that are able to sequence domestically and highlight that local sequencing enables faster turnaround times and more-regular routine surveillance. Despite limitations of low testing proportions, findings from this genomic surveillance study underscore the heterogeneous nature of the pandemic and illuminate the distinct dispersal dynamics of variants of concern-particularly Alpha, Beta, Delta, and Omicron-on the continent. Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve while the continent faces many emerging and reemerging infectious disease threats. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Caractérisation et remédiation des difficultés cognitives et émotionnelles dans l’anorexie mentale : une objectivation est-elle possible ?

Anorexia Nervosa (AN) is a complex and difficult-to-treat illness characterised by the severity of its prognosis. There is growing evidence suggesting that some cognitive difficulties (poor set-shifting, lack of central coherence) may be critically involved in the development and maintenance of AN. Studies in schizophrenia showed that it is possible to translate evidence-based research into clinical practice and to improve neuropsychological and cognitive functioning using Cognitive Remediation Therapy (CRT). CRT for AN was developed by Pr Tchanturia and colleagues to address the AN patients’ thinking styles. Rather than targeting eating symptoms, CRT is designed to encourage the patients to reflect on and try to modify their information-processing styles and behaviors, by using simple cognitive exercises, delivered in a motivational style. To date, studies on CRT for AN showed some improvements in cognitive functioning but also a good acceptability. The aims of the randomized controlled trial Trecogam were to adapt CRT for AN in French, then to compare its effectiveness with a sham therapy. The sham therapy has been designed to match the CRT format: an individual manualized therapist-led 10-sessions program (2 sessions/week). It avoids set-shifting and central coherence training but rather taps 3 domains: emotional expression and recognition, personality exploration and interpersonal functioning (PER: Personality – Emotions – Relationships). We recruited 64 AN inpatients in 4 specialized care units (Parisian area); they were randomized in CRT or PER arm. Clinical status, cognitive and socio-emotional functioning were assessed before and after intervention. Our first line of research (two studies) concerned cognitive functioning. First, in order to control for learning effects, we developed and explored, in the entire AN sample, alternative versions of neuropsychological tests that are widely used in the context of the evaluation of CRT. The aim of the second study was to assess the contribution of CRT (relative to the PER) on objective and subjective cognitive functioning. Our second line of research (two studies) concerned emotional difficulties in AN. A first study was conducted in a general sample of 824 young adults to validate a measure of Perceived Emotional Intelligence (PEI): the Trait-Meta-Mood-Scale (TMMS). The TMMS was completed by the AN patients and this study allowed to further characterize their emotional difficulties, in comparison with our normative sample. In a second study, we explored contributions of the PER intervention (versus the CRT) on the PEI dimensions and anxio-depressive symptoms. From a methodological perspective, this work helped to provide reliable measures of cognitive (alternative versions of Brixton task and Rey Complex Figure) and emotional functioning (TMMS). Regarding the interventions (CRT and PER), our results do not show superiority of one over another on our variables of interest. However, we observed a good retention and acceptability of both interventions, and an important satisfaction from patients’ perspective. We believe that they could be useful first steps and complementary approaches to the treatment as usual of patients with severe AN. We also discuss future potential improvements of these interventions.L’anorexie mentale (AM) est une pathologie psychiatrique caractérisée par sa gravité et la sévérité de son pronostic. A ce jour, si une approche pluridisciplinaire et multifocale est privilégiée pour prendre en charge les patients, il n’en demeure pas moins qu’aucun traitement n’a démontré sa supériorité chez l’adulte. Des avancées récentes dans le domaine des neurosciences cognitives et affectives ont permis d’ouvrir la voie au développement de nouvelles modalités thérapeutiques. Ainsi, la thérapie de remédiation cognitive (CRT) a été adaptée à l’AM par l’équipe du Pr. Tchanturia. Cette approche se base sur les difficultés cognitives mises en évidence chez ces patients (notamment le manque de flexibilité et de cohérence centrale) et propose leur remédiation par une approche courte, motivationnelle et décentrée des problématiques alimentaires, de manière complémentaire aux soins habituels. Plusieurs études ont été menées sur les apports de la CRT et soulignent son intérêt dans l’amélioration de certains critères cognitifs ainsi que sa bonne acceptabilité. L’essai clinique randomisé Trecogam développé par notre équipe avait pour objectif l’adaptation en français de la CRT dans l’AM ainsi que son évaluation en comparaison à une thérapie « contrôle » appelée PER (Personnalité-Emotions-Relations) axée sur les difficultés socio-émotionnelles mises en évidence dans l’AM. La partie expérimentale de ce travail de thèse s’inscrit dans le cadre de cette étude plus large. Soixante-quatre patientes hospitalisées pour AM sévère ont été recrutées dans 4 hôpitaux parisiens et randomisées dans l’un ou l’autre des bras de traitement. Le fonctionnement cognitif et émotionnel ainsi que la sévérité clinique ont été évalués avant et après la prise en charge. Ce travail s’organise donc autour de deux axes. Dans un premier axe ciblant le fonctionnement cognitif, nous nous sommes tout d’abord intéressés au développement et à l’étude de versions alternatives aux évaluations neuropsychologiques fréquemment employées dans le cadre de l’évaluation de la CRT, afin de contrôler l’effet d’apprentissage. Une seconde étude avait pour objectif d’évaluer les apports de la CRT sur le fonctionnement cognitif objectif et auto-rapporté, en comparaison à une thérapie basée sur les émotions et relations interpersonnelles (PER). Le second axe de ce travail concerne les difficultés émotionnelles dans l’AM. Une première étude a permis la validation d’un instrument de mesure de l’Intelligence Emotionnelle Perçue (IEP) dans un échantillon de 824 jeunes adultes issus de la population générale et la caractérisation des difficultés rencontrées par les patientes souffrant d’AM comparativement à ces données normatives. Une seconde étude a concerné l’évaluation des apports de la PER sur les dimensions de l’IEP et sur les symptômes anxio-dépressifs, en comparaison à la CRT. Sur le plan méthodologique, ce travail a permis de mettre à disposition des cliniciens-chercheurs des outils d’évaluation fiables, tant concernant le fonctionnement cognitif (versions alternatives au Brixton et à la Figure de Rey) qu’émotionnel (Trait Meta-Mood Scale). Concernant l’efficacité thérapeutique des approches testées, nos résultats ne mettent pas en évidence de supériorité de l’une ou l’autre sur les variables théoriquement ciblées. Cependant, nous faisons le constat d’une bonne acceptabilité de la CRT et de la PER ainsi que d’une satisfaction importante de la part des patientes, et faisons l’hypothèse qu’ils pourraient constituer de bons leviers thérapeutiques dans un parcours de soins pour AM. Ce travail a également nourri des réflexions concernant les potentielles améliorations pouvant être apportées à ces programmes

Characterisation and remediation of cognitive and emotional difficulties in anorexia nervosa

L’anorexie mentale (AM) est une pathologie psychiatrique caractérisée par sa gravité et la sévérité de son pronostic. A ce jour, si une approche pluridisciplinaire et multifocale est privilégiée pour prendre en charge les patients, il n’en demeure pas moins qu’aucun traitement n’a démontré sa supériorité chez l’adulte. Des avancées récentes dans le domaine des neurosciences cognitives et affectives ont permis d’ouvrir la voie au développement de nouvelles modalités thérapeutiques. Ainsi, la thérapie de remédiation cognitive (CRT) a été adaptée à l’AM par l’équipe du Pr. Tchanturia. Cette approche se base sur les difficultés cognitives mises en évidence chez ces patients (notamment le manque de flexibilité et de cohérence centrale) et propose leur remédiation par une approche courte, motivationnelle et décentrée des problématiques alimentaires, de manière complémentaire aux soins habituels. Plusieurs études ont été menées sur les apports de la CRT et soulignent son intérêt dans l’amélioration de certains critères cognitifs ainsi que sa bonne acceptabilité. L’essai clinique randomisé Trecogam développé par notre équipe avait pour objectif l’adaptation en français de la CRT dans l’AM ainsi que son évaluation en comparaison à une thérapie « contrôle » appelée PER (Personnalité-Emotions-Relations) axée sur les difficultés socio-émotionnelles mises en évidence dans l’AM. La partie expérimentale de ce travail de thèse s’inscrit dans le cadre de cette étude plus large. Soixante-quatre patientes hospitalisées pour AM sévère ont été recrutées dans 4 hôpitaux parisiens et randomisées dans l’un ou l’autre des bras de traitement. Le fonctionnement cognitif et émotionnel ainsi que la sévérité clinique ont été évalués avant et après la prise en charge. Ce travail s’organise donc autour de deux axes. Dans un premier axe ciblant le fonctionnement cognitif, nous nous sommes tout d’abord intéressés au développement et à l’étude de versions alternatives aux évaluations neuropsychologiques fréquemment employées dans le cadre de l’évaluation de la CRT, afin de contrôler l’effet d’apprentissage. Une seconde étude avait pour objectif d’évaluer les apports de la CRT sur le fonctionnement cognitif objectif et auto-rapporté, en comparaison à une thérapie basée sur les émotions et relations interpersonnelles (PER). Le second axe de ce travail concerne les difficultés émotionnelles dans l’AM. Une première étude a permis la validation d’un instrument de mesure de l’Intelligence Emotionnelle Perçue (IEP) dans un échantillon de 824 jeunes adultes issus de la population générale et la caractérisation des difficultés rencontrées par les patientes souffrant d’AM comparativement à ces données normatives. Une seconde étude a concerné l’évaluation des apports de la PER sur les dimensions de l’IEP et sur les symptômes anxio-dépressifs, en comparaison à la CRT. Sur le plan méthodologique, ce travail a permis de mettre à disposition des cliniciens-chercheurs des outils d’évaluation fiables, tant concernant le fonctionnement cognitif (versions alternatives au Brixton et à la Figure de Rey) qu’émotionnel (Trait Meta-Mood Scale). Concernant l’efficacité thérapeutique des approches testées, nos résultats ne mettent pas en évidence de supériorité de l’une ou l’autre sur les variables théoriquement ciblées. Cependant, nous faisons le constat d’une bonne acceptabilité de la CRT et de la PER ainsi que d’une satisfaction importante de la part des patientes, et faisons l’hypothèse qu’ils pourraient constituer de bons leviers thérapeutiques dans un parcours de soins pour AM. Ce travail a également nourri des réflexions concernant les potentielles améliorations pouvant être apportées à ces programmes.Anorexia Nervosa (AN) is a complex and difficult-to-treat illness characterised by the severity of its prognosis. There is growing evidence suggesting that some cognitive difficulties (poor set-shifting, lack of central coherence) may be critically involved in the development and maintenance of AN. Studies in schizophrenia showed that it is possible to translate evidence-based research into clinical practice and to improve neuropsychological and cognitive functioning using Cognitive Remediation Therapy (CRT). CRT for AN was developed by Pr Tchanturia and colleagues to address the AN patients’ thinking styles. Rather than targeting eating symptoms, CRT is designed to encourage the patients to reflect on and try to modify their information-processing styles and behaviors, by using simple cognitive exercises, delivered in a motivational style. To date, studies on CRT for AN showed some improvements in cognitive functioning but also a good acceptability. The aims of the randomized controlled trial Trecogam were to adapt CRT for AN in French, then to compare its effectiveness with a sham therapy. The sham therapy has been designed to match the CRT format: an individual manualized therapist-led 10-sessions program (2 sessions/week). It avoids set-shifting and central coherence training but rather taps 3 domains: emotional expression and recognition, personality exploration and interpersonal functioning (PER: Personality – Emotions – Relationships). We recruited 64 AN inpatients in 4 specialized care units (Parisian area); they were randomized in CRT or PER arm. Clinical status, cognitive and socio-emotional functioning were assessed before and after intervention. Our first line of research (two studies) concerned cognitive functioning. First, in order to control for learning effects, we developed and explored, in the entire AN sample, alternative versions of neuropsychological tests that are widely used in the context of the evaluation of CRT. The aim of the second study was to assess the contribution of CRT (relative to the PER) on objective and subjective cognitive functioning. Our second line of research (two studies) concerned emotional difficulties in AN. A first study was conducted in a general sample of 824 young adults to validate a measure of Perceived Emotional Intelligence (PEI): the Trait-Meta-Mood-Scale (TMMS). The TMMS was completed by the AN patients and this study allowed to further characterize their emotional difficulties, in comparison with our normative sample. In a second study, we explored contributions of the PER intervention (versus the CRT) on the PEI dimensions and anxio-depressive symptoms. From a methodological perspective, this work helped to provide reliable measures of cognitive (alternative versions of Brixton task and Rey Complex Figure) and emotional functioning (TMMS). Regarding the interventions (CRT and PER), our results do not show superiority of one over another on our variables of interest. However, we observed a good retention and acceptability of both interventions, and an important satisfaction from patients’ perspective. We believe that they could be useful first steps and complementary approaches to the treatment as usual of patients with severe AN. We also discuss future potential improvements of these interventions

The psycho-affective roots of obesity: Results from a french study in the general population

International audienceThe aim of the study was to examine the extent to which obese people differ in their emotionally driven and addictive-like eating behaviors from normal-weight and overweight people. A total of 1142 participants were recruited from a general population, by a web-based cross-sectional survey assessing anxiety/depression (Hospital Anxiety and Depression Scale), emotional eating (Emotional Appetite Questionnaire), food addiction (modified Yale Food Addiction Scale), and intuitive eating (Intuitive Eating Scale-2). The statistical design was based on analyses of (co)variance, correlograms, and mediations. A set of Body Mass Index (BMI) group comparisons showed that obese people reported higher levels of depression and emotional eating and that they experienced more severe and frequent food addiction symptoms than overweight and normal-weight people. Associations between anxiety, depression, food addiction symptoms’ count, and the difficulties to rely on hunger and satiety cues were found across all weight classes, suggesting that addictive-like eating may represent a unique phenotype of problematic eating behavior that is not synonymous with high BMI or obesity. Conversely, the interrelation between anxiety/depression, emotional eating, and the difficulties to rely on hunger and satiety cues was found only among obese participants, and negative emotional eating mediated the association between depression and anxiety and the difficulties to rely on hunger and satiety cues. This study emphasizes the necessity to develop more comprehensive approaches integrating emotional dysregulation and addictive-like eating behaviors to improve weight management and quality of life of obese people