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Intermittent (on 4 days per week) antiretroviral therapy (ART) for patients with HIV-1 might be more convenient, better tolerated, and cheaper than continuous treatment. We aimed to establish the efficacy and safety of a 4-days-on and 3-days-off (intermittent) maintenance regimen versus a standard 7 day (continuous) maintenance regimen.In a randomised, open-label, multicentre, parallel, non-inferiority trial, we randomly assigned (1:1) adults with HIV-1 infection with a plasma viral load (pVL) of less than 50 copies per mL for more than 12 months and no drug-resistance mutations to either the intermittent regimen or their existing continuous maintenance regimen, with stratification according to third therapeutic agent (protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or integrase-strand transfer inhibitor). Participants were recruited from 59 hospitals throughout France. The main exclusion criteria were CD4 cell count lower than 250 cells per μL and chronic hepatitis B virus infection. The primary endpoint was the proportion of participants in the modified intention-to-treat (mITT) population who started the study strategy presenting treatment success at week 48 (pVL50 copies per mL without strategy modification), estimated using the US Federal Drug Administration snapshot approach, with a 5% non-inferiority margin. The study was registered with ClinicalTrials.gov (NCT03256422) and EudraCT (2017-000040-17). The trial is now closed.From Sept 7, 2017, to Jan 22, 2018, 850 potential participants were screened for eligibility. 647 participants were enrolled and randomly assigned (1:1) to either the intermittent or the continuous treatment group. The mITT population included 636 participants (318 per group). At week 48, in the mITT population, treatment success was recorded in 304 (96%) of 318 participants in the intermittent treatment group and 308 (97%) of 318 in the continuous treatment group (adjusted difference -1·3%, 95% CI -4·2 to 1·7). Six (2%) participants in the intermittent treatment group and four (1%) participants in the continuous treatment group had virological failure. Grade 3-4 adverse events were reported in 29 (9%) participants in the intermittent treatment group and 39 (12%) participants in the continuous treatment group (p=0·320). Daily life satisfaction improved in 153 (59%) of 258 participants in the intermittent treatment group versus 19 (7%) of 255 in the continuous treatment group (p0·0001). ART costs were 43% lower in the intermittent treatment group than in the continuous treatment group (p0·0001).These findings show the non-inferiority of the treatment strategy of 4-consecutive-days-on and 3-days-off strategy maintenance regimen relative to standard continuous ART triple therapy over 48 weeks. 4 days on and off treatment represents a workable, effective alternative strategy for patients with high adherence to ART, and using a drug combination with a high genetic barrier to resistance.Institut National de la Santé et de la Recherche Médicale Agence Nationale de Recherche sur le Sida et les Hépatites Virales, Maladies Infectieuses Emergentes.

Background Lack of insight is a frequent characteristic of psychotic disorders, both in patients who recently experienced a first episode of psychosis (FEP) and those who experience recurrent multiple episodes (MEP). Insight is a multifaceted construct: its clinical form notably includes the unawareness of being ill, of symptoms, and of the need for treatment. Cognitive capacity is among the key determinants of insight into symptoms, but less is known about whether stage of illness (FEP vs. MEP) moderates this association. Methods Our aim is to evaluate the association between cognitive capacity and symptom unawareness using structural equation modeling and moderated multiple regression. A total of 193 FEP and MEP patients were assessed using the CogState battery and the Scale to Assess Unawareness of Mental Disorder. Results Analyses suggest that cognitive capacity accounts for a relatively small proportion of the total variation in symptom unawareness (6.4%). There was no evidence to suggest a moderating effect of stage of illness on this association. Conclusions The effect of general cognitive capacity on symptom unawareness is relatively small, and this basic relation was unrelated to stage of illness. It is possible that stage of illness could moderate this association only for certain facets of insight not assessed in this study (e.g., unawareness of the need for treatment).

Most monogenic disorders are caused by a pathologic deficit or excess of a single transcript and/or protein. Given that small molecules, including drugs, can affect levels of mRNA and protein, the pharmacologic normalization of such pathogenic dosage represents a possible therapeutic approach for such conditions. Here, we review the literature exploring pharmacologic modulation of mRNA and/or protein levels for disorders with paralogous modifier genes, for haploinsufficient disorders (insufficient gene-product), as well as toxic gain-of-function disorders (surplus or pathologic gene-product). We also discuss challenges facing the development of rare disease therapy by pharmacologic modulation of mRNA and protein. Finally, we lay out guiding principles for selection of disorders which may be amenable to this approach.

Background Patients in every stage of the psychosis continuum can present with negative symptoms. While no treatment is currently available to address these symptoms, a more refined characterization of their course over the lifetime could help in elaborating interventions. Previous reports have separately investigated the prevalence of negative symptoms within each stage of the psychosis continuum. Our aim in this review is to compare those prevalences across stages, thereby disclosing the course of negative symptoms. Methods We searched several databases for studies reporting prevalences of negative symptoms in each one of our predetermined stages of the psychosis continuum: clinical or ultra-high risk (UHR), first-episode of psychosis (FEP), and younger and older patients who have experienced multiple episodes of psychosis (MEP). We combined results using the definitions of negative symptoms detailed in the Brief Negative Symptom Scale, a recently developed tool. For each negative symptom, we averaged and weighted by the combined sample size the prevalences of each negative symptom at each stage. Results We selected 47 studies totaling 1872 UHR, 2947 FEP, 5039 younger MEP, and 669 older MEP patients. For each negative symptom, the prevalences showed a comparable course. Each negative symptom decreased from the UHR to FEP stages and then increased from the FEP to MEP stages. Conclusions Certain psychological, environmental, and treatment-related factors may influence the cumulative impact of negative symptoms, presenting the possibility for early intervention to improve the long-term course.

We investigated the feasibility of a short intervention using the Method of Loci (MoL), a well-known visuospatial mnemonic, to improve episodic memory recall performance in schizophrenia. The MoL training protocol comprised encoding and recall of two lists of items (words and images), a training session and practice with MoL. Then, participants had the opportunity to put into practice the newly learned MoL and were instructed to encode and recall two new lists of items using. This approach was first validated with healthy individuals (N = 71). Subsequently, five individuals with schizophrenia completed the protocol. Improvement in healthy individuals was observed for the word list (Wilcoxon effect size r = 0.15). No significant memory improvement was denoted in the schizophrenia group, possibly due to participants' difficulties using the method efficiently and due to fatigue. The MoL seems to require episodic memory, working memory monitoring and executive functions, making it suboptimal for a population with impairments in all those domains. Future research should examine the use of other strategies, better suited for individuals with cognitive impairments like those found in schizophrenia.

Background: Culicoides obsoletus is an abundant and widely distributed Holarctic biting midge species, involved in the transmission of bluetongue virus (BTV) and Schmallenberg virus (SBV) to wild and domestic ruminants. Females of this vector species are often reported jointly with two morphologically very close species, C. scoticus and C. montanus, forming the Obsoletus/Scoticus Complex. Recently, cryptic diversity within C. obsoletus was reported in geographically distant sites. Clear delineation of species and characterization of genetic variability is mandatory to revise their taxonomic status and assess the vector role of each taxonomic entity. Our objectives were to characterize and map the cryptic diversity within the Obsoletus/Scoticus Complex. Methods: Portion of the cox1 mitochondrial gene of 3763 individuals belonging to the Obsoletus/Scoticus Complex was sequenced. Populations from 20 countries along a Palaearctic Mediterranean transect covering Scandinavia to Canary islands (North to South) and Canary islands to Turkey (West to East) were included. Genetic diversity based on cox1 barcoding was supported by 16S rDNA mitochondrial gene sequences and a gene coding for ribosomal 28S rDNA. Species delimitation using a multi-marker methodology was used to revise the current taxonomic scheme of the Obsoletus/Scoticus Complex. Results: Our analysis showed the existence of three phylogenetic clades (C. obsoletus clade O2, C. obsoletus clade dark and one not yet named and identified) within C. obsoletus. These analyses also revealed two intra-specific clades within C. scoticus and raised questions about the taxonomic status of C. montanus. Conclusions: To our knowledge, our study provides the first genetic characterization of the Obsoletus/Scoticus Complex on a large geographical scale and allows a revision of the current taxonomic classification for an important group of vector species of livestock viruses in the Palaearctic region.[Figure not available: See fulltext.]

We present RADD, an innovative analytic pipeline used to measure reliability and availability for cloud-based distributed databases by leveraging the vast amount of telemetry present in the cloud. RADD can perform root cause analysis (RCA) to provide a minute-by-minute summary of the availability of a database close to real-time. On top of this data, RADD can raise alerts, analyze the stability of new versions during their deployment, and provide Key Performance Indicators (KPIs) that allow us to understand the stability of our system across all deployed databases. RADD implements an event correlation framework that puts the emphasis on data compliance and uses information entropy to measure causality and reduce noisy signals. It also uses statistical modelling to analyze new versions of the product and detect potential regressions early in our software development lifecycle. We demonstrate the application of RADD on top of Azure Synapse Analytics, where the system has helped us identify top-hitting and new issues and support on-call teams regarding every aspect of database health.

Background: Social interactions require rapid, real-time information integration and performative application of dynamic social information, and can be especially difficult for patients with schizophrenia. Their difficulty processing social information could lie in challenges extracting the information or in updating their actions to accommodate the new information, resulting in behaviors that may appear rigid or inappropriate. Disruptions may emerge in the underlying, requisite behavioral or neural processes. Methods: Seventeen matched healthy controls and seventeen patients with schizophrenia participated in an fMRI study, which included a social interaction priming procedure wherein they met a friendly stranger who held opposite social values from their own. They answered self-judgement questions about their social values two days before the priming experiment and again during the fMRI scan. Results: Controls suppress social values when interacting with the stranger whereas patients with schizophrenia augment the opposite values, simultaneously holding two sets of social values. Compared to controls, patients display hyperactivity in dorsomedial prefrontal cortex and atypical activity in caudate, posterior cingulate and precuneus. Discussion: Patients appear to correctly extract social information but apply the information atypically. They display evidence of atypical social flexibility on both performative and neural measures, resulting in confusion between self and other.

Cognitive impairments in psychotic disorders (PD) present heterogeneously across patients. Between 2 and 5 clusters have been identified in previous studies with first-episode (FEP) and multiple-episodes of psychosis (MEP) patients suggesting different profiles of impairment. Past findings suggest there are differences between FEP and MEP patients regarding severity and number of affected cognitive domains. Heterogeneity of cognitive deficits in PD has perhaps hindered our understanding of their course. The present study compared non-affective FEP and MEP patients to assess whether illness chronicity could influence cognitive impairment profiles. We analyzed cognitive data, collected with the Cogstate Schizophrenia Battery, of FEP and MEP patients using cluster analysis. We compared clustering methods to obtain a more robust solution. For FEP patients, data were collected at their entry to a specialized clinic; the MEP group consisted of in- and outpatients. Results suggested cognitive heterogeneity was similar in FEP and MEP samples, although in different proportions. Three clusters were identified as the most stable solution and comprised groups of patients with either 1- no cognitive impairment (over-representation of FEP), 2- generalized deficits (over-representation of MEP), or 3- intermediate impairments. These findings encourage early interventions adapted to the profile of impairment.

Social interactions require fluid self-concepts to adapt to real-time dynamics – in theory. In practice, fluid processes have been difficult to experimentally quantify. Active self-concepts theoretically respond to social contexts while stable self-concepts are context-independent. Such fluctuations in ‘typical’ adults have rarely been reported. Self-concept research has broad implications; inducing and quantifying active fluctuations is long-sought-after in social psychology. However, since their inception, self-concepts were studied using bicultural participants (e.g., cultural priming experiments) and characterized in psychiatric patients (e.g., ‘fragmented self’). By increasing methodological saliency and ecological validity of popular methods, three studies tested an adapted scale and social interaction priming procedure for differentiating between active and stable self-concepts. Psychometrics, reproducibility and clinical relevance are compared to a common measure of bicultural self-concept fluidity using optimized statistics. Pre-Study controls (N=42) characterize repetition effects. Study 1: Active self-concepts are suppressed in convenience sample of 62 W.E.I.R.D. students. Study 2: Diverse, locally-representative and randomly-sampled adults (N=43) replicates Study 1 findings. Study 3: Patients with schizophrenia (N=27) hold opposing self-concepts, adopting their interlocutor’s while keeping their own. Four distinct flexibility phenotypes emerge. These studies are the first to quantify active self-concepts. This article precedes a manuscript series interrogating replicability, neural activations and cultural-clinical implications.