Differences in the neural correlates of schizophrenia with positive and negative formal thought disorder in patients with schizophrenia in the ENIGMA dataset.

Formal thought disorder (FTD) is a clinical key factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, the relationship between FTD symptom dimensions and patterns of regional brain volume loss in schizophrenia remains to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles by enrolling a large multi-site cohort acquired by the ENIGMA Schizophrenia Working Group (752 schizophrenia patients and 1256 controls), to unravel the neuroanatomy of FTD in schizophrenia and using virtual histology tools on implicated brain regions to investigate the cellular basis. Based on the findings of previous clinical and neuroimaging studies, we decided to separately explore positive, negative and total formal thought disorder. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but positive and negative FTD demonstrated a dissociation: negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD also showed associations with microglial cell types. These results provide an important step towards linking FTD to brain structural changes and their cellular underpinnings, providing an avenue for a better mechanistic understanding of this syndrome.

Adaptive coding of reward in schizophrenia, its change over time and relationship to apathy.

Adaptive coding of reward is the process by which neurons adapt their response to the context of available compensations. Higher rewards lead to a stronger brain response, but the increase of the response depends on the range of available rewards. A steeper increase is observed in a narrow range and a more gradual slope in a wider range. In schizophrenia, adaptive coding appears to be affected in different domains, especially in the reward domain. Here, we tested adaptive coding of reward in a large group of patients with schizophrenia (n = 86) and control subjects (n = 66). We assessed: (i) the association between adaptive coding deficits and symptoms; (ii) the longitudinal stability of deficits (the same task was performed 3 months apart); and (iii) the stability of results between two experimental sites. We used functional MRI and the monetary incentive delay task to assess adaptation of participants to two different reward ranges: a narrow range and a wide range. We used a region-of-interest analysis to evaluate adaptation within striatal and visual regions. Patients and control subjects underwent a full demographic and clinical assessment. We found reduced adaptive coding in patients, with a decreased slope in the narrow reward range with respect to that of control participants, in striatal but not visual regions. This pattern was observed at both research sites. Upon retesting, patients increased their narrow-range slopes, showing improved adaptive coding, whereas control subjects slightly reduced them. At retesting, patients with overly steep slopes in the narrow range also showed higher levels of negative symptoms. Our data confirm deficits in reward adaptation in schizophrenia and reveal an effect of practice in patients, leading to improvement, with steeper slopes upon retesting. However, in some patients, an excessively steep slope may result in poor discriminability of larger rewards, owing to early saturation of the brain response. Together, the loss of precision of reward representation in new (first exposure, underadaptation) and more familiar (retest, overadaptation) situations might contribute to the multiple motivational symptoms in schizophrenia.

Noncollinear Electric Dipoles in a Polar Chiral Phase of CsSnBr3 Perovskite.

Polar and chiral crystal symmetries confer a variety of potentially useful functionalities upon solids by coupling otherwise noninteracting mechanical, electronic, optical, and magnetic degrees of freedom. We describe two phases of the 3D perovskite, CsSnBr3, which emerge below 85 K due to the formation of Sn(II) lone pairs and their interaction with extant octahedral tilts. Phase II (77 K < T < 85 K, space group P21/m) exhibits ferroaxial order driven by a noncollinear pattern of lone pair-driven distortions within the plane normal to the unique octahedral tilt axis, preserving the inversion symmetry observed at higher temperatures. Phase I (T < 77 K, space group P21) additionally exhibits ferroelectric order due to distortions along the unique tilt axis, breaking both inversion and mirror symmetries. This polar and chiral phase exhibits second harmonic generation from the bulk and pronounced electrostriction and negative thermal expansion along the polar axis (Q22 ≈ 1.1 m4 C-2; αb = -7.8 × 10-5 K-1) through the onset of polarization. The structures of phases I and II were predicted by recursively following harmonic phonon instabilities to generate a tree of candidate structures and subsequently corroborated by synchrotron X-ray powder diffraction and polarized Raman and 81Br nuclear quadrupole resonance spectroscopies. Preliminary attempts to suppress unintentional hole doping to allow for ferroelectric switching are described. Together, the polar symmetry, small band gap, large spin-orbit splitting of Sn 5p orbitals, and predicted strain sensitivity of the symmetry-breaking distortions suggest bulk samples and epitaxial films of CsSnBr3 or its neighboring solid solutions as candidates for bulk Rashba effects.

The Cerebellum and Cognitive Function: Anatomical Evidence from a Transdiagnostic Sample.

Multiple lines of evidence across human functional, lesion, and animal data point to a cerebellar role, in particular of crus I, crus II, and lobule VIIB, in cognitive function. However, a mapping of distinct facets of cognitive function to cerebellar structure is missing. We analyzed structural neuroimaging data from the Healthy Brain Network (HBN). Cerebellar parcellation was performed with a validated automated segmentation pipeline (CERES) and stringent visual quality check (n = 662 subjects retained from initial n = 1452). Canonical correlation analyses (CCA) examined regional gray matter volumetric (GMV) differences in association to cognitive function (quantified with NIH Toolbox Cognition domain, NIH-TB), accounting for psychopathology severity, age, sex, scan location, and intracranial volume. Multivariate CCA uncovered a significant correlation between two components entailing a latent cognitive canonical (NIH-TB subscales) and a brain canonical variate (cerebellar GMV and intracranial volume, ICV), surviving bootstrapping and permutation procedures. The components correspond to partly shared cerebellar-cognitive function relationship with a first map encompassing cognitive flexibility (r = 0.89), speed of processing (r = 0.65), and working memory (r = 0.52) associated with regional GMV in crus II (r = 0.57) and lobule X (r = 0.59) and a second map including the crus I (r = 0.49) and lobule VI (r = 0.49) associated with working memory (r = 0.51). We show evidence for a structural subspecialization of the cerebellum topography for cognitive function in a transdiagnostic sample.

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium.

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Comparing adaptive coding of reward in bipolar I disorder and schizophrenia.

Deficits in neural processing of reward have been described in both bipolar disorder (BD) and schizophrenia (SZ), but it remains unclear to what extent these deficits are caused by similar mechanisms. Efficient reward processing relies on adaptive coding which allows representing large input spans by limited neuronal encoding ranges. Deficits in adaptive coding of reward have previously been observed across the SZ spectrum and correlated with total symptom severity. In the present work, we sought to establish whether adaptive coding is similarly affected in patients with BD. Twenty-five patients with BD, 27 patients with SZ and 25 healthy controls performed a variant of the Monetary Incentive Delay task during functional magnetic resonance imaging in two reward range conditions. Adaptive coding was impaired in the posterior part of the right caudate in BD and SZ (trend level). In contrast, BD did not show impaired adaptive coding in the anterior caudate and right precentral gyrus/insula, where SZ showed deficits compared to healthy controls. BD patients show adaptive coding deficits that are similar to those observed in SZ in the right posterior caudate. Adaptive coding in BD appeared more preserved as compared to SZ participants especially in the more anterior part of the right caudate and to a lesser extent also in the right precentral gyrus. Thus, dysfunctional adaptive coding could constitute a fundamental deficit in severe mental illnesses that extends beyond the SZ spectrum.

The pathophysiology of negative symptoms of schizophrenia: main hypotheses and open challenges.

Important developments in the conceptualisation and classification of negative symptoms have contributed to refining hypotheses on their pathophysiology. The uptake of recent progress is still only partial and the whole field might make a leap forward once relevant studies fully make use of assessment tools based on current conceptualisations.

Intranasal Oxytocin for Negative Symptoms of Schizophrenia: Systematic Review, Meta-Analysis, and Dose-Response Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Negative symptoms are a core aspect of psychopathology in schizophrenia. Currently available pharmacological agents have proven minimally efficacious for remediating negative symptoms. A promising treatment avenue is the intranasal administration of the neuropeptide oxytocin. However, there have been inconsistencies in effects of oxytocin on negative symptoms throughout the literature, and factors leading to inconsistent effects are unclear. METHODS: We conducted a systematic review and meta-analysis of randomized clinical trials to compare the effectiveness of oxytocin with placebo for the treatment of negative symptoms and determine moderators of treatment effect. Random effects meta-analyses and dose-response meta-analysis were performed on mean changes in negative symptoms. RESULTS: In an initial analysis of all 9 identified randomized clinical trials, intranasal oxytocin showed no significant effect on negative symptoms. For higher doses (>40-80 IU), a beneficial effect on negative symptoms was found with a moderate effect size, but this effect disappeared after exclusion of 1 outlier study. The dose-response meta-analysis predicted that higher doses of oxytocin may be more efficacious for negative symptoms. For positive symptoms, no beneficial effect of oxytocin was found in the main meta-analysis, but the dose-response meta-analysis suggested a potential advantage of higher doses. CONCLUSIONS: The present results show no consistent beneficial effect of intranasal oxytocin for the treatment of negative and positive symptoms. The dose-response meta-analysis does not allow drawing any firm conclusions but suggests that high doses of intranasal oxytocin may be more efficacious. If future studies are conducted, an effort to reach adequate CNS concentrations for a sufficient duration is required.

Negative symptoms in schizophrenia: reconsidering evidence and focus in clinical trials.

Negative symptoms of schizophrenia have been documented in the literature for over a century. Nevertheless, research has not convincingly produced effective interventions for their treatment. We propose to re-analyse currently published evidence on treatment of negative symptoms, using narrower definitions for symptom dimensions, to better understand what works for whom.

The impact of implementing a psychiatric emergency hotline on the reduction of acute hospitalizations in a Swiss tertiary hospital.

BACKGROUND: Inpatient treatment is not the most beneficial treatment setting for many patients with psychiatric disorders and overcrowding is a recurrent problem for psychiatric hospitals. Therefore, it is important to develop strategies to limit avoidable inpatient treatment. This study sought to evaluate the impact of an emergency hotline that was developed to better manage psychiatric patients, particularly for identifying those requiring a hospital admission. METHODS: This pre-post intervention quality improvement study compared changes in the management of psychiatric patients' admission before and after the introduction of an emergency hotline where a specialist in psychiatry examines all inpatient referral from private practitioners. Main outcomes were the change in proportion of hospital admissions after referral from a private practitioner before and within 3 months after the intervention. Secondary outcomes were the average length of hospital stay, proportion of non-voluntary admission, the time required for triage and the impact of the intervention on treatments' costs. Fisher's Exact test was used to test the primary hypothesis of difference in the proportion of hospitalized patients before and after introduction of the emergency hotline. Secondary outcomes were tested with Student's t-test for continuous variables and Fishers's Exact test for proportions. RESULTS: Among 45 admission requests from private practitioners during the 3 months after introduction of the new emergency hotline, 25 (55.6%) were accepted as inpatient treatment, while 20 (44%) were redirected to more appropriate outpatient treatments. There was a highly significant difference from the baseline period during which all 34 requests were accepted (44% vs 100%, p < 0.001). In addition, for the patients hospitalized after the introduction of the emergency hotline there was a trend-level reduction of the average length of stay (9.32 days vs 17.35 days). CONCLUSION: Implementation of an emergency hotline manage by a specialist in psychiatry for admissions to acute psychiatric wards is feasible and simple to use. Importantly, it allows to significantly decrease the proportion of hospitalizations. Additional studies are needed to assess the generalizability of these exploratory results to other health care settings.

Prevalence and risk factors for seclusion and restraint in old-age psychiatry inpatient units.

BACKGROUND AND OBJECTIVES: Coercion in psychiatry is legally tolerated as a last resort. The reduction of the use of coercion is a shared goal of hospital administrators, medical and nursing staff and representatives of patients and families but requires the identification of risk factors for coercion. These risk factors in geriatric psychiatric inpatient settings are not well known, especially regarding seclusion. Through examining the prevalence of coercion and patients' characteristics, this study aims to identify risk factors for coercion in elderly people. METHODS: The use of coercion in the geriatric psychiatry division of Geneva University Hospital in 2017 was retrospectively analyzed. The incidence rate ratios were estimated with multivariable Poisson regressions to assess risk factors for coercion. RESULTS: Eighty-one of 494 patients (16.4%) experienced at least one coercive measure during their stay (mainly seclusion). The risk factors for coercion were younger age, male gender, being divorced or married, cognitive disorders, high item 1 of the Health of the Nation Outcome Scales (HoNOS) score (overactive, aggressive, disruptive or agitated behavior) at admission, previous psychiatric hospitalizations and involuntary referrals from the emergency department. Other disorders and global HoNOS scores were not associated with the use of coercion. CONCLUSION: Higher risks of coercion were outlined in men with cognitive disorders, agitated behaviors, and previous psychiatric hospitalizations. They differed from those observed in younger adults in terms of age, civil status, disorders, global HoNOS scores and referrals. Therefore, geriatric psychiatric populations should be specifically investigated for the development of interventions aiming coercion reduction.

Psychiatric emergency admissions during and after COVID-19 lockdown: short-term impact and long-term implications on mental health.

BACKGROUND: The 'lockdown' measures, adopted to restrict population movements in order to help curb the novel coronavirus disease 2019 (COVID-19) pandemic, contributed to a global mental health crisis. Although several studies have extensively examined the impact of lockdown measures on the psychological well-being of the general population, little is known about long-term implications. This study aimed to identify changes in psychiatric emergency department (ED) admissions between two 8-week periods: during and immediately after lifting the lockdown. METHODS: Socio-demographic and clinical information on 1477 psychiatric ED consultations at the University Hospital of Geneva (HUG) were retrospectively analyzed. RESULTS: When grouped according to admission dates, contrary to what we expected, the post-lockdown group presented with more severe clinical conditions (as measured using an urgency degree index) compared to their lockdown counterparts. Notably, after the lockdown had been lifted we observed a statistically significant increase in suicidal behavior and psychomotor agitation and a decrease in behavior disorder diagnoses. Furthermore, more migrants arrived at the HUG ED after the lockdown measures had been lifted. Logistic regression analysis identified diagnoses of suicidal behavior, behavioral disorders, psychomotor agitation, migrant status, involuntary admission, and private resident discharge as predictors of post-lockdown admissions. CONCLUSIONS: Collectively, these findings can have implications concerning the prioritization of mental health care facilities and access for patients at risk of psychopathological decompensation in time of confinement policies, but above all, provide a foundation for future studies focusing on the long-term impact of the pandemic and its associated sanitary measures on mental health. TRIAL REGISTRATION: Research Ethics Committee of Geneva, Registration number 2020-01510, approval date: 29 June 2020.

Shared and dissociable features of apathy and reward system dysfunction in bipolar I disorder and schizophrenia.

BACKGROUND: Bipolar disorder I (BD-I) is defined by episodes of mania, depression and euthymic states. These episodes are among other symptoms characterized by altered reward processing and negative symptoms (NS), in particular apathy. However, the neural correlates of these deficits are not well understood. METHODS: We first assessed the severity of NS in 25 euthymic BD-I patients compared with 25 healthy controls (HC) and 27 patients with schizophrenia (SZ). Then, we investigated ventral (VS) and dorsal striatal (DS) activation during reward anticipation in a Monetary Incentive Delayed Task and its association with NS. RESULTS: In BD-I patients NS were clearly present and the severity of apathy was comparable to SZ patients. Apathy scores in the BD-I group but not in the SZ group correlated with sub-syndromal depression scores. At the neural level, we found significant VS and DS activation in BD-I patients and no group differences with HC or SZ patients. In contrast to patients with SZ, apathy did not correlate with striatal activation during reward anticipation. Explorative whole-brain analyses revealed reduced extra-striatal activation in BD-I patients compared with HC and an association between reduced activation of the inferior frontal gyrus and apathy. CONCLUSION: This study found that in BD-I patients apathy is present to an extent comparable to SZ, but is more strongly related to sub-syndromal depressive symptoms. The findings support the view of different pathophysiological mechanisms underlying apathy in the two disorders and suggest that extra-striatal dysfunction may contribute to impaired reward processing and apathy in BD-I.

Microbiological Control of Cellular Products: The Relevance of the Cellular Matrix, Incubation Temperature, and Atmosphere for the Detection Performance of Automated Culture Systems.

BACKGROUND: The microbiological control of cellular products sometimes causes significant procedural issues for quality control laboratories. According to the European Pharmacopoeia (EP), the microbiological control of cellular products requires a 7- to 14-day incubation period at two different incubation temperatures using aerobic and anaerobic growth media. However, the suitability of these test conditions for efficient quality control can be influenced by many conditions, such as the expected microbial spectrum of contamination or the texture and composition of the cellular product. Because of interference, direct inoculation and membrane filtration as reference methods of pharmacopoeia are largely unsuitable for the microbiological control of cellular products; therefore, alternative and, above all, automated methods are the focus of interest. OBJECTIVE: The aim of our study was to evaluate the method suitability and possible effects of cell matrix, incubation temperature, and oxygen pressure on the detection performance of automated culture systems. METHODS: The BacT/ALERT® 3DTM Dual T system (bioMérieux, Nürtingen, Germany) was used to evaluate the factors influencing automated microbiological control of cellular products. The tests were performed using microbial strains recommended by the EP for microbiological method suitability testing and additional relevant possible contaminants of human-derived stem-cell products under varying culture and cell matrix conditions. RESULTS: All contaminants were detected by the system in the required period of 2-5 days. Low incubation temperatures (22°C) had overall negative effects on the detection kinetics of each type of microbial contamination. The adverse effects of the accompanying cell matrix on the detection properties of the system could be compensated in our study by incubation at 32°C in both the aerobic and the anaerobic culture conditions. CONCLUSION: Automated culture techniques represent a sufficient approach for the microbiological control of cellular products. The negative effects of the cell matrix and microbial contamination on the detection performance can be compensated by the application of variable culture conditions in the automated culture system.

[COVID-19 and psychiatry†: urgent opening of a cohort ward at Geneva's psychiatric hospital]. / Covid-19 et psychiatrie†: ouverture en urgence d'une unité de cohortage à la Clinique psychiatrique de Genève.

Due to the rapid spread of the novel coronavirus pandemic, a reorganization of the health care sector was needed. Many questions arose concerning the specificity of psychiatric care in this unprecedented situation. In Geneva, Switzerland, the department of psychiatry decided to open a new ward for its infected patients. Beyond the challenge of setting it up quickly, we faced the challenges of taking care of a heterogeneous group of patients and of incorporating protection measures we were not accustomed to, which add a significant amount of time to the daily care of patients. The staff recruitment on a voluntary basis, close supervision, availability of the personal protective material as well as support from the infection prevention and control unit have enabled proper functioning of the ward.

Devant la vitesse de propagation de la pandémie due au nouveau coronavirus, une réorganisation des systèmes de santé a été nécessaire. De nombreuses questions se sont posées quant à la spécificité de la psychiatrie dans cette situation exceptionnelle. À Genève, le département de psychiatrie a pris la décision d'ouvrir une nouvelle unité de cohortage pour ses patients contaminés. Outre le défi du délai court pour la mettre en place, nous avons été confrontés à celui de prendre en charge une patientèle hétérogène et de devoir appliquer des mesures de protections avec lesquelles nous étions peu familiers, chronophages. Le recrutement de l'équipe sur une base volontaire, un encadrement très présent, la disponibilité du matériel de protection et le soutien du service prévention et contrôle de l'infection ont permis un bon fonctionnement de l'unité.

Prodopaminergic Drugs for Treating the Negative Symptoms of Schizophrenia: Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: The negative symptoms of schizophrenia pose a heavy burden on patients and relatives and represent an unmet therapeutic need. The observed association of negative symptoms with impaired reward system function has stimulated research on prodopaminergic agents as potential adjunctive treatments. METHODS: We conducted a systematic review and meta-analysis of published randomized controlled trials of amphetamine, methylphenidate, modafinil, armodafinil, lisdexamphetamine, L-dopa, levodopa, bromocriptine, cabergoline, quinagolide, lisuride, pergolide, apomorphine, ropinirole, pramipexole, piribedil, and rotigotine augmentation in schizophrenia and schizoaffective disorder.Medline, EMBASE, and several other databases as well as trial registries were searched for placebo-controlled trials. RESULTS: Ten randomized controlled trials were included in the meta-analysis, 6 trials on modafinil, 2 on armodafinil, 1 on L-dopa, and 1 on pramipexole. Overall, prodopaminergic agents did not significantly reduce negative symptoms. Restricting the analysis to studies requiring a minimum threshold for negative symptom severity, modafinil/armodafinil showed a significant but small effect on negative symptoms. A subset of studies allowed for calculating specific effects for the negative symptom dimensions diminished expression and amotivation, but no significant effect was found. Prodopaminergic agents did not increase positive symptom scores. CONCLUSIONS: The currently available evidence does not allow for formulating recommendations for the use of prodopaminergic agents for the treatment of negative symptoms. Nevertheless, the observed improvement in studies defining a minimum threshold for negative symptom severity in the absence of an increase in positive symptoms clearly supports further research on these agents.

Cerebral blood flow in striatal regions is associated with apathy in patients with schizophrenia.

BACKGROUND: Striatal dysfunction has been proposed as a pathomechanism for negative symptoms in schizophrenia. There is consensus that negative symptoms can be grouped into 2 dimensions: apathy and diminished expression. Recent studies suggest that different neural mechanisms underlie these dimensions, but the relationship between regional resting-state cerebral blood flow (rCBF) and negative symptom dimensions has not been investigated. METHODS: This study included 29 patients with schizophrenia and 20 healthy controls. We measured rCBF in the striatum using arterial spin labelling (ASL) MRI. We assessed negative symptoms using the Brief Negative Symptom Scale. RESULTS: In the ventral and dorsal striatum, rCBF was not different between patients with schizophrenia and controls. However, we did find a positive association between the severity of apathy and increased rCBF in the ventral and dorsal striatum in patients with schizophrenia. This effect was not present for diminished expression. LIMITATIONS: All patients were taking atypical antipsychotics, so an effect of antipsychotic medication on rCBF could not be excluded, although we did not find a significant association between rCBF and chlorpromazine equivalents. CONCLUSION: The main finding of this study was a specific association between increased striatal rCBF and the negative symptom dimension of apathy. Our results further support the separate assessment of apathy and diminished expression when investigating the neural basis of negative symptoms. The ASL technique can provide a direct and quantitative approach to investigating the role of rCBF changes in the pathophysiology of negative symptoms.

Distribution of carbapenem resistance mechanisms in clinical isolates of XDR Pseudomonas aeruginosa.

Our study aims to define the epidemiology of carbapenem resistance mechanisms in clinical isolates of Pseudomonas aeruginosa (PA). We evaluated 11,457 clinical PA strains isolated between 2009 and 2015 at the tertiary care University Hospital in Heidelberg, Germany. Thirty-four percent of the isolates (3867/11,457) were MDR (multidrug-resistant), 16% (1816/11,457) were XDR (extensively drug resistant), and less than 1% (82/11,457) had a PDR (pandrug-resistant) profile. Of those, 23% carried a carbapenemase gene (CPM positive) with 12% VIM-2, 10% VIM-1, and less than 1% IMP-1. Comparing MIC (minimal inhibitory concentration) distributions, the mean rank for meropenem, imipenem, gentamicin, and fosfomycin was significantly higher in the CPM-positive group than in the CPM-negative XDR group (p ≤ 0.004). oprD (outer membrane protein) mutations were found in 19/19 tested strains; 12/19 carried a CPM and had a higher mutation rate. Meropenem resistance was mostly associated with the presence of CPM. Only 1/19 strains was meropenem resistant in the absence of CPM genes; nevertheless, it carried an oprD mutation in a strategic site (loop 2). Of 19 CPM-negative strains tested, 7 (36%) showed EP (efflux pumps) hyperexpression versus 12 in the CPM-positive strains. In our study, nearly 50% of the PA isolates exhibited resistance to the tested first-line antibiotics. Our study also demonstrates that carbapenemase genes can be isolated in approximately 23% of XDR PA strains in our population. This finding supports the clinical relevance of PA driven by the possible presence of multiple resistance mechanisms acquired under exposure to antibiotics or by horizontal transfer of resistance genes.

Deficits in context-dependent adaptive coding in early psychosis and healthy individuals with schizotypal personality traits.

Adaptive coding of information is a fundamental principle of brain functioning. It allows for efficient representation over a large range of inputs and thereby alleviates the limited coding range of neurons. In the present study, we investigated for the first time potential alterations in context-dependent reward adaptation and its association with symptom dimensions in the schizophrenia spectrum. We studied 27 patients with first-episode psychosis, 26 individuals with schizotypal personality traits and 25 healthy controls. We used functional MRI in combination with a variant of the monetary incentive delay task and assessed adaptive reward coding in two reward conditions with different reward ranges. Compared to healthy controls, patients with first-episode psychosis and healthy individuals with schizotypal personality traits showed a deficit in increasing the blood oxygen level-dependent response slope in the right caudate for the low reward range compared to the high reward range. In other words, the two groups showed inefficient neural adaptation to the current reward context. In addition, we found impaired adaptive coding of reward in the caudate nucleus and putamen to be associated with total symptom severity across the schizophrenia spectrum. Symptom severity was more strongly associated with neural deficits in adaptive coding than with the neural coding of absolute reward outcomes. Deficits in adaptive coding were prominent across the schizophrenia spectrum and even detectable in unmedicated (healthy) individuals with schizotypal personality traits. Furthermore, the association between total symptom severity and impaired adaptive coding in the right caudate and putamen suggests a dimensional mechanism underlying imprecise neural adaptation. Our findings support the idea that impaired adaptive coding may be a general information-processing deficit explaining disturbances within the schizophrenia spectrum over and above a simple model of blunted absolute reward signals.