Integrative Genetic Variation, DNA Methylation, and Gene Expression Analysis of Escitalopram and Aripiprazole Treatment Outcomes in Depression: A CAN-BIND-1 Study.

INTRODUCTION: Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, CYP2C19, CYP2D6, CYP3A4, and ABCB1, and its effect on these outcomes. METHODS: The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were tested for associations with our outcomes, followed by causal inference tests (CITs) to identify methylation-mediated genetic effects. RESULTS: Eleven cis-SNP-CpG pairs (q<0.05) constituting four unique SNPs were identified. Although no significant associations were observed between mQTLs and response/remission, CYP2C19 rs4244285 was associated with treatment-related weight gain (q=0.027) and serum concentrations of ESCadj (q<0.001). Between weeks 2-4, 6.7% and 14.9% of those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers) genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2 genotype (poor metabolizers) did not report weight gain during this period and demonstrated the highest ESCadj concentrations. CITs did not indicate that these effects were epigenetically mediated. DISCUSSION: These results elucidate functional mechanisms underlying the established associations between CYP2C19 rs4244285 and ESC pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight gain needs to be further explored.

Influence of CYP2C19, CYP2D6, and ABCB1 Gene Variants and Serum Levels of Escitalopram and Aripiprazole on Treatment-Emergent Sexual Dysfunction: A Canadian Biomarker Integration Network in Depression 1 (CAN-BIND 1) Study.

OBJECTIVES: Treatment-emergent sexual dysfunction is frequently reported by individuals with major depressive disorder (MDD) on antidepressants, which negatively impacts treatment adherence and efficacy. We investigated the association of polymorphisms in pharmacokinetic genes encoding cytochrome-P450 drug-metabolizing enzymes, CYP2C19 and CYP2D6, and the transmembrane efflux pump, P-glycoprotein (i.e., ABCB1), on treatment-emergent changes in sexual function (SF) and sexual satisfaction (SS) in the Canadian Biomarker Integration Network in Depression 1 (CAN-BIND-1) sample. METHODS: A total of 178 adults with MDD received treatment with escitalopram (ESC) from weeks 0-8 (Phase I). At week 8, nonresponders were augmented with aripiprazole (ARI) (i.e., ESC + ARI, n = 91), while responders continued ESC (i.e., ESC-Only, n = 80) from weeks 8-16 (Phase II). SF and SS were evaluated using the sex effects (SexFX) scale at weeks 0, 8, and 16. We assessed the primary outcomes, SF and SS change for weeks 0-8 and 8-16, using repeated measures mixed-effects models. RESULTS: In ESC-Only, CYP2C19 intermediate metabolizer (IM) + poor metabolizers (PMs) showed treatment-related improvements in sexual arousal, a subdomain of SF, from weeks 8-16, relative to CYP2C19 normal metabolizers (NMs) who showed a decline, F(2,54) = 8.00, p < 0.001, q = 0.048. Specifically, CYP2C19 IM + PMs reported less difficulty with having and sustaining vaginal lubrication in females and erection in males, compared to NMs. Furthermore, ESC-Only females with higher concentrations of ESC metabolite, S-desmethylcitalopram (S-DCT), and S-DCT/ESC ratio in serum demonstrated more decline in SF (r = -0.42, p = 0.004, q = 0.034) and SS (r = -0.43, p = 0.003, q = 0.034), respectively, which was not observed in males. ESC-Only females also demonstrated a trend for a correlation between S-DCT and sexual arousal change in the same direction (r = -0.39, p = 0.009, q = 0.052). CONCLUSIONS: CYP2C19 metabolizer phenotypes may be influencing changes in sexual arousal related to ESC monotherapy. Thus, preemptive genotyping of CYP2C19 may help to guide selection of treatment that circumvents selective serotonin reuptake inhibitor-related sexual dysfunction thereby improving outcomes for patients. Additionally, further research is warranted to clarify the role of S-DCT in the mechanisms underlying ESC-related changes in SF and SS. This CAN-BIND-1 study was registered on clinicaltrials.gov (Identifier: NCT01655706) on 27 July 2012.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults. METHODS: CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process. RESULTS: The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted. CONCLUSIONS: The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.

Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies.

Understanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) recognition, a function of the viral protein spike. Mutations in spike impacting antibody and/or ACE2 binding are appearing worldwide, imposing the need to monitor SARS-CoV2 evolution and dynamics in the population. Determining signatures in SARS-CoV-2 that render the virus resistant to neutralizing antibodies is critical. We engineered 25 spike-pseudotyped lentiviruses containing individual and combined mutations in the spike protein, including all defining mutations in the variants of concern, to identify the effect of single and synergic amino acid substitutions in promoting immune escape. We confirmed that E484K evades antibody neutralization elicited by infection or vaccination, a capacity augmented when complemented by K417N and N501Y mutations. In silico analysis provided an explanation for E484K immune evasion. E484 frequently engages in interactions with antibodies but not with ACE2. Importantly, we identified a novel amino acid of concern, S494, which shares a similar pattern. Using the already circulating mutation S494P, we found that it reduces antibody neutralization of convalescent and post-immunization sera, particularly when combined with E484K and with mutations able to increase binding to ACE2, such as N501Y. Our analysis of synergic mutations provides a signature for hotspots for immune evasion and for targets of therapies, vaccines and diagnostics.

Prediction of depression treatment outcome from multimodal data: a CAN-BIND-1 report.

BACKGROUND: Prediction of treatment outcomes is a key step in improving the treatment of major depressive disorder (MDD). The Canadian Biomarker Integration Network in Depression (CAN-BIND) aims to predict antidepressant treatment outcomes through analyses of clinical assessment, neuroimaging, and blood biomarkers. METHODS: In the CAN-BIND-1 dataset of 192 adults with MDD and outcomes of treatment with escitalopram, we applied machine learning models in a nested cross-validation framework. Across 210 analyses, we examined combinations of predictive variables from three modalities, measured at baseline and after 2 weeks of treatment, and five machine learning methods with and without feature selection. To optimize the predictors-to-observations ratio, we followed a tiered approach with 134 and 1152 variables in tier 1 and tier 2 respectively. RESULTS: A combination of baseline tier 1 clinical, neuroimaging, and molecular variables predicted response with a mean balanced accuracy of 0.57 (best model mean 0.62) compared to 0.54 (best model mean 0.61) in single modality models. Adding week 2 predictors improved the prediction of response to a mean balanced accuracy of 0.59 (best model mean 0.66). Adding tier 2 features did not improve prediction. CONCLUSIONS: A combination of clinical, neuroimaging, and molecular data improves the prediction of treatment outcomes over single modality measurement. The addition of measurements from the early stages of treatment adds precision. Present results are limited by lack of external validation. To achieve clinically meaningful prediction, the multimodal measurement should be scaled up to larger samples and the robustness of prediction tested in an external validation dataset.

Comparative Genomics Reveal the High Conservation and Scarce Distribution of Nitrogen Fixation nif Genes in the Plant-Associated Genus Herbaspirillum.

The genus Herbaspirillum gained the spotlight due to the several reports of diazotrophic strains and promising results in plant-growth field assays. However, as diversity exploration of Herbaspirillum species gained momentum, it became clearer that the plant beneficial lifestyle was not the only form of ecological interaction in this genus, due to reports of phytopathogenesis and nosocomial infections. Here we performed a deep search across all publicly available Herbaspirillum genomes. Using a robust core genome phylogeny, we have found that all described species are well delineated, being the only exception H. aquaticum and H. huttiense clade. We also uncovered that the nif genes are only highly prevalent in H. rubrisubalbicans; however, irrespective to the species, all nif genes share the same gene arrangement with high protein identity, and are present in only two main types, in inverted strands. By means of a NifHDKENB phylogenetic tree, we have further revealed that the Herbaspirillum nif sequences may have been acquired from the same last common ancestor belonging to the Nitrosomonadales order.

Mental health challenges, treatment experiences, and care needs of post-secondary students: a cross-sectional mixed-methods study.

BACKGROUND: Post-secondary students frequently experience high rates of mental health challenges. However, they present meagre rates of treatment-seeking behaviours. This elevated prevalence of mental health problems, particularly after the COVID-19 pandemic, can lead to distress, poor academic performance, and lower job prospects following the completion of education. To address the needs of this population, it is important to understand students' perceptions of mental health and the barriers preventing or limiting their access to care. METHODS: A broad-scoping online survey was publicly distributed to post-secondary students, collecting demographic, sociocultural, economic, and educational information while assessing various components of mental health. RESULTS: In total, 448 students across post-secondary institutions in Ontario, Canada, responded to the survey. Over a third (n = 170; 38.6%) of respondents reported a formal mental health diagnosis. Depression and generalized anxiety disorder were the most commonly reported diagnoses. Most respondents felt that post-secondary students did not have good mental health (n = 253; 60.5%) and had inadequate coping strategies (n = 261; 62.4%). The most frequently reported barriers to care were financial (n = 214; 50.5%), long wait times (n = 202; 47.6%), insufficient resources (n = 165; 38.9%), time constraints (n = 148; 34.9%), stigma (n = 133; 31.4%), cultural barriers (n = 108; 25.5%), and past negative experiences with mental health care (n = 86; 20.3%). The majority of students felt their post-secondary institution needed to increase awareness (n = 231; 56.5%) and mental health resources (n = 306; 73.2%). Most viewed in-person therapy and online care with a therapist as more helpful than self-guided online care. However, there was uncertainty about the helpfulness and accessibility of different forms of treatment, including online interventions. The qualitative findings highlighted the need for personal strategies, mental health education and awareness, and institutional support and services. CONCLUSIONS: Various barriers to care, perceived lack of resources, and low knowledge of available interventions may contribute to compromised mental health in post-secondary students. The survey findings indicate that upstream approaches such as integrating mental health education for students may address the varying needs of this critical population. Therapist-involved online mental health interventions may be a promising solution to address accessibility issues.

Inoculation of Herbaspirillum seropedicae strain SmR1 increases biomass in maize roots DKB 390 variety in the early stages of plant development.

Herbaspirillum seropedicae is a plant growth-promoting bacteria isolated from diverse plant species. In this work, the main objective was to investigate the efficiency of H. seropedicae strain SmR1 in colonizing and increasing maize growth (DKB 390 variety) in the early stages of development under greenhouse conditions. Inoculation with H. seropedicae resulted in 19.43 % (regarding High and Low N controls) and 10.51% (regarding Low N control) in mean of increase of root biomass, for 1st and 2nd greenhouse experiments, respectively, mainly in the initial stages of plant development, at 21 days after emergence (DAE). Quantification of H. seropedicae in roots and leaves was performed by quantitative PCR. H. seropedicae was detected only in maize inoculated roots by qPCR, and a slight decrease in DNA copy number g-1 of fresh root weight was observed from 7 to 21 DAE, suggesting that there was initial effective colonization on maize plants. H. seropedicae strain SmR1 efficiently increased maize root biomass exhibiting its potential to be used as inoculant in agricultures systems.

Identification of Endocannabinoid Predictors of Treatment Outcomes in Major Depressive Disorder: A Secondary Analysis of the First Canadian Biomarker Integration Network in Depression (CAN-BIND 1) Study.

INTRODUCTION: An increasing number of studies are examining the link between the endocannabinoidome and major depressive disorder (MDD). We conducted an exploratory analysis of this system to identify potential markers of treatment outcomes. METHODS: The dataset of the Canadian Biomarker Integration Network in Depression-1 study, consisting of 180 patients with MDD treated for eight weeks with escitalopram followed by eight weeks with escitalopram alone or augmented with aripiprazole was analyzed. Association between response Montgomery-Asberg Depression Rating Scale (MADRS; score reduction≥50%) or remission (MADRS score≤10) at weeks 8 and 16 and single nucleotide polymorphisms (SNPs), methylation, and mRNA levels of 33 endocannabinoid markers were examined. A standard genome-wide association studies protocol was used for identifying SNPs, and logistic regression was used to assess methylation and mRNA levels. RESULTS: Lower methylation of CpG islands of the diacylglycerol lipase alpha gene (DAGLA) was associated with non-remission at week 16 (DAGLA; OR=0.337, p<0.003, q=0.050). Methylation of DAGLA was correlated with improvement in Clinical Global Impression (p=0.026), Quick Inventory of Depressive Symptomatology (p=0.010), and Snaith-Hamilton Pleasure scales (p=0.028). We did not find any association between SNPs or mRNA levels and treatment outcomes. DISCUSSION: Methylation of DAGLA is a promising candidate as a marker of treatment outcomes for MDD and needs to be explored further.

"One Degree of Separation": A Mixed-Methods Evaluation of Canadian Mental Health Care User and Provider Experiences With Remote Care During COVID-19.

OBJECTIVES: The COVID-19 pandemic has contributed to a shift from in-person to remote mental health care. While remote care methods have long existed, their widespread use is unprecedented. There is little research about mental health care user and provider experiences with this transition, and no published studies to date have compared satisfaction between these groups. METHODS: Canadian mental health care users (n = 332) and providers (n = 107) completed an online self-report survey from October 2020 to February 2021 hosted by the Canadian Biomarker Integration Network in Depression. Using a mixed-methods approach, participants were asked about their use of remote care, including satisfaction, barriers to use, helpful and unhelpful factors, and suggestions for improvement. RESULTS: Overall, 59% to 63% of health care users and 59% of health care providers were satisfied with remote care. Users reported the greatest satisfaction with the convenience of remote care, while providers were most satisfied with the speed of provision of care; all groups were least satisfied with therapeutic rapport. Health care providers were less satisfied with the user-friendliness of remote care (P < 0.001) than users, while health care users were less satisfied than providers with continuity of care (P < 0.001). The use of a video-based platform was associated with remote care satisfaction among health care users (P < 0.02), and qualitative responses support the importance of visual cues in maintaining therapeutic rapport remotely. The majority of users (55%) and providers (87%) reported a likelihood of using remote care after the pandemic. CONCLUSIONS: Remote mental health care is generally accepted by both users and providers, and the majority would consider using remote care following the pandemic. Suggestions for improvement include greater use of video, increased attention to body language and eye contact, consistency with in-person care, as well as increased provider training and administrative support.

Identification and phytoremediation potential of spontaneous species in vineyard soils contaminated with copper.

Copper (Cu) contents in vineyard soils due to the application of cupric fungicides cause changes in the native covering flora. Under these conditions, the surviving individuals accumulate the metal in and decrease its availability in the soil, reducing the potential toxicity to grapevine. We have identified spontaneous plant species and their phytoremediation potential from vineyards of Isabella (Vitis labrusca) on two distinct soil types (Inceptisol and Entisol) contaminated with Cu. The results demonstrated that wild species displayed higher Cu contents in the roots than in the shoot, but had low bioaccumulation potential. During summer, the plants were unable to extract and stabilize the metal, although during the winter, Lolium multiflorum, Cyperus compressus and Chrysanthemum leucanthemum demonstrated phytostabilization potential. Among the investigated species, dry matter production and Cu accumulation by Lolium multiflorum indicated that the species is effective to decrease Cu availability in the soil.

Proposition of critical thresholds for copper and zinc transfer to solution in soils.

Several studies have reported increased copper (Cu) and zinc (Zn) levels in agricultural soils worldwide, mainly due to organic waste and successive leaf fungicide applications in crops. However, the critical transfer thresholds in soils, which can indicate the real risk of environmental contamination and toxicity to plants, remain poorly understood. This study aimed to define the maximum Cu and Zn adsorption capacity (MAC) and threshold (T-Cu and T-Zn) in different soils in Southern Brazil, which present different clay and organic matter (OM) levels. Bw (Oxisol) and A horizon (Inceptisol) samples were used to obtain soils with clay and OM contents ranging from 4 to 70% and from 0.5 to 9.5%, respectively. Cu and Zn adsorption curves were plotted for MAC determination purposes. Based on Cu and Zn MAC values, different concentrations of these elements were applied to the soils for subsequent quantification of available Cu and Zn levels (Mehlich-1 and water). T-Cu in soils with different clay contents ranged from 81 to 595 mg Cu kg-1, whereas T-Zn, from 195 to 378 mg Zn kg-1. T-Cu in soils with different OM levels ranged from 97 to 667 mg Cu kg-1, whereas T-Zn, from 226 to 495 mg Zn kg-1. T-Cu can be calculated through the equation: T-Cu = 75 × (%CL0.34) × (%OM0.39), whereas T-Zn: T-Zn = 2.7 × (CL) + 126 (by taking into consideration the clay content) and T-Zn = - 9.3 × (%OM)2 + 92.4 × (%OM) + 66 (by taking into consideration OM content). T-Cu and T-Zn can be used by researchers, inspection bodies, technical assistance institutions, and farmers as safe indicators to monitor the potential for environmental contamination.

Machine learning in the prediction of depression treatment outcomes: a systematic review and meta-analysis.

BACKGROUND: Multiple treatments are effective for major depressive disorder (MDD), but the outcomes of each treatment vary broadly among individuals. Accurate prediction of outcomes is needed to help select a treatment that is likely to work for a given person. We aim to examine the performance of machine learning methods in delivering replicable predictions of treatment outcomes. METHODS: Of 7732 non-duplicate records identified through literature search, we retained 59 eligible reports and extracted data on sample, treatment, predictors, machine learning method, and treatment outcome prediction. A minimum sample size of 100 and an adequate validation method were used to identify adequate-quality studies. The effects of study features on prediction accuracy were tested with mixed-effects models. Fifty-four of the studies provided accuracy estimates or other estimates that allowed calculation of balanced accuracy of predicting outcomes of treatment. RESULTS: Eight adequate-quality studies reported a mean accuracy of 0.63 [95% confidence interval (CI) 0.56-0.71], which was significantly lower than a mean accuracy of 0.75 (95% CI 0.72-0.78) in the other 46 studies. Among the adequate-quality studies, accuracies were higher when predicting treatment resistance (0.69) and lower when predicting remission (0.60) or response (0.56). The choice of machine learning method, feature selection, and the ratio of features to individuals were not associated with reported accuracy. CONCLUSIONS: The negative relationship between study quality and prediction accuracy, combined with a lack of independent replication, invites caution when evaluating the potential of machine learning applications for personalizing the treatment of depression.

Mycorrhizal root colonization in maize fields is more affected by soil management and climate conditions than by plant genotype.

This work aims to characterize the arbuscular mycorrhizal association between maize genotypes and the effects of soil physical-chemical attributes on the symbiosis. A preliminary greenhouse assay evaluated five maize landraces and five conventional modern genotypes in non-sterile, low-P soil. Sixty days after sowing, we measured plant height, stem diameter, shoot and root dry biomass, root colonization structures, and shoot P concentration and total accumulation. In a second stage, a 2-year on-farm study evaluated how soil physical-chemical attributes in fields with three plant genotype groups affected the arbuscular mycorrhizal fungal symbiosis in a maize diversity microcenter in Southern Brazil. We collected soil and plant material in farms growing landrace, conventional modern genotypes, or genetically modified (GM) maize. There were five collection points at each group, and we measured mycorrhizal colonization, soil physicochemical attributes, and shoot phosphorus concentration. The greenhouse study showed that genotypes have different growth strategies for root production and shoot growth. No differences in mycorrhizal colonization rates occurred among landraces and modern maize genotypes in the low-P soil. The field study showed that soil and climate conditions had a more marked effect on mycorrhizal root colonization than plant genotype groups (landrace, conventional modern genotypes, or GM maize).

Guideline No. 422c: Menopause: Mood, Sleep, and Cognition.

OBJECTIVE: Provide strategies for improving the care of perimenopausal and postmenopausal women based on the most recent published evidence. TARGET POPULATION: Perimenopausal and postmenopausal women. BENEFITS, HARMS, AND COSTS: Target population will benefit from the most recent published scientific evidence provided via the information from their health care provider. No harms or costs are involved with this information since women will have the opportunity to choose among the different therapeutic options for the management of the symptoms and morbidities associated with menopause, including the option to choose no treatment. EVIDENCE: Databases consulted were PubMed, MEDLINE, and the Cochrane Library for the years 2002-2020, and MeSH search terms were specific for each topic developed through the 7 chapters. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). INTENDED AUDIENCE: physicians, including gynaecologists, obstetricians, family physicians, internists, emergency medicine specialists; nurses, including registered nurses and nurse practitioners; pharmacists; medical trainees, including medical students, residents, fellows; and other providers of health care for the target population. SUMMARY STATEMENTS: RECOMMENDATIONS.

Directive clinique n° 422c : Ménopause : Humeur, sommeil et cognition.

OBJECTIF: Proposer des stratégies fondées sur les plus récentes données publiées pour améliorer les soins aux femmes ménopausées ou en périménopause. POPULATION CIBLE: Les femmes ménopausées ou en périménopause. BéNéFICES, RISQUES ET COûTS: La population cible bénéficiera des plus récentes données scientifiques publiées communiquées par leurs fournisseurs de soins de santé. Aucun coût ni préjudice ne sont associés à cette information, car les femmes seront libres de choisir parmi les différentes options thérapeutiques, y compris le statu quo, pour la prise en charge des symptômes et morbidités associés à la ménopause. DONNéES PROBANTES: Les auteurs ont interrogé les bases de données PubMed, MEDLINE et Cochrane Library pour extraire des articles publiés entre 2002 et 2020 en utilisant des termes MeSH spécifiques à chacun des sujets abordés dans les 7 chapitres. MéTHODES DE VALIDATION: Les auteurs ont évalué la qualité des données probantes et la force des recommandations en utilisant l'approche d'évaluation, de développement et d'évaluation (GRADE). Voir l'annexe A en ligne (tableau A1 pour les définitions et tableau A2 pour l'interprétation des recommandations fortes et conditionnelles [faibles]). PROFESSIONNELS CONCERNéS: gynécologues, obstétriciens, médecins de famille, internistes, urgentologues, infirmières (autorisées et praticiennes), pharmaciens, stagiaires (étudiants en médecine, résidents, moniteurs cliniques) et autres fournisseurs de soins de santé pour la population cible. DÉCLARATIONS SOMMAIRES: RECOMMANDATIONS.

F508del disturbs the dynamics of the nucleotide binding domains of CFTR before and after ATP hydrolysis.

The cystic fibrosis transmembrane conductance regulator (CFTR) channel is an ion channel responsible for chloride transport in epithelia and it belongs to the class of ABC transporters. The deletion of phenylalanine 508 (F508del) in CFTR is the most common mutation responsible for cystic fibrosis. Little is known about the effect of the mutation in the isolated nucleotide binding domains (NBDs), on dimer dynamics, ATP hydrolysis and even on nucleotide binding. Using molecular dynamics simulations of the human CFTR NBD dimer, we showed that F508del increases, in the prehydrolysis state, the inter-motif distance in both ATP binding sites (ABP) when ATP is bound. Additionally, a decrease in the number of catalytically competent conformations was observed in the presence of F508del. We used the subtraction technique to study the first 300 ps after ATP hydrolysis in the catalytic competent site and found that the F508del dimer evidences lower conformational changes than the wild type. Using longer simulation times, the magnitude of the conformational changes in both forms increases. Nonetheless, the F508del dimer shows lower C-α RMS values in comparison to the wild-type, on the F508del loop, on the residues surrounding the catalytic site and the portion of NBD2 adjacent to ABP1. These results provide evidence that F508del interferes with the NBD dynamics before and after ATP hydrolysis. These findings shed a new light on the effect of F508del on NBD dynamics and reveal a novel mechanism for the influence of F508del on CFTR.

The Effects of Probiotics on Symptoms of Depression: Protocol for a Double-Blind Randomized Placebo-Controlled Trial.

BACKGROUND: A growing body of evidence has linked mental health outcomes to the gut microbiome. This has led to the investigation of the GI tract as a target for novel treatments and interventions for depression, including probiotic supplementation. Our recent pilot study provided the first evidence of probiotics improving symptoms of depression in treatment-naive depressed patients. To further support and expand upon this evidence, data from the pilot study were used to plan a 16-week, double-blind, randomized, placebo-controlled trial to assess the effects of probiotics on depression. Here, we report the protocol for this trial. METHODS: Participants diagnosed with depression will orally consume a probiotic supplement containing Lactobacillus helveticus and Bifidobacterium longum or placebo once daily. Participants will undergo assessments measuring clinical outcomes using a battery of validated clinical scales and questionnaires. Sleep architecture and quality will be measured using polysomnography. Neuroimaging data will be collected using magnetic resonance imaging to examine functional and structural neurophysiological changes. Molecular data will be collected from blood, stool, and urine samples to examine cytokine levels and explore potential genes and proteins that may predict outcomes in depression. RESULTS: We expect results to replicate and expand on our pilot data demonstrating that probiotics may be effective in alleviating symptoms of depression, and to find biomarkers that will predict these outcomes. CONCLUSIONS: The findings from this study will add to the growing body of research in this emerging field, which eventually may provide evidence for probiotics having a role in alleviating symptoms of depression.

Predictors of functional response and remission with desvenlafaxine 50 mg and 100 mg: a pooled analysis of randomized, placebo-controlled studies in patients with major depressive disorder.

OBJECTIVE: The value of early functional improvement at week 2 for predicting subsequent functional outcomes at week 8 was assessed in a pooled analysis of patients with major depressive disorder (MDD) treated with desvenlafaxine (50 or 100 mg/d) or placebo. METHODS: Data were pooled from eight double-blind, placebo-controlled studies of desvenlafaxine 50 mg/d or 100 mg/d for the treatment of MDD. Optimal week-2 improvement thresholds in Sheehan Disability Scale (SDS) score, which best predicted week-8 treatment success, were determined using receiver operating characteristic (ROC) analysis. Four definitions of treatment success were established: (1) functional response, (2) functional/depression response, (3) functional remission, and (4) functional/depression remission. Odds ratios (ORs) of early improvement for prediction (based on thresholds determined in the ROC analysis) of week-8 treatment success were computed using logistic regression models. RESULTS: Functional early improvement thresholds of 17%-32% were predictive of week-8 treatment success across treatment groups and definitions of treatment success. Optimal thresholds were higher for more stringent definitions. Negative predictive value exceeded positive predictive value, indicating that failure to achieve early functional improvement was more informative about later treatment success than was the achievement of early functional improvement. Early change in SDS was a highly significant predictor of functional response/remission (ORs, 4.981-8.737; all p < 0.0001); the interaction between treatment and early functional improvement was not significant. CONCLUSION: Early improvement in SDS total score was predictive of functional outcomes for patients treated with desvenlafaxine 50 mg, desvenlafaxine 100 mg, or placebo.

Root colonization and arbuscular mycorrhizal fungal community composition in a genetically modified maize, its non-modified isoline, and a landrace.

The use of genetically modified (GM) plants has increased in recent decades, but there are uncertainties about their effects on soil microbial communities. Aiming to quantify root colonization and characterize arbuscular mycorrhizal fungi (AMF) communities associated with roots and rhizosphere soil of different maize genotypes, a field trial was carried out in Southern Brazil with three maize genotypes as follows: a GM hybrid (DKB 240 VTPRO), its non-modified isoline (DKB 240), and a landrace (Pixurum). Soil samples were collected to evaluate the occurrence of AMF during the growth of corn genotypes at sowing and V3 (vegetative), R1 (flowering), and R3 (grain formation) stages of the crop. The occurrence of AMF was determined by the morphological identification of spores, and by analyzing AMF community composition in soil and roots of maize, using PCR-DGGE. The GM genotype of maize promoted lower mycorrhizal colonization in the vegetative stage and had lower sporulation at grain development than the conventional hybrid and the landrace maize. Twenty AMF morphotypes were identified and 13 were associated with all maize genotypes. The genera Acaulospora, Glomus, and Dentiscutata had the largest numbers of species. There were no differences in AMF community composition due to maize genotypes or genetic modification, but crop phenological stages affected AMF communities associated with maize roots.