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The residual feed intake (RFI) model has recently gained popularity for ranking dairy cows for feed efficiency. The RFI model ranks the cows based on their expected feed intake compared to the observed feed intake, where a negative phenotype (eating less than expected) is favourable. Yet interpreting the biological implications of the regression coefficients derived from RFI models has proven challenging. In addition, multitrait modelling of RFI has been proposed as an alternative to the least square RFI in nutrition and genetic studies. To solve the challenge with the biological interpretation of RFI regression coefficients and suggest ways to improve the modelling of RFI, an interdisciplinary effort was required between nutritionists and geneticists. Therefore, this paper aimed to explore the challenges with the traditional least square RFI model and propose solutions to improve the modelling of RFI. In the traditional least square RFI model, one set of fixed effects is used to solve systematic effects (e.g., seasonal effects and age at calving) for traits with different means and variances. Thereby, measurement and model fitting errors can accumulate in the phenotype, resulting in undesirable effects. A multivariate RFI model will likely reduce this problem, as trait-specific fixed effects are used. In addition, regression coefficients for DM intake on milk energy tend to have more biologically meaningful estimates in multitrait RFI models, which indicates a confounding effect between the fixed effects and regression coefficients in the least square RFI model. However, defining precise expectations for regression coefficients from RFI models or sourcing for accurate feed norm coefficients seems difficult, especially if the coefficients are applied to a wide cattle population with varying diets or management systems, for example. To improve multitrait modelling of RFI, we suggest improving the modelling of changes in energy status. Furthermore, a novel method to derive the energy density of the diet and individual digestive efficiency is proposed. Digestive efficiency is defined as the part of the efficiency associated with digestive processes, which primarily reflects the conversion from gross energy to metabolisable energy. We show the model was insensitive to prior values of energy density in feed and that there was individual variation in digestive efficiency. The proposed method needs further development and validation. In summary, using multitrait RFI can improve the accuracy of the ranking of dairy cows' feed efficiency, consequently improving economic and environmental sustainability on dairy farms.
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PURPOSE: The consequent use of malaria rapid diagnostic tests (RDTs) preceding a treatment decision has improved the global management of malaria. A combination RDT, including an inflammation marker to potentially guide antibiotic prescription, could improve the management of acute febrile illness (AFI). METHODS: We performed a prospective, cross-sectional study in Gabon evaluating the STANDARD Malaria/CRP DUO (S-DUO) RDT. Participants aged 2 to 17 years with fever at presentation and/or a history of fever < 7 days were enrolled. Expert microscopy, SD Bioline Malaria Ag P.f/Pan test for malaria detection, and NycoCard CRP device for CRP were used as comparators. AFI cases were classified on a spectrum encompassing bacterial vs. non-bacterial infection. RESULTS: 415 participants with AFI were enrolled. S-DUO RDT sensitivity and specificity for malaria detection vs. microscopy were 99·1% (95·2-100%) and 72·7% (64·3-80·1%); and for CRP detection (20 mg/L and above) 86·9% (80-92%) and 87% (79·2-92·7%), respectively. The difference in CRP levels between bacterial infection (mean = 41·2 mg/L) and other causes of fever, measured from our study population using the Nycocard device, was statistically significant (p < 0·01); CRP precision-recall AUC to distinguish bacterial infection class vs. non-bacterial classifications was 0·79. CONCLUSION: S-DUO RDT is suitable for malaria detection in moderate-to-high malaria transmission settings such as in Lambaréné; however, a CRP band detection limit > 40 mg/L is more adequate for indication of antibiotic prescription for AFI cases in Gabon.
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Background: In the absence of targeted mutations and immune checkpoints, platinum-based chemotherapy remains a gold standard agent in the treatment of patients with lung squamous cell carcinoma (LUSC). However, cisplatin resistance greatly limits its therapeutic efficacy and presents challenges in the treatment of lung cancer patients. Therefore, the potential clinical needs for this research focus on identifying novel molecular signatures to further elucidate the underlying mechanisms of cisplatin resistance in LUSC. A growing body of evidence indicates that alternative splicing (AS) events significantly influence the tumor progression and survival of patients with LUSC. However, there are few systematic analyses of AS reported in LUSC. This study aims to explore the role of messenger RNA (mRNA), microRNA (miRNA), and AS in predicting prognosis in patients with cisplatin-resistant LUSC and provide potential therapeutic targets and drugs. Methods: Gene expression and miRNA expression, using RNA sequencing (RNA-seq), and SpliceSeq data were downloaded from The Cancer Genome Atlas (TCGA) database. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis were used to construct predictive models. Kaplan-Meier survival analyses were used to evaluate patients' prognosis. Single-sample gene set enrichment analysis (ssGSEA) conducted via the R package "GSEAbase" was used to evaluate the immune-related characteristics. Immunohistochemistry was used to examine protein expression. The Connectivity Map (CMap) database was used to screen for potential drugs. The 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay was used to determine and calculate the half-maximal inhibitory concentration (IC50) of the drugs, sulforaphane and parthenolide. Results: In this study, bioinformatics were used to identify mRNAs, miRNAs, and AS events related to response to cisplatin and to establish an integrated prognostic signature for 70 patients with LUSC and cisplatin resistance. The prognostic signature served as an independent prognostic factor with high accuracy [hazard ratio (HR) =2.346, 95% confidence interval (CI): 1.568-3.510; P<0.001], yielding an area under the curve (AUC) of 0.825, 0.829, and 0.877 for 1-, 3-, and 5-year survival, respectively. It also demonstrated high predictive performance in this cohort of patients with LUSC, with an AUC of 0.734, 0.767, and 0.776 for 1-, 3-, and 5-year survival, respectively. This integrated signature was also found to be an independent indicator among conventional clinical features (HR =2.288, 95% CI: 1.547-3.383; P<0.001). In addition, we analyzed the correlation of the signature with immune infiltration and identified several small-molecule drugs that had the potential to improve the survival of patients with LUSC. Conclusions: This study provides a framework for the mRNA-, miRNA-, and AS-based evaluation of cisplatin response and several potential therapeutic drugs for targeting cisplatin resistance in LUSC. These findings may serve as a theoretical basis for the clinical alleviation of cisplatin resistance and thus help to improve treatment responses to chemotherapy in patients with LUSC.
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Multi-parent populations (MPPs) are attractive for genetic and breeding studies because they combine genetic diversity with an easy-to-control population structure. Most methods for mapping QTLs in MPPs focus on the detection of QTLs in single environments. Little attention has been given to mapping QTLs in multienvironment trials (METs) and to detecting and modeling QTL-by-environment interactions (QEIs). We present mixed model approaches for the detection and modeling of consistent versus environment-dependent QTLs, i.e., QTL-by-environment interaction (QEI). QTL effects are assumed to be normally distributed with variances expressing consistency or dependence on environments and families. The entries of the corresponding design matrices are functions of identity-by-descent (IBD) probabilities between parents and offspring and follow from the parental origin of offspring DNA. A polygenic effect is added to the models to account for background genetic variation. We illustrate the wide applicability of our method by analyzing several public MPP datasets with observations from METs. The examples include diallel, nested association mapping (NAM), and multi-parent advanced inter-cross (MAGIC) populations. The results of our approach compare favorably with those of previous studies that used tailored methods.
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BACKGROUND: Dysregulation of fear processing through altered sensitivity to threat is thought to contribute to the development of anxiety disorders and major depressive disorder (MDD). However, fewer studies have examined fear processing in MDD than in anxiety disorders. The current study used propensity matching to examine the hypothesis that comorbid MDD and anxiety (AnxMDD) shows greater neural correlates of fear processing than MDD, suggesting that the co-occurrence of AnxMDD is exemplified by exaggerated defense related processes. METHODS: 195 individuals with MDD (N = 65) or AnxMDD (N = 130) were recruited from the community and completed multi-level assessments, including a Pavlovian fear learning task during functional imaging. Visual images paired with threat (conditioned stimuli: CS+) were compared to stimuli not paired with threat (CS-). RESULTS: MDD and AnxMDD showed significantly different patterns of activation for CS+ vs CS- in the dorsal anterior insula/inferior frontal gyrus (partial eta squared; ηp2 = 0.02), dorsolateral prefrontal cortex (ηp2 = 0.01) and dorsal anterior/mid cingulate cortex (ηp2 = 0.01). These differences were driven by greater activation to the CS+ in AnxMDD versus MDD. LIMITATIONS: Limitations include the cross-sectional design, a scream US rather than shock and half the number of MDD as AnxMDD participants. CONCLUSIONS: AnxMDD showed a pattern of increased activation in regions identified with fear processing. Effects were consistently driven by threat, further suggesting fear signaling as the emergent target process. Differences emerged in regions associated with salience processing, attentional orienting/conflict, self-relevant processing and executive functioning in comorbid anxiety and depression, thereby highlighting potential treatment targets for this prevalent and treatment resistant group.
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Tree-ring widths contain valuable historical information related to both forest disturbances and climate variability and changes within forests. However, current methods are still unable to accurately distinguish between disturbances and climate signals in tree rings, especially in the case of climate anomalies. To address this issue, we developed a novel method, called Growth Trends Clustering (GTC) that uses the distribution characteristics of tree-ring widths within a stand to distinguish the effects of climate and other forest disturbances. GTC employed a Gaussian mixture model to fit the probability density distribution of annual ring-width index (RWI) in a stand. Discriminative criteria were established to cluster diverse sub-distributions from the Gaussian mixture model into categories of growth release, suppression, or normal trends. This approach allowed us to identify the occurrence, duration, and severity of forest disturbances based on percentage changes in the growth release or suppression categories of trees. And the effect of climate on tree growth was assessed according to the mean statistics of the growth normal categories. Using common forest disturbances such as defoliating insects and thinning as examples, we validated our method using tree-ring collections from six sites in British Columbia and Quebec, Canada. We found that the GTC method was superior to traditional time-series analysis methods (e.g., Radial Growth Averaging, Boundary Line, Absolute Increase, and Curve Intervention Detection) for detecting past forest disturbances and was able to significantly enhance climate signals. In summary, the GTC method presented in this study introduces a novel statistical approach for accurately distinguishing between forest disturbances and climate signals in tree rings. This is particularly important for understanding forest disturbance regimes under climate change and for developing future disturbance mitigation strategies.
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Mudança Climática , Monitoramento Ambiental , Florestas , Árvores , Árvores/crescimento & desenvolvimento , Monitoramento Ambiental/métodos , Colúmbia Britânica , Quebeque , Clima , Análise por ConglomeradosRESUMO
BACKGROUND: Dyslipidemia increases cardiovascular disease risk, the leading cause of death worldwide. Under time-restricted feeding (TRF), wherein food intake is restricted to a consistent window of <12 hours, weight gain, glucose intolerance, inflammation, dyslipidemia, and hypercholesterolemia are all reduced in mice fed an obesogenic diet. LDLR (low-density lipoprotein receptor) mutations are a major cause of familial hypercholesterolemia and early-onset cardiovascular disease. METHODS: We subjected benchmark preclinical models, mice lacking LDLR-knockout or ApoE knockout to ad libitum feeding of an isocaloric atherogenic diet either ad libitum or 9 hours TRF for up to 13 weeks and assessed disease development, mechanism, and global changes in hepatic gene expression and plasma lipids. In a regression model, a subset of LDLR-knockout mice were ad libitum fed and then subject to TRF. RESULTS: TRF could significantly attenuate weight gain, hypercholesterolemia, and atherosclerosis in mice lacking the LDLR-knockout mice under experimental conditions of both prevention and regression. In LDLR-knockout mice, increased hepatic expression of genes mediating ß-oxidation during fasting is associated with reduced VLDL (very-low-density lipoprotein) secretion and lipid accumulation. Additionally, increased sterol catabolism coupled with fecal loss of cholesterol and bile acids contributes to the atheroprotective effect of TRF. Finally, TRF alone or combined with a cholesterol-free diet can reduce atherosclerosis in LDLR-knockout mice. However, mice lacking ApoE, which is an important protein for hepatic lipoprotein reuptake do not respond to TRF. CONCLUSIONS: In a preclinical animal model, TRF is effective in both the prevention and regression of atherosclerosis in LDLR knockout mice. The results suggest TRF alone or in combination with a low-cholesterol diet can be a lifestyle intervention for reducing cardiovascular disease risk in humans.
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Aterosclerose , Modelos Animais de Doenças , Fígado , Camundongos Knockout para ApoE , Receptores de LDL , Animais , Receptores de LDL/genética , Receptores de LDL/deficiência , Aterosclerose/prevenção & controle , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/etiologia , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fatores de Tempo , Jejum/sangue , Camundongos , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Hipercolesterolemia/complicações , Dieta Aterogênica , Aumento de Peso , Camundongos Knockout , Doenças da Aorta/prevenção & controle , Doenças da Aorta/genética , Doenças da Aorta/patologia , Doenças da Aorta/metabolismo , Lipídeos/sangue , Apolipoproteínas ERESUMO
Background: Cardiovascular complications of COVID-19 are numerous and aspects of this phenomenon are not well known. The main objective of this manuscript is a systematic review of the acute and chronic cardiovascular complications secondary to COVID-19. Methods: A systematic review of the literature through Medline via PubMed was conducted (2020-2024). Results: There is a plethora of effects of COVID-19 on the heart in the acute setting. Here we discuss pathophysiology, myocardial infarctions, heart failure, Takotsubo Cardiomyopathy, myocardial injury, myocarditis and arrhythmias that are caused by COVID-19. Additionally, these cardiovascular injuries can linger and may be an underlying cause of some Long COVID symptoms. Conclusions: Cardiovascular complications of COVID-19 are numerous and life-threatening. Long COVID can affect cardiovascular health. Microclotting induced by SARS-CoV-2 infection could be a therapeutic target for some aspects of Long Covid.
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A subset of major depressive disorder (MDD) is characterized by immune system dysfunction, but the intracellular origin of these immune changes remains unclear. Here we tested the hypothesis that abnormalities in endoplasmic reticulum (ER) stress, inflammasome activity and mitochondrial biogenesis contribute to the development of systemic inflammation in MDD. RT-qPCR was used to measure mRNA expression of key organellar genes from peripheral blood mononuclear cells (PBMCs) isolated from 186 MDD and 67 healthy control (HC) subjects. The comparative CT (2-ΔΔCT) method was applied to quantify mRNA expression using GAPDH as the reference gene. After controlling for age, sex, BMI, and medication status using linear regression models, expression of the inflammasome (NLRC4 and NLRP3) and the ER stress (XBP1u, XBP1s, and ATF4) genes was found to be significantly increased in the MDD versus the HC group. Sensitivity analyses excluding covariates yielded similar results. After excluding outliers, expression of the inflammasome genes was no longer statistically significant but expression of the ER stress genes (XBP1u, XBP1s, and ATF4) remained significant and the mitochondrial biogenesis gene, MFN2, was significantly increased in the MDD group. NLRC4 and MFN2 were positively correlated with serum C-reactive protein concentrations, while ASC trended significant. The altered expression of inflammasome activation, ER stress, and mitochondrial biogenesis pathway components suggest that dysfunction of these organelles may play a role in the pathogenesis of MDD.
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The 2023 wildfire season in Canada was unprecedented in its scale and intensity, spanning from mid-April to late October and across much of the forested regions of Canada. Here, we summarize the main causes and impacts of this exceptional season. The record-breaking total area burned (~15 Mha) can be attributed to several environmental factors that converged early in the season: early snowmelt, multiannual drought conditions in western Canada, and the rapid transition to drought in eastern Canada. Anthropogenic climate change enabled sustained extreme fire weather conditions, as the mean May-October temperature over Canada in 2023 was 2.2 °C warmer than the 1991-2020 average. The impacts were profound with more than 200 communities evacuated, millions exposed to hazardous air quality from smoke, and unmatched demands on fire-fighting resources. The 2023 wildfire season in Canada not only set new records, but highlights the increasing challenges posed by wildfires in Canada.
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Introduction The internet is increasingly the first port of call for patients introduced to new treatments. Unfortunately, many websites are of poor quality, thereby limiting patients' ability to make informed health decisions. Within thoracic surgery, the treatment options for pneumothoraces may be less intuitive for patients to understand compared to procedures such as lobectomies and wedge resections. Therefore, patients must receive high-quality information to make informed treatment decisions. No study to date has evaluated online information regarding pneumothorax surgery. Knowledge regarding the same may allow physicians to recommend appropriate websites to patients and supplement remaining knowledge gaps. Objective This study aims to evaluate the content, readability, and reliability of online information regarding pneumothorax surgery. Methods A total of 11 search terms including "pneumothorax surgery," "pleurectomy," and "pleurodesis" were each entered into Google, Bing, and Yahoo. The top 20 websites found through each search were screened, yielding 660 websites. Only free websites designed for patient consumption that provided information on pneumothorax surgery were included. This criterion excluded 581 websites, leaving 79 websites to be evaluated. To evaluate website reliability, the Journal of American Medical Association (JAMA) and DISCERN benchmark criteria were applied. To evaluate the readability, 10 standardized tools were utilized including the Flesch-Kincaid Reading Ease Score. To evaluate website content, a novel, self-designed 10-part questionnaire was utilized to assess whether information deemed essential by the authors was included. It evaluated whether websites comprehensively described the surgery process for patients, including pre- and post-operative care. Website authorship and year of publication were also noted. Results The mean JAMA score was 1.69 ± 1.29 out of 4, with only nine websites achieving all four reliability criteria. The median readability score was 13.42 (IQR: 11.48-16.23), which corresponded to a 13th-14th school grade standard. Only four websites were written at a sixth-grade reading level. In the novel content questionnaire, 31.6% of websites (n = 25) did not mention any side effects of pneumothorax surgery. Similarly, 39.2% (n = 31) did not mention alternative treatment options. There was no correlation between the date of website update and JAMA (r = 0.158, p = 0.123), DISCERN (r = 0.098, p = 0.341), or readability (r = 0.053, p = 0.606) scores. Conclusion Most websites were written above the sixth-grade reading level, as recommended by the US Department of Health and Human Services. Furthermore, the exclusion of essential information regarding pneumothorax surgery from websites highlights the current gaps in online information. These findings emphasize the need to create and disseminate comprehensive, reliable websites on pneumothorax surgery that enable patients to make informed health decisions.
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Background and Objectives: Point-of-care testing using nonsputum samples like serum or plasma proteins can improve tuberculosis (TB) patients access to a definitive diagnosis, especially in resource-constrained and remote areas. Recently, approximately 400 proteins were identified as playing a role in the pathogenesis of TB, offering a translational clinical research repository for TB. In a previous manuscript, we proved the potential use of these proteins for point-of-care testing for active TB diagnosis. The present work aims to confirm the performance of single and combination proteins to select the best candidate biomarkers for further development as a diagnostic testing tool for active TB. Methods: Seventy-four participants were assessed on the diagnostic performance of 17 single proteins and combinations of 2 to 4 proteins to diagnose active TB. The selection criteria included differential expression of the proteins between active TB and community-acquired pneumonia (CAP) and a performance rate ≥70% for active TB. Results: SULT4A1, WASPF3, SPTLC1, FAM107B, SORCS2, and CYTOb561 were differentially expressed in TB compared to CAP patients. Two single proteins, SULT4A1 and WASPF3, performed ≥70% to discriminate active TB from CAP patients. The diagnostic performance of 3 protein-based combinations of active TB was 81% after leave-one-out cross-validation. Conclusion: Single proteins and 3 protein-based combinations are candidate biomarkers for diagnosing active TB disease. A large and prospective study will confirm their performance as complementary diagnostic tools to rapid diagnostic methods for detecting active TB.
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The characterization of interactions between autophagy modifiers (Atg8-family proteins) and their natural ligands (peptides and proteins) or small molecules is important for a detailed understanding of selective autophagy mechanisms and for the design of potential Atg8 inhibitors that affect the autophagy processes in cells. The fluorescence polarization (FP) assay is a rapid, cost-effective, and robust method that provides affinity and selectivity information for small molecules and peptide ligands targeting human Atg8 proteins.This chapter introduces the basic principles of FP assays. In addition, a case study on peptide interaction with human Atg8 proteins (LC3/GABARAPs) is described. Finally, data analysis and quality control of FP assays are discussed for the proper calculation of Ki values for the measured compounds.
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Polarização de Fluorescência , Ensaios de Triagem em Larga Escala , Proteínas Associadas aos Microtúbulos , Ligação Proteica , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Ensaios de Triagem em Larga Escala/métodos , Polarização de Fluorescência/métodos , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Autofagia/efeitos dos fármacos , Peptídeos/metabolismo , Peptídeos/química , Ligantes , Família da Proteína 8 Relacionada à Autofagia/metabolismoRESUMO
Isothermal titration calorimetry (ITC) is a widely used technique for the characterization of protein-protein and protein-ligand interactions. It provides information on the stoichiometry, affinity, and thermodynamic driving forces of interactions. This chapter exemplifies the use of ITC to investigate interactions between human autophagy modifiers (LC3/GABARAP proteins) and their interaction partners, the LIR motif-containing sequences. The purpose of this report is to present a detailed protocol for the production of LC3/GABARAP-interacting LIR peptides using E. coli expression systems. In addition, we outline the design of ITC experiments using the LC3/GABARAP:peptide interactions as an example. Comprehensive troubleshooting notes are provided to facilitate the adaptation of these protocols to different ligand-receptor systems. The methodology outlined for studying protein-ligand interactions will help to avoid common errors and misinterpretations of experimental results.
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Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de Apoptose , Calorimetria , Proteínas Associadas aos Microtúbulos , Ligação Proteica , Termodinâmica , Calorimetria/métodos , Humanos , Ligantes , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/química , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Escherichia coli/metabolismo , Peptídeos/química , Peptídeos/metabolismoRESUMO
Chromosome substitution lines (CSLs) are tentatively supreme resources to investigate non-allelic genetic interactions. However, the difficulty of generating such lines in most species largely yielded imperfect CSL panels, prohibiting a systematic dissection of epistasis. Here, we present the development and use of a unique and complete panel of CSLs in Arabidopsis thaliana, allowing the full factorial analysis of epistatic interactions. A first comparison of reciprocal single chromosome substitutions revealed a dependency of QTL detection on different genetic backgrounds. The subsequent analysis of the complete panel of CSLs enabled the mapping of the genetic interactors and identified multiple two- and three-way interactions for different traits. Some of the detected epistatic effects were as large as any observed main effect, illustrating the impact of epistasis on quantitative trait variation. We, therefore, have demonstrated the high power of detection and mapping of genome-wide epistasis, confirming the assumed supremacy of comprehensive CSL sets.
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Arabidopsis , Mapeamento Cromossômico , Cromossomos de Plantas , Epistasia Genética , Locos de Características Quantitativas , Arabidopsis/genética , Mapeamento Cromossômico/métodos , Cromossomos de Plantas/genética , Genoma de Planta , FenótipoRESUMO
BACKGROUND: Socioeconomic inequalities in cognitive impairment may partly act through structural brain damage and reduced connectivity. This study investigated the extent to which the association of early-life socioeconomic position (SEP) with later-life cognitive functioning is mediated by later-life SEP, and whether the associations of SEP with later-life cognitive functioning can be explained by structural brain damage and connectivity. METHODS: We used cross-sectional data from the Dutch population-based Maastricht Study (n = 4,839; mean age 59.2 ± 8.7 years, 49.8% women). Early-life SEP was assessed by self-reported poverty during childhood and parental education. Later-life SEP included education, occupation, and current household income. Participants underwent cognitive testing and 3-T magnetic resonance imaging to measure volumes of white matter hyperintensities, grey matter, white matter, cerebrospinal fluid, and structural connectivity. Multiple linear regression analyses tested the associations between SEP, markers of structural brain damage and connectivity, and cognitive functioning. Mediation was tested using structural equation modeling. RESULTS: Although there were direct associations between both indicators of SEP and later-life cognitive functioning, a large part of the association between early-life SEP and later-life cognitive functioning was explained by later-life SEP (72.2%). The extent to which structural brain damage or connectivity acted as mediators between SEP and cognitive functioning was small (up to 5.9%). CONCLUSIONS: We observed substantial SEP differences in later-life cognitive functioning. Associations of structural brain damage and connectivity with cognitive functioning were relatively small, and only marginally explained the SEP gradients in cognitive functioning.
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Imageamento por Ressonância Magnética , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Transversais , Países Baixos , Idoso , Cognição/fisiologia , Classe Social , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva , Fatores Socioeconômicos , Lesões Encefálicas/complicações , Lesões Encefálicas/psicologiaRESUMO
Background: Treatment-resistant depression (TRD) is a major challenge in mental health, affecting a significant number of patients and leading to considerable economic and social burdens. The etiological factors contributing to TRD are complex and not fully understood. Objective: To investigate the genetic factors associated with TRD using polygenic scores (PGS) across various traits, and to explore their potential role in the etiology of TRD using large-scale genomic data from the All of Us Research Program (AoU). Methods: Data from 292,663 participants in the AoU were analyzed using a case-cohort design. Treatment resistant depression (TRD), treatment responsive Major Depressive Disorder (trMDD), and all others who have no formal diagnosis of Major Depressive Disorder (non-MDD) were identified through diagnostic codes and prescription patterns. Polygenic scores (PGS) for 61 unique traits from seven domains were used and logistic regressions were conducted to assess associations between PGS and TRD. Finally, Cox proportional hazard models were used to explore the predictive value of PGS for progression rate from the diagnostic event of Major Depressive Disorder (MDD) to TRD. Results: In the discovery set (104128 non-MDD, 16640 trMDD, and 4177 TRD), 44 of 61 selected PGS were found to be significantly associated with MDD, regardless of treatment responsiveness. Eleven of them were found to have stronger associations with TRD than with trMDD, encompassing PGS from domains in education, cognition, personality, sleep, and temperament. Genetic predisposition for insomnia and specific neuroticism traits were associated with increased TRD risk (OR range from 1.05 to 1.15), while higher education and intelligence scores were protective (ORs 0.88 and 0.91, respectively). These associations are consistent across two other independent sets within AoU (n = 104,388 and 63,330). Among 28,964 individuals tracked over time, 3,854 developed TRD within an average of 944 days (95% CI: 883 ~ 992 days) after MDD diagnosis. All eleven previously identified and replicated PGS were found to be modulating the conversion rate from MDD to TRD. Thus, those having higher education PGS would experiencing slower conversion rates than those who have lower education PGS with hazard ratios in 0.79 (80th versus 20th percentile, 95% CI: 0.74 ~ 0.85). Those who had higher insomnia PGS experience faster conversion rates than those who had lower insomnia PGS, with hazard ratios in 1.21 (80th versus 20th percentile, 95% CI: 1.13 ~ 1.30). Conclusions: Our results indicate that genetic predisposition related to neuroticism, cognitive function, and sleep patterns play a significant role in the development of TRD. These findings underscore the importance of considering genetic and psychosocial factors in managing and treating TRD. Future research should focus on integrating genetic data with clinical outcomes to enhance our understanding of pathways leading to treatment resistance.
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Current theories suggest individuals with methamphetamine use disorder (iMUDs) have difficulty considering long-term outcomes in decision-making, which could contribute to risk of relapse. Aversive interoceptive states (e.g., stress, withdrawal) are also known to increase this risk. The present study analyzed computational mechanisms of planning in iMUDs, and examined the potential impact of an aversive interoceptive state induction. A group of 40 iMUDs and 49 healthy participants completed two runs of a multi-step planning task, with and without an anxiogenic breathing resistance manipulation. Computational modeling revealed that iMUDs had selective difficulty identifying the best overall plan when this required enduring negative short-term outcomes - a mechanism referred to as aversive pruning. Increases in reported craving before and after the induction also predicted greater aversive pruning in iMUDs. These results highlight a novel mechanism that could promote poor choice in recovering iMUDs and create vulnerability to relapse.